Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

 

PART THREE – Clinical Management of Special Surgical Problems

Chapter 28 – Anesthesia for Pediatric Organ Transplantation

Kerri M. Robertson,Avinash C. Shukla,
Francis X. McGowan Jr.,
David S. Beebe,
Kumar G. Belani,
Victor L. Scott

  

 

Determination of Brain Death in Children, 896

  

 

Donor Management, 897

  

 

Organ Retrieval, 897

  

 

Organ Preservation,900

  

 

Living-Related Organ Transplantation, 901

  

 

Immunosuppression, 902

  

 

Drugs for Immunosuppression,902

  

 

Heart, Lung, and Heart-Lung Transplantation, 904

  

 

Heart Transplantation, 904

  

 

Lung Transplantation, 915

  

 

Heart-Lung Transplantation,917

  

 

Liver Transplantation, 921

  

 

Pathophysiology of End-Stage Liver Disease, 922

  

 

Systemic Manifestations of End-Stage Liver Disease,923

  

 

Preoperative Evaluation, 927

  

 

Surgical Technique, 928

  

 

Anesthetic Management, 929

  

 

Graft Reduction and Split-Liver Transplantation, 937

  

 

Artificial Liver Assist Devices, 939

  

 

Multivisceral and Intestinal Transplantation, 941

  

 

Preoperative Assessment, 942

  

 

Surgical Technique: Recipient Operation,942

  

 

Anesthetic Management, 944

  

 

Kidney Transplantation, 944

  

 

Pathophysiology of Renal Failure,946

  

 

Preoperative Assessment, 946

  

 

Surgical Technique, 946

  

 

Anesthetic Management, 947

  

 

Pancreas and Islet Cell Transplantation, 949

  

 

Islet Cell Transplantation, 950

  

 

Pancreas and Kidney-Pancreas Transplantation,952

  

 

Bone Marrow Transplantation, 956

  

 

Preoperative Assessment,957

  

 

Anesthetic Management, 957

  

 

Posttransplant Lymphoproliferative Disease, 958

  

 

Infectious Diseases, 958

  

 

Graft-Versus-Host Disease and Chimerism, 959

  

 

Xenotransplantation, 960

  

 

Summary, 963

With the exception of kidney transplantation, which became standard therapy by the mid 1970s, solid organ transplantation has only recently achieved status as an accepted treatment for a multitude of systemic organ dysfunctions. The introduction of cyclosporine in the early 1980s spurred rapid growth in transplantation. However, the number of cases worldwide has plateaued as donor-limited maximum levels have been reached ( UNOS, 2005 ). Approximately 27,000 solid organ transplantations are performed in the United States each year. As of spring 2005, the number of patients on the waiting list by the United Network of Organ Sharing (UNOS) is 87,750, and this list only continues to increase in volume yearly ( UNOS, 2005 ). Because the incidence of end-stage organ disease increases with age, children account for only a small, yet ever increasing, fraction (5% to 7%) of the total number of transplant recipients. Nevertheless, this means that approximately 2000 children undergo solid organ transplantation each year ( Table 28-1 ).

In 1973, the U.S. Congress legally recognized organ donation as a voluntary gift by adopting the Uniform Anatomical Gift Act. In addition, the Omnibus Budget Reconciliation Act (implemented in October 1987) stipulates that hospitals will not receive reimbursement from Medicare or Medicaid unless written protocols for the identification of potential organ donors are established. Physicians now are routinely expected to approach families of terminally ill patients and request organ donation. Since 1987, the UNOS established uniform policies and standards, with a guarantee of equitable access of member institutions to available donor organs. Patients under this system are classified according to the severity of disease on a scale from UNOS 1 to 4.

  

   

A UNOS 1 patient is the sickest and is confined to an intensive care unit (ICU).

  

   

A UNOS 2 patient is one who is hospitalized but does not require ICU care.

  

   

UNOS 3 and 4 patients do not require hospitalization; however, the status 3 patient is more debilitated than the status 4 patient, conceivably with secondary organ dysfunction by the particular disease process.

This system of stratification has been more refined for each organ system in the 2000s and is elaborated on in each section of this chapter as it pertains to the specific organ systems.

Organs procured in a local region must first be offered to patients within that particular geographic region, based on their UNOS status, before they can be sent elsewhere. Arizona is the only state that prevents its organs being sent out without being first offered to a patient specifically within that state. There are 236 kidney, 88 liver, 67 pancreas, 151 heart, 43 heart-lung, and 55 lung transplantation centers across the United States ( UNOS, 2005 ). UNOS reports a total of 256 Solid Organ Transplantation Centers in the United States managed by 11 Organ Procurement and Transplantation Networks (OPTNs), which includes all states inclusive of Hawaii, Puerto Rico, and Alaska ( UNOS, 2005 ).

Although collectively transplantation procedures are relatively uncommon, there are many published reports devoted to care of organ donors and recipients reflecting the broad experience accumulated with kidney, liver, heart, heart-lung, and isolated lung transplantation. Maintenance of physiologic homeostasis during the removal of a failed native organ and the subsequent allograft reperfusion period is among the most challenging of endeavors for anesthesiologists and surgeons alike. This chapter discusses the current body of knowledge for each type of major solid organ transplantation, with a specific focus on special considerations for clinical management of children. In addition, attention is focused on xenotransplantation, immunosuppression, graft-versus-host disease (GVHD), and posttransplant lymphoproliferative disease (PTLD), as well as artificial assist devices currently being used in the treatment of end-organ failure or as bridges to transplantation.


TABLE 28-1   -- Number of solid organ transplants in the United States 1990–2004

 

All Ages

Pediatrie

Dercent of Transplants

1990–2004

336,359

26,607

7.9%

2004

27,022

1,816

6.8%

2003

25,462

1,794

6.7%

2002

24,897

1,749

6.6%

2001

24,208

1,719

6.5%

2000

23,236

1,604

6.0%

1999

22,012

1,654

6.2%

1998

21,511

1,653

6.2%

1997

20,300

1,647

6.2%

1996

19,748

1,595

6.0%

1995

19,389

1,608

6.0%

1994

18,296

1,553

5.8%

1993

17,631

1,533

5.8%

1992

16,133

1,378

5.2%

1991

15,754

1,456

5.5%

1990

15,001

1,397

5.3%

Data from UNOS.

Recipients with unknown ages were not included

 

 

 

▪ DETERMINATION OF BRAIN DEATH IN CHILDREN

Brain death is defined as the absence of cortical and cerebral function without preservation of brainstem function. Cerebral blood flow measured in this setting must also be absent. Publication of brain death criteria specifically addressing findings in infants and children has clarified most of the ambiguities created by age-related neurologic differences ( Report of Special Task Force, Pediatrics, 1988) . The currently accepted guidelines for determination of brain death in neonates, infants, and children are summarized ( Box 28-1 ). Detailed reviews of this topic providing a thorough discussion of these guidelines and their application have been published ( Ashwal and Schneider, 1991 ; Ashwal, 1993 ). Prospective donors must fully meet the age-appropriate criteria and be declared legally brain dead before personnel attempt to obtain consent for organ donation from the family. A physician must record the official time of death in the chart before transferring the donor to the operating room for the organ procurement procedure. Although the donor is officially dead, the care of an anesthesiologist is required to continue all needed procedures to maintain cardiac output and organ perfusion, at least until the viscera have been flushed with the cold preservative solution. At this point, ventilation can be discontinued and the responsibility of the anesthesiologist is concluded.

BOX 28-1 

Brain Death Guidelines in Children

  

1.   

Diagnosis of irreversible coma
Exclude all potentially reversible causes of coma: drug intoxication (barbiturates, sedatives, hypnotics, and alcohol)

  

2.   

Physical examination

  

a.   

Coma

  

b.   

Apnea (determined by standardized testing)

  

c.   

Absence of brainstem function (no cough, gag, or sucking reflexes; no oculocephalic or cold caloric-induced eye movements)

  

d.   

Normothermia

  

e.   

Normotension

  

f.    

Flaccid tone, absence of spontaneous movement

  

g.   

Atropine resistance (failure to increase the heart rate by more than 5 beats per minute after atropine sulfate is given intravenously

  

3.   

Consistent physical examination during period of observation, as follows:

  

a.   

Seven days to 2 months of age: two exams and isoelectric electroencephalograms (EEGs) 48 hours apart

  

b.   

Two months to 1 year of age: two exams and isoelectric EEGs 24 hours apart, or one exam and isoelectric EEG, plus radionuclide angiogram showing absence of cerebral blood flow

  

c.   

Over 1 year of age: two exams 12 to 24 hours apart, EEGs and isotope angiography optional, physiologic support measures established usually in the ICU. These measures include administration of inotropes, blood volume replacement and blood product transfusions

From Hosenpud and others, 1994 .

 

One area that remains particularly controversial is the appropriateness of organ donation from anencephalic newborns. This tragic developmental anomaly results in the absence of the cerebral cortex and upper brainstem, so that these infants possess no potential for normal neurologic development. Despite the uniformly fatal outcome in these cases, such infants can never meet the usual criteria for brain death ( Baird, 1984) . The use of prenatal ultrasonography has made the intrauterine diagnosis of anencephaly commonplace, thus providing the significant advantage of “planned donation.” Because neonatal-sized organs are in extremely short supply, many professionals look to anencephalic neonates as a potential source to alleviate this shortage ( Peabody, 1989) . In addition, the positive aspects of organ donation for the parents of an anencephalic infant, which can be realized, is another benefit. However, there is no legal framework in the United States allowing the use of anencephalic infants asorgan donors, and the ethical questions surrounding this practice are far from being resolved. Although at least one country has established legal parameters allowing organ procurement from these infants (Girvin, 1993 ), a significant change in societal attitudes must occur before such a practice becomes legal.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

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▪ DONOR MANAGEMENT

Successful donor-directed strategies for the 2000s focus on increasing the size of the donor pool through expansion of acceptable donor criteria, adoption of a comprehensive donor management strategy, and innovative surgical techniques that allow organ sharing. Few cadaveric pediatric donors exist, so organ availability for transplantation is increasingly dependent on living donors (kidney, liver, lung, small bowel, and pancreas), split-liver transplantation, and asystolic, non-heart-beating donors.

Recovery of organs from the cadaveric/deceased donors requires continuing care of the patient's preexisting condition, with a shift in primary emphasis from minimizing neurologic injury and preserving life to protection of specific organs. Principles of pediatric donor care are comparable to those of adults, but meticulous adjustments are necessary due to special physiologic needs of children. The leading causes of death in children are asphyxia and trauma, and as such, a history of cardiac resuscitation, hypotension, and hypoxemia is frequent in this donor population ( Fischer-Froehlich et al., 2002 ).

The primary responsibility of the intensivist and anesthesiologist is to direct therapy toward maintaining the normal physiologic sequelae of brain death and normalizing gross alterations in physiologic and biochemical parameters. Organs from cadaveric/deceased donors may be injured or damaged from preexisting comorbid factors, hemodynamic instability, endocrine, metabolic and electrolyte imbalances, hypoxemia, endotoxin release, and immune activation inherent in the brain death process ( Jawan et al., 2002 ; Zaroff et al., 2002 ) ( Table 28-2 ). By implementing an aggressive approach to donor care, it is possible to increase the donor retrieval rate by 30% without prejudicing outcome ( Wheeldon, 1995) . Use of the UNOS Critical Pathway for the Organ Donor has resulted in an 11.3% increase in the number of organs transplanted per 100 donors ( Hommquist et al., 1999 ; Rosendale et al., 2002 ).

TABLE 28-2   -- Normal physiologic sequelae of brain death

Sequela

Cause

Management

Hypotension

Neurogenic shock, hypovolemia, hypothermia, electrolyte disorders, endocrine abnormalities, myocardial dysfunction

Mean arterial pressure >60 mm Hg

CVP 4 to 12 mmHg

PCWP 8 to 12 mmHg

SVR 800 to 1200 dyne/s per cm5

Cardiac index >2.4 L/min per m2

Inotropic support in order of preference (in mcg/kg per min):

 Dopamine <10

 Dobutamine <10

 Epinephrine <0.1

Norepinephrine and renal-dose dopamine
Infrarenal aortic cross-clamp

Endocrine abnormalities

Disruption of the hypothalamic pituitary axis resulting in adrenal insufficiency; hypothyroidism, or diabetes insipidus

Volume replacement: correct electrolytes; inotropic support

Steroids: methylprednisolone 15 mg/kg

T3: 4-mcg bolus and 3 mcg/hr infusion

Arginine vasopressin 1-U bolus, then continuous infusion at 0.5 to 4 U/h, titrated to a systemic vascular resistance of 800 to 1200 dyne/s per cm5

Insulin: 1 U/hr minimum. Titrate to maintain blood sugar 120 to 180 mg/dL

Hypothermia

Loss of hypothalamic, neural, or endocrine regulation; resuscitation with cold fluids or blood products

Early aggressive warming to maintain the temperature above 36°C

At <30°C may be unresponsive

ACLS drug therapy, defibrillation, or pacing

Anemia coagulopathies

Hemorrhage, hemodilution DIC, fibrinolysis, dilutional hypothermia

Transfuse to keep hematocrit >30%

Factor replacement, transfusion rewarming, early organ retrieval

Modified from Rosengard, 2002 .

 

 

 

▪ ORGAN RETRIEVAL

Organ procurement is usually completed in 6 hours or less, depending on the operating team's experience, the number of organs intended for retrieval, and the presence of variations in the vascular anatomy. In the face of worsening hypoxemia, coagulopathy, or refractory hypotension, the organ recovery surgery should be expedited to prevent ischemic injury to transplantable organs. The specific organ(s) to be retrieved determine type of fluid management and ideal central venous pressure (CVP), FIO2, and the choice of allowable maximum doses for inotropic or vasoactive support. Management decisions are dictated by which organs are being considered, as, for example, hemodynamic goals preferred by surgeons transplanting abdominal organs are occasionally directly opposed to those of thoracic transplant surgeons.

Preoperative donor evaluation includes determining hemodynamic stability and vasopressor support, electrolytes and therapy for diabetes insipidus, pulmonary status, renal function and urine output, coagulopathy, and the degree of hypothermia. Routine anesthetic monitoring is supplemented with the placement of an intra-arterial catheter in an upper extremity to facilitate sampling and monitoring of the arterial blood pressure. The need for measuring CVP is especially important if the heart and lungs are being considered for donation. Arterial blood gases, hematocrit, electrolytes, blood glucose, and osmolality are assessed every hour, or more frequently as needed.

Strict asepsis is observed, prophylactic antibiotics are administered, and the donor is positioned and prepared surgically. The eyelids are taped shut and covered with cold saline compresses or ice packs for corneal protection. After 300 U/kg of heparin is administered and cardioplegia is achieved, the liver, intestines, and kidneys are flushed with cold preservation solution and sequential removal of organs can proceed. The spleen and omental lymph nodes are removed for tissue typing, and the aorta, inferior vena cava, and common carotid and iliac vessels are taken for vascular grafts. Anesthetic support of the organ donor is necessary until the proximal aorta is surgically occluded, and in situ flushing of organs has begun. Subsequently, the ventilator should be disconnected and monitoring discontinued as electrocardiographic (ECG) activity may persist for up to 70 minutes following cardiac arrest ( Oaknine, 1975 ; Logigian and Ropper, 1985 ).

To avoid reflex muscular contractions and facilitate surgical exposure, a long-acting muscle relaxant is administered intravenously. The declaration of brain death requires the loss of cerebral and brainstem reflexes, but spinal reflexes may remain intact. Complex movements of the limbs and trunk can be confused with reflex movements of cerebral origin and may create tremendous anxiety for the operating room personnel.

In addition to spinal reflexes, a reflex pressor response to nociceptive stimuli is sometimes observed. This pressor response may lead to excessive operative blood loss and damage to the renal grafts. Management requires a reduction in preload, afterload, or both, while minimizing any possible adverse drug toxicity, especially to the liver and kidneys. Thus antihypertensive agents such as nitroglycerin or nitroprusside may be required if the volatile anesthetic, preferably isoflurane, is not successful in ablating this response.

Because brain death results in the loss of central mechanisms that control the endocrine and autonomic nervous systems, despite maximum physiologic support, cardiac death usually occurs within 48 to 72 hours. Up to 25% of potential brain-dead organ donors are lost each year in North America due to cardiovascular collapse ( Jenkins et al., 1999 ). Hypotension and hemodynamic instability secondary to neurogenic shock and hypovolemia, due to the absence of brainstem function, should be anticipated in all donors and aggressively treated.

Intravascular Volume Management

Brainstem injury produces a sequence of hemodynamic events evolving from an initial increase in parasympathetic tone to a massive catecholamine surge with hypertension and tachycardia. Despite an increased perfusion pressure, the resulting vasoconstriction may cause tissue ischemia that disrupts the production of ATP, generates oxygen free radicals, increases cytosolic calcium concentration, and activates various enzymatic cascades, such as endonucleases or nitric oxide syntheses ( Kunzendorf et al., 2002 ). A subsequent hypotensive phase caused by loss of autonomic regulation of the peripheral vasculature and unopposed vasodilatation may further reduce the oxygen supply to tissues. Hypovolemia is seen with inadequate replacement of blood and fluid losses, uncontrolled diabetes insipidus, and osmotic diuresis caused by hyperglycemia, mannitol, or systemic radiocontrast dyes administered during the evaluation process.

Aggressive fluid replacement therapy with colloid or crystalloid solutions and cytomegalovirus (CMV)-negative blood products directed at restoring and maintaining the intravascular volume is the first step in donor resuscitation. The hemodynamic status and adequacy of intravenous fluid resuscitation should be monitored continuously with arterial and central venous pressure catheters. In adults, hemodynamic targets include systolic blood pressure greater than 85 mm Hg, mean arterial pressure greater than 60 mm Hg, CVP of 6 to 10 mm Hg, and heart rate less than 100 beats per minute, with a urine output greater than 1 to 2 mL/kg/hr. The hematocrit should be maintained at 30%. The choice of crystalloid- or colloid-containing solutions usually depends on institutional preference and the sensitivity of the liver and lungs to low osmotic pressure-mediated tissue edema. When only the kidneys are to be harvested, the donor can be maximally fluid-loaded. For lung or heart-lung retrieval, relative hypovolemia is preferred. Infusion of colloids is recommended, with limited use of crystalloid and early initiation of inotropic support to maintain a systolic blood pressure above 90 mm Hg and CVP between 6 and 8 mm Hg. During the initial echocardiographic evaluation, if left ventricular ejection fraction is less than 45%, aggressive management with placement of a pulmonary arterial catheter, if possible, and hormonal (steroids, vasopressin, and T3 or T4) resuscitation is strongly recommended ( Zaroff, 2002) .

Hemodynamic Support

The goals of hemodynamic support are to achieve euvolemia, to adjust vasoconstrictors and vasodilators to maintain a normal afterload, and to optimize cardiac output without relying on high doses of β-agonists or other inotropes, which increase myocardial oxygen consumption and deplete the myocardium of high-energy phosphates ( Zaroff, 2002) . With persistent hypotension, despite volume replacement, vasopressor therapy should be initiated. Dopamine up to 10 mcg/kg per min is the preferred drug of choice because the glomerular filtration rate is increased as well as cardiac output while dilating the renal, mesenteric, and coronary vasculature.

When dopamine is used for inotropic support in infants, doses significantly higher than those needed in the adult may be required, presumably because of catecholamine receptor immaturity or deficiency (Kelly et al., 1984 ). At these higher doses (15 mcg/kg per min), no adverse effects on glomerular filtration rate or urine output are apparent ( Outwater and Rockoff, 1984 ). An infusion of phenylephrine, epinephrine, and norepinephrine may be useful to increase peripheral vascular tone, but they have the inherent risk of causing marked peripheral vasoconstriction or an increase in pulmonary artery pressure (PAP). An infusion of vasopressin starting at 0.5 mU/kg per hr, then doubling every 30 minutes to effect or maximum infusion of 10 mU/kg per hr, may be efficacious in the setting of hypotension and low systemic vascular resistance (SVR), especially in combination with an inotropic infusion such as epinephrine. There is evidence that dopamine may reduce allograft rejection, not only through support of blood pressure but possibly also through more complex mechanisms that inhibit expression of adhesion molecules, which are required for leukocyte migration into the graft, to produce acute rejection (Carlos et al., 1997 ; Schnuelle et al., 1999 ). Dobutamine should be used where cardiac output is decreased because of reduced myocardial contractility and pulmonary hypertension.

It has been recognized that the state of brain death is a dynamic inflammatory process. The activation of inflammatory mediators leads to a nonspecific immune response, which may be associated with accelerated acute graft rejection and poorer long-term outcome ( Kunzendorf, 2002) . In addition, a significant part of organ injury after storage and cold ischemia is caused by reperfusion, initiated by leukocyte adhesion to endothelial cells and the production of oxygen-derived free radicals and peroxides.

ECG abnormalities are common during the brain death process, such as marked ST-T wave abnormalities or other ischemic changes, inverted T waves, widened QRS complexes, and prolonged QT interval. In addition, atrial and ventricular arrhythmias and various degrees of conduction abnormalities may occur. These arrhythmias usually result from autonomic instability (catecholamine storm and loss of the vagal motor nucleus) compounded by electrolyte abnormalities (e.g., low magnesium and potassium), acid-base disturbances ( Newsome, 1979 ), or increased intracranial pressure (ICP) (Cushing's reflex). The difficulty lies in differentiating these transient findings from those of catecholamine-induced myocardial injury or irreversible ischemia, which can produce decreased biventricular systolic and diastolic function and contractility. Bradycardia is not a problem unless it contributes to hypotension. It may be treated with any inotropic agents or temporary transthoracic or venous pacing.

Eventually, the heart stops. Despite all therapeutic efforts, the arrhythmias encountered are usually resistant to therapy ( Logigian and Popper, 1985) . Bradyarrhythmias leading to asystole rather than ventricular fibrillation, as seen in adults, are the terminal cardiac rhythms in pediatric patients. The propensity for this particular dysrhythmia may be related to an immature autonomic nervous system and small muscle mass in the pediatric donor ( Walsh and Krongrad, 1983 ). In the event of a sudden cardiac arrest during the procurement procedure, cardiopulmonary resuscitation should be started to facilitate organ perfusion, and liver, pancreas, intestines, and kidney procurement should proceed rapidly with cross-clamping of the aorta at the diaphragm and infusion of cold preservation solution into the distal aorta and portal vein.

Pulmonary Management

All potential organ donors require mechanical ventilation, usually for a period of several days. Subsequent deterioration of lung function may result from pulmonary contusions due to trauma, aspiration pneumonitis, fat emboli, and pulmonary edema (cardiogenic and neurogenic). Any of these may result in hypoxia, putting all organs at risk. In addition, infectious complications, oxygen toxicity, barotrauma, and atelectasis may contribute to an increase in the alveolar-arterial gradient a–aDO2. Only approximately 25% of cadaveric/deceased donors of other organs are satisfactory lung donors. High-dose methylprednisolone administration has been shown to significantly improve oxygenation and increase donor lung recovery ( Follette et al., 1998 ). The beneficial effects of steroids probably result from attenuation of the effects of proinflammatory cytokines released as a consequence of brain death ( Glasser et al., 2001 ). As the total lung water increases from a combination of pulmonary capillary leakage and disruption of the Starling forces in the lung, pulmonary compliance decreases with resultant impedance of alveolar gas exchange. Neurogenic pulmonary edema is easily managed with positive end-expiratory pressure (PEEP). Lung protective strategies include maintenance of an arterial saturation of 95% or a PaO2 greater than 100 mm Hg with the lowest possible FIO2 setting, preferably no higher than 40%. Limiting high distention pressures in the lung during volume control modes of ventilation using small tidal volumes, low peak inspiratory pressure (PIP) and avoiding PEEP in excess of 7.5 cm H2O is desirable. PaCO2 (30 to 35 mm Hg) and pH (7.35 to 7.45) should be normalized. The maintenance of a mild to moderate alkalemia has been reported by some to reduce the likelihood of ventricular fibrillation ( Becker et al., 1981 ).

Diabetes Insipidus

Diabetes insipidus (DI) occurs in the vast majority of brain-dead donors. It is a direct result of hypothalamic-pituitary dysfunction, with a resultant deficiency of antidiuretic hormone (ADH) from the posterior lobe of the pituitary. Typically DI is clinically manifested by a frequently massive urine output that bears no relationship to the intravascular fluid volume with urine hypo-osmolarity, serum hyperosmolarity, normal sodium excretion, and worsening hypernatremia. This massive hypotonic diuresis (>4 mL/kg per hr) then leads to dehydration, hypotension, and oliguria ( Newsome, 1979 ).

Once the diagnosis is confirmed, treatment should begin with appropriate fluid and hormone replacement. Therapeutic intervention includes replacement of urinary losses with warmed isotonic or hypotonic crystalloid solutions on a volume-for-volume basis. In addition, vasopressin (controlled intravenous low-dose infusion of L-arginine vasopressin [AVP] at 2 to 10 mcg/kg per min) or desmopressin acetate (DDAVP) when the urine output exceeds 3 mL/kg per hr is administered ( Levitt et al., 1984 ). DDAVP is an analog of AVP that is highly selective for the vasopressin V2 receptor subtype found in the renal collecting duct and without the vasopressor activity in humans that is mediated by V1 receptors on vascular smooth muscle. There are several mechanisms regulating the release of AVP. Hypovolemia, as occurs during hemorrhage, results in a decrease in atrial pressure. Specialized stretch receptors within the atrial walls and large veins (cardiopulmonary baroreceptors) entering the atria decrease their firing rate when there is a fall in atrial pressure. Afferent nerve fibers from these receptors synapse within the nucleus tractus solitarius of the medulla, which sends fibers to the hypothalamus, a region of the brain that controls AVP release by the pituitary gland. Atrial receptor firing normally inhibits the release of AVP by the posterior pituitary. With hypovolemia or decreased CVP, the decreased firing of atrial stretch receptors leads to an increase in AVP release. Hypothalamic osmoreceptors sense extracellular osmolarity and stimulate AVP release when osmolarity rises, as occurs with dehydration. Finally, angiotensin II receptors located in a region of the hypothalamus regulate AVP. Therapy should always be guided by serum electrolyte and osmolality measurements made every 2 to 4 hours. Several investigators have demonstrated prolonged hemodynamic stability in donors with the addition of an infusion of AVP to existing pressor support. Donors without clinically apparent DI can demonstrate a baroreflex-mediated defect of vasopressin secretion and pressor hypersensitivity to exogenous hormones. In these patients, low-dose vasopressin significantly increases blood pressure ( Chen et al., 1999 ). Absence of AVP may be a predominant factor responsible for the eventual cardiac arrest in all brain-dead patients.

Vasopressin is a potent vasoconstrictor. Its hemodynamic effects are dose dependent and include generalized systemic vasoconstriction, increased blood pressure, decreased cardiac output, diminished coronary and renal blood flow, bradycardia, and arrhythmias. These effects potentially may cause irreversible ischemia to donor organs. Therefore, it is desirable to discontinue the infusion at least 1 hour before surgery. An infusion of nitroglycerin or nitroprusside is occasionally recommended to prevent myocardial ischemia and the potential untoward renal effects of diminished renal perfusion. Vasopressin supplementation (2 to 10 mcg/kg per min continuous infusion) in a porcine model of brain-dead potential organ donors resulted in physiologic levels of the hormone, with normal plasma osmolarity and serum sodium levels, and decreased urine output, potassium needs, and fluid requirements without effects on the peripheral vascular resistance or microscopic evidence of organ ischemia ( Blaine et al., 1984 ). The benefits of early treatment for the polyuria of DI with a vasopressin infusion appear to outweigh the potential detrimental effects.

Endocrine and Metabolic Functions

Despite disruption of the hypothalamic-pituitary axis, hormone production from the anterior lobe of the pituitary gland persists in most brain-dead patients. Rapid depletion of vasopressin, cortisol, insulin, T4, and free T3 occurs in experimental animal models of brain death ( Novitzky et al., 1984 ), but endocrine dysfunction in humans is usually solely manifested as DI ( Wijdicks et al., 2001) . Novitzky and others (1987) claim that true hypothyroidism exists as evidenced by a decrease in free T3. They have shown that hormonal replacement therapy (T3, cortisol, and insulin with glucose) improves cardiac output and reduces the need for pressor support. As such, many transplant groups administer thyroid hormones to hemodynamically “rescue” unstable donors who show evidence of anaerobic metabolism or profound hypotension refractory to volume resuscitation and therapy with multiple vasopressors. Three-drug hormonal resuscitation (steroids, vasopressin, and T3 or T4) has been shown to increase the number of organs transplanted per donor by 22.5% ( Rosendale et al., 2003 ). Intravenous T4 has the disadvantage of a slower and unpredictable onset of action. As a result of the inconsistent findings reported in the literature, the indication for T3 or T4 therapy is unclear. In fact, evaluation of a complete thyroid panel assay reveals a characteristic picture of euthyroid sick syndrome with T3, T4, free T4index, and free T4 decreased or borderline, reverse T3 increased, and a normal thyroid-stimulating hormone level ( Robertson et al., 1988 ). One should keep in mind that while T3 may rescue the donor heart, it may have detrimental effects, including tachycardia, arrhythmia, metabolic acidosis, and profound hypotension. Moreover, potentially many of the noted physiologic responses may in fact be a result of the absence of brain-blood flow in the brain-dead patient even with the partial circulation of the cavernous sinus system.

Electrolyte disturbances are routine, most being iatrogenic, as a result of treatment of the original injury or in response to physiologic perturbations during the brain death process. Hypernatremia is inevitable as a result of DI and a variety of strategies used to treat elevated ICP. The liver is exquisitely sensitive to hypernatremia (>155 mEq/L) with increased levels correlating with primary graft loss after transplantation ( Figueras, 1996) . Serum potassium, magnesium, calcium, and phosphate levels are often depleted and require prompt replacement therapy. Hyperglycemia may be due to peripheral insulin resistance or administration of large amounts of dextrose-containing solution for fluid resuscitation.

Hypothermia

Hypothermia is universal due to loss of thermal regulation by the central nervous system (CNS) (rendering the patient poikilothermic), exposure to a cold ambient temperature, and massive infusions of cold intravenous fluids. Although a mild degree of hypothermia may be beneficial to organ protection and preservation, the consequences of hypothermia, which are clinically significant, include diuresis, hyperglycemia, coagulopathy, arrhythmias, myocardial depression, pulmonary hypertension, hypotension, and eventually cardiac arrest ( Reuler, 1978 ). Hypothermia further complicates the process of certification of brain death by causing the pupils to appear fixed and dilated. Active rewarming measures to maintain a core temperature above 36°C are mandatory and should be initiated early.

▪ ORGAN PRESERVATION

Traditionally, optimal organ preservation has been achieved by the combination of maximizing donor hemodynamics, using improved surgical procurement techniques with minimal dissection of vascular structures, cannulation of the abdominal aorta for rapid in situ core cooling, en bloc removal of abdominal organs with separation of graft components on the back table. Cold storage techniques with a hyperkalemic hyperosmolar solution at a temperature of 4°C and treating the donor or recipient pharmacologically can preserve the kidneys for up to 72 hours but rarely do well in the recipient after 36 to 48 hours. The heart and lungs should be transplanted within 4 to 6 hours and the pancreas preferably within 6 to 12 hours. The preservation solution introduced from the University of Wisconsin (UW solution) in 1988 has allowed extension of the safe preservation time of the donor liver from 8 to 24 hours ( Jamieson et al., 1988 ) ( Box 28-2 ). Iced storage and core cooling result in a slowing of cellular metabolism and energy consumption; glucose or hydrogen ion buffers prevent cellular acidosis; and donor heparinization (30,000 U or 300 U/kg) prevents microvascular thrombosis, promoting even organ flushing and reperfusion. The use of hypertonic solutions or impermeates suppresses hypothermic-induced cell swelling. Addition of antioxidants and free radical scavengers protect against reperfusion injury. Pharmacologic manipulations available for pediatric donors include allopurinol (free radical scavenger), prostaglandin E1 (vasodilation, membrane stabilization, antiplatelet effect), and methylprednisolone ( Belzer and Southard, 1988 ).

BOX 28-2 

University of Wisconsin (UW) Solution Composition

  

 

Potassium lactobionate: 100 mmol/L

  

 

KH2PO4: 25 mmol/L

  

 

MgSO4: 5 mmol/L

  

 

Raffinose: 30 mmol/L

  

 

Adenosine: 5 mmol/L

  

 

Glutathione: 3 mmol/L

  

 

Allopurinol: 1 mmol/L

  

 

Hydroxyethyl starch: 50 g/L

  

 

Adjust pH to 7.4 with KOH

  

 

Add before use: dexamethasone (8 mg/L), insulin (40 units/L), penicillin (200,000 U/L) Final values: Na+ = 25 ± 5 mmol/L; K+ = 120 ± 5 mmol/L; mOsm/L = 320 ± 10

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ LIVING-RELATED ORGAN TRANSPLANTATION

Over the past several years, a consistently widening gap has become evident between the demand for and supply of transplantable organs. At the end of 2002, there were 2307 pediatric transplant candidates on the waiting lists for various organs, which was a small decline from 2382 candidates from the previous year. This was the first decline in 10 years and reflects a decrease in the size of the liver and lung waiting lists, with the majority of children wait-listed for liver and kidney organs. Unfortunately, the number of cadaveric pediatric donors has steadily decreased from a high of 1214 in 1995 to 805 in 2004 ( OPTN/UNOS, January 1988 to October 2004 ). Pediatric cadaveric/deceased donors are more likely to donate each specific organ compared with adult cadaveric/deceased donors, as evident in data reported from 2002: kidneys (92%), livers (87%), lungs (16%), heart (50%), pancreas (40%), and intestine (9%) ( UNOS/OPTN, 2005 ). With this serious shortage of donor organs of appropriate size and suitability for infants and small children, the waiting times for some organs has increased dramatically. For example, with only 20% of lungs from cadaveric/deceased donors meeting stringent donor criteria, the waiting period varies with 42% of pediatric patients waiting less than 1 year to 15% listed for 5 or more years. In 2004, 179 children registered on the waiting list died before a suitable organ was identified.

This chronic shortage has prompted the development of programs for living-related organ donation. The original concept was developed for renal transplantation in the early 1950s, and currently in the United States, 49% of pediatric transplants are from living donors ( Seikaly et al., 2001 ). Justification was relatively easy, because a healthy relative could “safely” donate one of his or her two kidneys without jeopardizing renal function in the remaining solitary kidney and the results from living related pediatric renal transplantation had been superior to those of cadaveric transplantation, at all ages. Later, techniques were developed to use one or more left lateral segments of a parent's liver that would be suitable for a small child with chronic liver disease ( Broelsch et al., 1991 ; Lang et al., 2004 ). Lessons learned from “split” or “reduced-size” cadaveric adult livers for implantation into children were used in the development of living-related liver transplantation programs, which can accommodate large children and small adults using the right lobe of the liver. From 1989 to 2004, 941 pediatric liver transplants from living donors were performed in the United States (see Table 28-1 ).

With similar methodology, living donor transplantation has been successfully developed for pancreas, lung (unilateral and bilateral lower lobes), and small bowel transplantation. In addition, there has been increasing interest in donation after cardiac death (DCD) with a National Consensus Conference in April 2005 and the hope of expanding this pool from 200 to 1000 donors per year in the United States. Although pediatric donors constitute close to 20% of the total DCD donor pool, very few of the kidneys (3 of 291) and livers (1 of 78) recovered are allocated to pediatric recipients ( UNOS/OPTN, 2005 ). This practice may reflect concerns regarding long-term graft function, given the limited outcomes data available.

Living-related organ donation has, for the most part, been performed from parent to child. The use of children for living kidney donation remains highly controversial, and in general, most transplant programs will not use a donor younger than 18 years of age except in very limited circumstances, such as identical twins or an emancipated minor for his or her own child ( Abecassis et al., 2000 ). Living-related donor procedures have several advantages, including the fact that they can be electively scheduled when the recipient is in optimal condition. However, with the exception of living-related renal transplantation, which has excellent outcomes with 1-year graft survival in children older than 1 year of age ranging from 94% to 96%, due to the relatively small number of transplants performed, the long-term functional outcome of living lung, pancreas, and small intestine transplants remains to be established. The incidence of mortality and graft loss is less for children younger than 2 years if they receive a liver allograft from a living donor compared with a decreased donor ( Reding et al., 2003 ). In addition, many troubling ethical issues arise, such as the risk to the donor and recipient, validity of informed consent, and concerns about donor privacy and confidentiality.

Uncomplicated unilateral nephrectomy has an exceedingly low mortality (<0.1%), but the same is not true for right lobe liver donors (0.2% to 1%), left segment/lobe liver donors (0.06% to 0.2%), and right lobectomy of the lung (<5% mortality) ( Middleton et al., 2005 ). Between 2000 and 2004, there were three mishaps in the United States in the field of living-related organ transplantation, and in one instance, the hospital's liver transplantation program was forced to close because an organ donor died due to seemingly avoidable causes. These cases have highlighted the significant risks associated with these procedures and why some have called for a moratorium in living-related organ transplantation (Stagg-Elliott V, Am Med News. April 2002; Grady D, NY Times. January 2002). Also, the true number of living related donor deaths remains in a quandary as worldwide there have been fewer than 20 deaths reported in donors for all organ transplants, hence, the skepticism of the known, unpublished data (Hayashi and Trotter, 2002 ; Trotter et al., 2002 ).

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ IMMUNOSUPPRESSION

Since the early 1980s, organ transplantation has emerged from an experimental therapy to a highly successful treatment for end-organ failure of multiple causes. The single most important factor in this progression has been the development of effective immunosuppressive regimens. This section focuses on the various immunosuppressive agents used, complications, and the emergence of newer agents.

History

The idea of organ transplantation dates from the early 1900s, and it has only been with the development of immunosuppressive agents that the viability of this field has reached its zenith today. Prior to 1981, patient survival was poor because of inadequate immunosuppressive regimens. Corticosteroids and azathioprine were the mainstays of therapy, with graft survival only in the 30% to 50% range. The introduction of the calcineurin inhibitors cyclosporine, in 1981, and, subsequently, tacrolimus revolutionized the field of solid organ transplantation with 1-year graft and patient survival rates as high as 90% and greater in some organ systems ( UNOS, 2005 ). The main goal of any effective immunosuppression regimen is the prevention of organ rejection with minimal side effects and complications. This section reviews the various immunosuppressive agents commonly used for induction (primary) therapy, maintenance therapy, and treatment of rejection after organ transplantation; although varied for the different organ systems, the applied principles are almost identical. There is an emphasis on the calcineurin inhibitors cyclosporine and tacrolimus, the major agents used by most transplant centers worldwide.

▪ DRUGS FOR IMMUNOSUPPRESSION

Corticosteroids

Corticosteroids were the initial mainstay of therapy for organ transplantation, although their use is on the decline. They are effective particularly in both prevention and treatment of acute rejection episodes. Their predominant mechanisms of action include the inhibition of interleukin (IL)-1 and IL-2 production, suppression of helper and suppressor T cells, suppression of cytotoxic T cells, and reduction in the migration and activity of neutrophils ( Cohen, 2002 ). The use of long-term corticosteroids has been questioned because of their adverse side effects, particularly in the pediatric population. The trend since the 1900s is to use fewer steroids for maintenance therapy ( Ascher, 1995 ; Margarit et al., 1989 ). Many centers do not currently use steroids as part of their long-term regimens. The first report of steroid withdrawal after transplantation was published in 1989 ( Margarit et al., 1989 ). Everson and associates ( Stegall et al., 1997 ; Everson et al., 1999 ) published a literature review that demonstrated that greater than 50% to 85% of patients can be withdrawn from steroids without changes in acute rejection episodes, patient survival, or graft survival rates. This percentile difference is noted depending on the antirejection agent used for maintenance therapy (i.e., tacrolimus versus cyclosporine). Steroid withdrawal is preferable as it is associated with significantly less incidence of hypertension, hypercholesterolemia, and diabetes mellitus; it is less likely to result in cushingoid features and delayed development and obesity in the pediatric patient. Despite controversy over their use in maintenance therapy, corticosteroids remain the first-line agents for the treatment of acute rejection. The response rates vary depending on organ system and depending on whether the patient is maintained on cyclosporine or tacrolimus ( The U.S. Multicenter FK506 Liver Study Group, 1994 ).

Azathioprine

Azathioprine, the imidazole derivative of 6-mercaptopurine, was introduced in the late 1950s and early 1960s. Its mechanism of action is by the inhibition of differentiation and proliferation of T- and B-lymphocytes by blocking DNA and RNA synthesis. The net effect is a resultant reduction in the numbers of circulating white cells, both lymphocytes and granulocytes. One notable advantage of this agent is its steroid-sparing effect, allowing lower doses of steroids to be used with equal efficacy and fewer side effects. The use of this agent is limited, however, by noteworthy side effects, particularly hematologic and gastrointestinal. As many as 50% of patients present with bone marrow suppression and exhibit a profound leukopenia and/or thrombocytopenia while on treatment with this agent (Cattaral et al., 2000 ). Gastrointestinal side effects include pancreatitis, nausea, vomiting, and hepatotoxicity. Patients are at increased risk for opportunistic infections. An increased risk of malignancy, especially lymphomas and its reported incidence, however, remains controversial. The primary pathway of metabolism is by its inactivation of this molecule by xanthine oxidase, an enzyme blocked by allopurinol. The recommended dose of azathioprine is 1 to 2 mg/kg per day. Blood levels are not monitored for this agent.

Mycophenolate Mofetil

Mycophenolate mofetil (MMF; CellCept) is a morpholinoethyl ester of mycophenolate. It is well absorbed orally and hydrolyzed to its active form mycophenolic acid. Mycophenolic acid acts by competitively inhibiting inosine monophosphate dehydrogenase and hence blocks de novo synthesis of purines, primarily guanine. Lymphocytes, in contrast to other rapidly replicating cells, depend entirely on this pathway for purine synthesis. Hence, MMF's primary mechanism of action is the selective inhibition of lymphocyte proliferation. This drug is one of the newer agents introduced in the past 10 years and has been shown to be more efficacious than azathioprine in combination therapy ( Fisher et al., 1998 ). There is also some experimental evidence to suggest that MMF may reduce the risk of chronic allograft rejection, which has been attributed to its antiproliferative activity against B-lymphocytes and arterial smooth-muscle cells ( Azuma et al., 1995 ; Schmid et al., 1995 ). The most common side effects are gastrointestinal, including nausea, abdominal pain, anorexia, gastritis, and diarrhea. Diarrhea affects as many as 30% of patients but usually responds to a decrease in dose. MMF also causes leukopenia and thus should be avoided in combination with azathioprine. The usual dosage is 600 mg/m2 per day orally in two divided doses. Like azathioprine, blood levels are not monitored with this agent. The antivirals acyclovir and ganciclovir increase MMF levels, and antacids decrease MMF absorption ( Cohen, 2002 ).

Calcineurin Inhibitors

These agents are the primary immunosuppressive pharmaceuticals that have been developed to date, and they include tacrolimus and cyclosporine. Their effectiveness is via their interaction with calcineurin. The single most important cytokine in the immunology of transplantation rejection appears to be IL-2. It is produced through a sequence of events, which commence when a recipient antigen-processing cell comes into contact with the donor cell's major histocompatibility antigens (MHCs). The donor MHC fragment is processed and placed on the antigen-processing cell surface. When an appropriate recipient T cell is encountered, the T-cell receptor and the donor MHC bind. This initiates a cascade of enzymatic intracellular reactions via phosphorylation and calcium stores are released, which then combine with calmodulin. This calcium-calmodulin complex then activates calcineurin. Calcineurin appears to be directly involved in the pathway that induces the production of the IL-2 molecule. Cyclosporine and tacrolimus primarily act by binding calcineurin via the cyclosporine-cyclophilin complex or the tacrolimus-FK binding protein complex, respectively. Binding of calcineurin by either of these complexes inhibits its enzymatic action, preventing the dephosphorylation of nuclear factor of activated T cells. This nuclear factor of activated T cells must be dephosphorylated to enter the nucleus, where it is required for IL-2 gene transcription.

Cyclosporine

Cyclosporine is a neutral lipophilic cyclic endocapeptide extracted from the fungus Tolypocladium inflatum in the early 1970s. Cyclosporine is poorly absorbed from the gastrointestinal tract, and there is considerable variation in its bioavailability as biliary flow is essential for absorption of the drug. Neoral (Novartis Pharmaceuticals Corp., East Hanover, NJ), the microemulsion formula of cyclosporine, is much less dependent on bile production and flow than is Sandimmune (Novartis Pharmaceuticals Corp.), the standard preparation. Neoral gives a more consistent level of cyclosporine and is associated with less evidence of rejection ( Graziadei et al., 1997 ; Pinson et al., 1998 ). Recommended oral dose is 10 to 15 mg/kg per day (3× IV dose). The IV dose is 3 to 5 mg/kg over a 20 hr continuous infusion. Neoral has replaced Sandimmune in most major transplant centers worldwide. Cyclosporine is metabolized by the cytochrome P-450-3A system ( Cantarovich et al., 1998 ). Agents that induce these enzymes increase the metabolism of cyclosporine, resulting in lower blood levels. Conversely, agents that inhibit P-450 activity will result in higher circulating cyclosporine levels. In addition, cyclosporine can interfere with the metabolism of other medications.

Digoxin, lovastatin, and prednisolone can have significantly decreased clearance with resultant toxicity. The side effects associated with cyclosporine are numerous. Nephrotoxicity is one of the most significant side effects of cyclosporine, and it may present as acute and/or chronic renal pathologic alterations. The acute nephrotoxicity, which often resolves on reduction or discontinuation of the medication, probably results from afferent arteriolar vasoconstriction with resulting decreased glomerular filtration rate. The chronic nephrotoxicity, which does not appear to be reversible, is associated with arteriolar hyalinosis, tubular vacuolization, interstitial nephritis, and cortical atrophy. Neurotoxicity is another common side effect seen in as many as 50% of patients. This can range from headaches and tremors to seizures and coma. Due to variations in absorption and metabolism, cyclosporine levels tend to fluctuate. Dosing (10 to 15 mg/kg P.O. per day) should be adjusted based on the formulation used (i.e., Neoral versus Sandimmune) and serum or blood levels. Several techniques exist for the measurement of cyclosporine levels, including radioimmunoassay and high-pressure liquid chromatography. The levels can be measured in whole blood, serum, or plasma. Most centers use whole blood trough levels by the radioimmunoassay technique. A level of 100 to 200 ng/mL is generally desirable in the first 3 to 6 months after transplant depending on the organ transplanted. The level can usually be maintained at lower levels thereafter, again depending on the organ transplanted.

Tacrolimus

This calcineurin inhibitor, initially researched and brought to market under the name FK506, is a novel immunosuppressant isolated from Streptomyces tsukubaensis in 1985 ( Kino et al., 1987 ; Starzl et al., 1989 ). Tacrolimus (FK506; Prograf) shares many similarities with cyclosporine, including their basic mechanism of action and metabolism by cytochrome P-450-3A, in addition to the side effect profiles. However, significant differences exist between these drugs, which have been elucidated in the past decade. Tacrolimus is 10 to 100 times more potent than cyclosporine, possesses hepatotrophic properties, and does not rely on bile for its absorption. Renal impairment, neurotoxicity, and hypertension occur with similar frequencies in both cyclosporine- and tacrolimus-based regimens. Tacrolimus is associated with more hyperglycemia. Reportedly, as many as 20% of tacrolimus recipients become insulin-dependent diabetics because of the agent's direct effect on pancreatic beta cells and peripheral insulin receptors. Tacrolimus appears to have a higher incidence of post-transplant lymphoproliferative disease (PTLD). Considering that accelerated atherosclerosis is an important issue after solid organ transplantation, it is important to note that tacrolimus produces less hyperlipidemia and thus results in a less adverse cardiovascular risk profile than cyclosporine. Statistically significant improvements have been seen in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels when patients were switched from cyclosporine to tacrolimus. A dose of 0.1 mg/kg b.i.d. is given orally (Manzarbeitia et al., 2001 ). Tacrolimus is given at an oral dose of 0.1 mg/kg b.i.d. Tacrolimus levels are usually measured in whole blood specimens by enzyme immunoassay techniques. As with cyclosporine, drug levels of 5 to 15 ng/mL are desirable in the first few months after transplantation depending on the organ system transplanted.

Efficacy of Cyclosporine and Tacrolimus

After its introduction, cyclosporine became the drug of choice for the prevention of allograft rejection. Tacrolimus, initially reserved for use as rescue therapy in refractory rejection, has now become a first-line immunosuppressive agent in many centers worldwide. Large multicenter U.S. and European randomized clinical trials have been performed to compare tacrolimus and cyclosporine (Sandimmune) for primary and maintenance immunosuppression ( European FK506 Multicenter Liver Study Group, 1994 ; The U.S. Multicenter FK506 Liver Study Group, 1994 ; Wiesner, 1998 ). In the European trial, patient and graft survival rates were similar; however, significantly lower rates of acute rejection were seen in the tacrolimus group in some organ systems. More episodes of acute and steroid-resistant rejection were seen in the cyclosporine group. The tacrolimus group had a lower cumulative steroid exposure and fewer requirements for monoclonal antibody therapy ( European FK506 Multicenter Liver Study Group, 1994 ). Patients on tacrolimus, however, had significantly more medication-related adverse effects.

At 5-year follow-up, tacrolimus recipients showed less rejection but there was no overall improvement in patient or graft survival for all solid organ transplants. Many of these large trials used Sandimmune as the cyclosporine preparation, hence confounding some of the data to date. Neoral has been shown to be superior to Sandimmune ( Freeman et al., 1995 ; Mirza et al., 1997 ). Tacrolimus appears to be superior to cyclosporine for the treatment of rejection episodes. Episodes of acute rejection, even steroid-resistant episodes, may resolve when patients are switched from cyclosporine- to tacrolimus-based therapy ( Jonas et al., 1996 ; Millis et al., 1996a,b; 1998 [411] [413] [412]). Also, chronic rejection has shown a response in more than half of patients converted from cyclosporine to tacrolimus for some solid organ transplants ( Klintmalm et al., 1993 ; Wiesner, 1998 ). The choice of calcineurin inhibitor tends to be a matter of institutional preference. Many units are using tacrolimus-based therapy, citing less rejection, less steroid use, less OKT3 needed for immunosuppression, and less hyperlipidemia. However, many centers still advocate the use of cyclosporine (usually Neoral) based on equivalent patient/graft survival rates and a lower incidence of diabetes mellitus and PTLD.

Rapamycin

Rapamycin (sirolimus) is a macrolide antibiotic isolated from the fungus Streptomyces hygroscopicus. It effectively inhibits both B- and T-cell activity ( Poon et al., 1996 ; Poston et al., 1999 ). Rapamycin is structurally similar to tacrolimus. It uses the same intracellular binding protein as tacrolimus but blocks B- and T-cell activation at a later stage than the calcineurin inhibitors. Rapamycin and cyclosporine appear to act synergistically to inhibit lymphocyte proliferation ( Kimball et al., 1991 ). The oral bioavailability of rapamycin is variable. Like the calcineurin inhibitors, it is metabolized by the cytochrome P-450-3A system. The efficacy of rapamycin in solid organ transplantation was initially shown in the renal transplant population ( Groth et al., 1999 ; Kahan et al., 1999 ; McAlister et al., 2000 ). Small studies in liver transplant patients have shown rapamycin to be an effective agent when combined with a calcineurin inhibitor ( Watson et al., 1999 ; Trotter et al., 2001 ). Most of these patients could be maintained on steroid-free regimens. Acute rejection episodes were significantly decreased compared with historical controls (30% versus 70%) (Kahan et al., 1999, 2000 [284] [283]).

The main role of rapamycin may be in allowing calcineurin inhibitor dose reduction in those patients with evidence of tacrolimus or cyclosporine toxicity ( Brattstrom et al., 1998 ; Groth et al., 1999 ). The most frequent dose-related adverse effects include hyperlipidemia, leukopenia, thrombocytopenia, oral ulcerations, and joint pains. Both cholesterol and triglyceride levels can significantly increase and should be monitored while on therapy. An increased risk exists of lymphocele. A “black box' warning of its associated risk of thrombotic episodes in its first month of use is given. Calcineurin inhibitor levels, especially those of cyclosporine, have been shown to significantly increase while on rapamycin therapy and should also be closely monitored.

Antilymphocyte and Antithymocyte Globulins

Antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) are produced by extracting immunoglobulins from animals (usually horse or rabbit) that have been immunized with human lymphocytes or thymocytes, respectively. The patient should be premedicated with acetaminophen (10 mg/kg, P.O.), diphenyl hydramine (1 mg/kg, P.O.), and methyl prednisone (2 mg/kg, I.V.) to prevent allergic or hypersensitivity reactions. The intravenous administration of these polyclonal antibodies (the dose of ATG, 5 mg/kg given over 6 hours) causes rapid and profound depletion of peripheral lymphocytes. A major limitation of all polyclonal antilymphocyte preparations is batch-to-batch heterogeneity, which results in unpredictable side effects and, importantly, variable efficacy. ALG and ATG are not typically used as first-line agents for immunosuppression. They appear to delay the onset of the first episodes of organ rejection, but the overall rates of rejection are similar to those seen with calcineurin inhibitors (Neuhaus et al., 2000 ). The focus of this form of therapy is as the primary immunosuppression in patients unable to tolerate calcineurin inhibitors (i.e., significant pretransplant renal insufficiency) and in the treatment of steroid-resistant (and possibly OKT3-resistant) rejection. Commonly observed side effects include allergic reactions, serum sickness, fever, and thrombocytopenia as with OKT3 and other systemically infused immunoglobulins. Cytokine release syndrome (cardiovascular collapse with a hemodynamic profile similar to septic shock, pulmonary edema, seizures, and renal failure) may be seen with the administration of these agents similar in kind to that sometimes seen with OKT3 or any other immunoglobulin. The incidence of lymphoproliferative disease is also increased among patients who have received ALG and ATG.

OKT3

OKT3 (Orthoclone-muromonab-CD3) is a monoclonal antibody specifically directed against the CD3 complex of the cell membrane of lymphocytes; it is an antibody specifically directed at the T3 antigen of human T cells—those cells that directly attack the transplanted organ—and is unlike the polyclonal antibody preparations. Intravenous infusion (0.1 mg/kg/day for 10 to 14 days) results in tremendous lymphocyte depletion. Induction with OKT3 has not shown any significant benefit over the calcineurin inhibitors ( McDiarmid et al., 1991 ). Because of its toxicity and the availability of less toxic agents, OKT3 is generally reserved for patients with severe steroid resistant rejection ( Portela et al., 1995 ; Wall and Adams, 1995 ). OKT3, ALG, and ATG provide 60% to 90% graft salvage rates for acute rejection in various organ system transplants. The side effect profile of OKT3 is similar to that of ALG and ATG, including the cytokine release syndrome, infectious complications, and malignancy potential. This protein, not unlike ALT and ATG, preferably is administered to a patient monitored for over 4 to 6 hours. Lymphocyte and platelet counts must be closely monitored.

Interleukin-2 Receptor Antagonists

As discussed earlier, IL-2 is the most noteworthy cytokine known to be involved in the rejection of transplanted solid organs. Although calcineurin inhibitors decrease the amount of IL-2 produced, IL-2 receptor antagonists prevent the protein itself from binding to the active lymphocytes by competitive inhibition. Unlike ALG, ATG, and OKT3, which target the entire lymphocyte population, IL-2 receptor antagonists specifically target the actively dividing cells by binding to the IL-2 receptor's CD25 moiety, which is only expressed in active cells ( Langrehr et al., 1998 ). There are two available IL-2 receptor antagonists: basiliximab and daclizumab. Given its recent introduction into the armamentarium for immunosuppression, these agents have not been fully studied. However, early studies have indicated that these agents need to be combined with calcineurin inhibitors to be effective ( Vincenti et al., 1998 ). No significant data exist at the time of this writing regarding the treatment of rejection episodes with these agents. While awaiting further studies, however, these agents should probably be used for induction of immunosuppression ( Eckhoff et al., 2000 ) in those patients at high risk for calcineurin inhibitor-related toxicity. Also, they appear to be well tolerated without significant adverse effects. Dosing and timing for administration of these agents vary depending on the organ system to be transplanted. Moreover, it appears that IL-2 receptor antagonists are needed only immediately at the time of the transplantation (immediately before or after reperfusion of the transplanted organ), with a second dose at approximately 4 days in the immediate immunosuppressive induction period.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ HEART, LUNG, AND HEART-LUNG TRANSPLANTATION

▪ HEART TRANSPLANTATION

History

Christian Barnard conducted the first heart transplantation on December 3, 1967. The patient lived for 18 days before succumbing to a fatal bout of pneumonia ( Barnard et al., 1967) . The first pediatric cardiac heart transplantation was carried out within a week of this landmark achievement. The group was led by Adrian Kantrowitz, and the patient was a 3-week-old child with Ebstein's anomaly and pulmonary atresia. The procedure involved immersion of both the donor and recipient in iced water to achieve topical cooling. As the recipient's chest was opened, the heart fibrillated and thus open cardiac massage was undertaken until such time as the patient's temperature was low enough to commence circulatory arrest ( Kantrowitz et al., 1968 ). Over the next few years, about 100 more heart transplantations were conducted, with a mean survival of 1 month ( Mendeloff et al., 2002) . The poor outcomes were probably due to inadequate technological advancements in key areas such as surgical techniques, cardiopulmonary bypass, immunosuppression, and the clinical diagnosis and management of rejection.

The preliminary understanding of the immunobiology of organ rejection and its role in transplantation failure, the development of the bioptome and a grading system for rejection, and the isolation of a fungal extract with immunosuppressive properties that came to be developed as cyclosporine: all helped spur renewed interest in transplantation ( Caves et al., 1973 ). Adult transplantation programs began to be established; pediatric transplantation during this early period was mostly in adolescents and was conducted under the aegis of adult programs. Infant and pediatric cardiac transplantation did not become established as a separate entity until the mid-1980s, when transplantation was recommended as a primary therapy for lethal congenital lesions, and successful heart transplantation in an 8-month-old was performed by Cooley and colleagues ( Bailey et al., 1985a ; Cooley et al., 1986 ).

There was a steady increase in the number of pediatric patients undergoing heart transplantation in the 1980s and early 1990s, with the rate peaking in the mid-1990s. According to the International Society for Heart and Lung Transplantation, 5002 pediatric heart transplants were performed in the period 1982 through 2002, representing just less than 8% of all heart transplants. Currently approximately 300 to 350 pediatric heart transplantations are carried out per year (compared with 3122 adult transplants in 2001). Mortality figures have improved significantly, with a 75% actuarial survival at 4 years for the period, in comparison with less than 55% for the early era of transplantation. As indications have continued to expand (see later), continued growth in pediatric heart transplantation has been limited primarily by the availability of donor hearts. In response, particularly for neonates, most programs have opted, whenever possible, for staged palliation of congenital heart defects, in order to avoid the uncertainty (and potential death) that placement on the transplant waiting list entails.

The issue of transplantation versus palliation in early infancy is far from settled. Proponents of transplantation believe that infant transplantation may be associated with enhanced engraftment and induction of tolerance, reducing the amount of immunosuppression required. Neonates in particular may experience a “window of immune tolerance,” with a lower likelihood of rejection and the ability to use less aggressive immunosuppression ( Boucek et al., 1990 ). Heart transplantation is technically more difficult and may be associated with higher mortality in those who have undergone prior palliative cardiac surgery. Transplantation as a primary therapy also may reduce the risk of progressive organ deterioration, particularly of the pulmonary parenchyma and vasculature, that can result from some palliative procedures or severe cardiac dysfunction arising after failed congenital procedures. On the other hand, the limited donor supply makes attempts at surgical correction the only option for many patients. Advocates of staged reconstruction argue that transplantation is a waste of resources in those for whom an alternative is available. Transplantation carries the attendant complications of rejection, immunosuppression, drug toxicity, infection, malignancy, and the need for retransplantation.

Hypoplastic left heart syndrome (HLHS) is an example that outlines the nature of this conflict. Five-year survival for this lesion following heart transplantation (including deaths while waiting for a donor) and the staged reconstruction procedures (Stage I Norwood palliation, bidirectional Glenn cavopulmonary shunt, and modified Fontan procedure) are essentially the same. The transplanted heart is structurally normal but is associated with all of the complications of antirejection therapy and, when done in neonates, may require one or more retransplantations due to chronic rejection and graft failure. Staged reconstruction for HLHS mandates life with Fontan physiology, and thus a significant likelihood of severe dysrhythmias and late ventricular dysfunction, potentially resulting in a need for transplantation.

Patient Demographics

Children younger than 1 year continue to make up the majority of the transplants performed ( Fig. 28-1 ). There then appears to be a decreasing number of transplants for the 5- to 7-year-old age group followed by a second peak in the teenage years. This distribution is closely linked to etiology, with congenital heart disease as the major indication for transplantation in the first year of life and cardiomyopathy the primary indication in the older age groups. In 2001, 76% of pediatric transplants in children less than 1 year of age were for congenital heart disease, whereas in the 1- to 10-year-old and 11- to 17-year-old age groups, the percentages undergoing transplantation for cardiomyopathy were 51% and 63%, respectively. The majority of heart transplants in older patients with congenital heart disease are performed as these patients' palliative or reconstructive surgeries become inadequate to sustain a quality of life (ventricular failure, dysrhythmias, etc.). Valvular heart disease, coronary artery disease associated with hyperlipidemia, and myocardial tumors are less frequent (<2%) indications for heart transplantation in children. Drug-induced cardiomyopathy (especially anthracycline) is another infrequent indication, although there is some evidence that this may become a more frequent problem in pediatric patients as they age. Retransplantation accounted for 4% of all transplantations; this rate has not changed appreciably in the past several years.

 
 

FIGURE 28-1  Indications for pediatric heart transplantation.  (From Hosenpud JD, Novick RJ, Breen TJ, et al.: The registry of the International Society for Heart and Lung Transplantation: Eleventh official report. J Heart Lung Transplant 13:561, 1994. With permission from the International Society for Heart and Lung Transplantation.)

 

 

 

Surgical Indications for Heart Transplantation

The development of cyclosporine and other immunosuppressive agents has enabled heart transplantation to become a viable therapy for end-stage heart failure regardless of etiology. Indeed, according to the International Society for Heart and Lung Transplantation, survival at 4 years now exceeds 75%. It may thus be considered an alternative treatment to standard surgical procedures for certain congenital heart defects such as HLHS and pulmonary atresia with intact interventricular septum. The decision to perform transplantation is best made when patient survival is known to be unlikely or of short duration and other options have failed. As mentioned previously, the mortality rate of pediatric heart transplantation and concerns about long-term graft survival and immunosuppression must still be balanced against the natural history of the disease process and the results of alternative surgical repairs. For example, in the instance of dilated cardiomyopathy, particularly in children who are older than 2 years, heart transplantation may offer the only alternative to death. The case for transplantation for HLHS is somewhat different. For infants with HLHS treated with heart transplantation, data indicate 1-year and overall survival rates of 84% and 63%, respectively ( Bailey and Gundry, 1990 ), which is similar to the survival figures for staged reconstructive procedures ( Norwood and Jacobs, 1992 ; Norwood et al., 1992 ). In the current era, both of these techniques would have to be considered palliative.

Of note, data from the Pediatric Heart Transplant Study Group suggest that if one were to list all neonates with HLHS for transplantation, less than 10% would receive a heart. It has been argued that using a scarce resource for conditions that can be palliated diverts donor organs from those for whom transplantation is the only option ( Morrow et al., 1997 ; Fricker et al., 1999 ).

Patient Selection

Congenital Heart Disease

Certain groups of infants have conditions that cannot be palliated. An example of this would be the child with HLHS that consists of aortic atresia and a perforated mitral valve. These children have abnormal coronary artery anatomy and coronary myointimal hyperplasia that can predispose to systemic (right) ventricular dysfunction after staged reconstruction. Infants with this anatomic variant might therefore be better candidates for transplantation, although this remains controversial ( Freedom, 1983 ; Weinberg et al., 1985 ; Pigott et al., 1988 ). Other lesions in neonates and infants that may be considered relatively strong indications in favor of heart transplantation include pulmonary atresia with intact ventricular septum, univentricular heart, and unbalanced forms of atrioventricular septal defect or double-outlet right ventricle. Although these conditions can usually be palliated with staged reconstructive techniques, transplantation is often favored for these infants because of the high perioperative mortality rates (the result of problematic cardiac anatomy) and because outcome studies have shown poor long-term results of the palliative procedures.

Patients with poor outcome after palliative or staged reconstructive attempts are another group with congenital heart disease who may require subsequent transplantation. Examples include (1) patients with univentricular heart physiology in whom ventricular dysfunction has developed, thus precluding a Fontan procedure (some of these patients will also develop pulmonary hypertension necessitating a heart-lung transplantation); (2) patients who had undergone a Fontan procedure and now present with end-stage ventricular dysfunction; (3) patients with significant myocardial damage in association with anomalous left coronary artery; and (4) patients with ventricular failure following an atrial baffle procedure (such as a Mustard or Senning procedure) for transposition of the great arteries.

Dilated Cardiomyopathy

Dilated cardiomyopathy is the most frequent type of cardiomyopathy encountered in children. Although most cases are believed to result from a viral or an inflammatory etiology, definitive proof is often lacking. Dilated cardiomyopathy can result from other metabolic and genetic defects as well. Potentially treatable causes of heart failure such as carnitine deficiency and other metabolic abnormalities should be excluded. Children diagnosed with dilated cardiomyopathy at ages greater than 2 have a worse prognosis ( Griffin et al., 1988 ; Chen et al., 1990 ); overall mortality exceeds 50% within 1 year of diagnosis. Factors other than age that are associated with poor outcome include severe cardiomegaly, decreased ejection fraction, and low cardiac output. These children usually present with systolic dysfunction (usually biventricular), congestive heart failure symptoms, and/or dysrhythmias. Occasionally, sudden death may be the first sign. Empirical treatment with diuretics, inotropes, and vasodilators is usually initiated. Although these therapies may provide some symptomatic improvement, it is unclear whether even maximal medical management can alter the natural course of the disease process. A subset of patients with dilated cardiomyopathy can present with acute fulminant myocarditis, which further exacerbates their condition. Some (approximately one third) patients with dilated cardiomyopathy may substantially improve after a period of intensive medical or mechanical (e.g., extracorporeal membrane oxygenation [ECMO] or ventricular assist device) cardiac support.

Dilated cardiomyopathy can also occur after the use of doxorubicin in patients who have undergone chemotherapy regimens for a variety of pediatric leukemias and solid tumors. Doxorubicin is particularly toxic to cardiac muscle, at least in part due to free radical-mediated mitochondrial injury. In addition to the total dose administered (especially in excess of 250 to 400 mg/m2), other risk factors appear to be female sex and an age less than 4 years when treated (Lipshultz et al., 1991, 1995 [355] [356]). It appears that early myocyte loss results in an inability of the heart to successfully adapt to the demands of growth and increasing afterload. These patients frequently present for heart transplantation a decade or more after cancer treatment ( Wallace, 2003 ). One major unresolved concern regarding transplantation for this group is the risk of cancer recurrence in the setting of intensive immunosuppression. It is believed that a candidate who has no evidence of the primary malignancy 1 year after treatment has an acceptable risk for the introduction of immunosuppression. ( Fricker et al., 1999 ).

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is another major form of cardiomyopathy that occurs with some frequency in the pediatric population. A study found that hypertrophic cardiomyopathy made up 42% of all new presentations of cardiomyopathy during a 3-year period ( Lipshultz et al., 2003 ). Left ventricular outflow obstruction and diastolic dysfunction as a result of increased ventricular mass secondary to left ventricular hypertrophy characterize this condition. Sudden death, most likely due to ventricular tachycardia, may also be the first presenting feature. Increased risk may be associated with young age at presentation, a family history of hypertrophic cardiomyopathy, and a history of syncope ( McKenna et al., 1981 ; Maron et al., 1987 ). There does not appear to be a good correlation between the severity of ventricular outflow obstruction and the risk of fatal arrhythmia. Furthermore, although symptomatic improvement may occur with the use of β-adrenergic blockers or calcium channel antagonists, these therapies (as well as others that may be used to improve symptoms arising from outflow obstruction such as asynchronous biventricular pacing and ventricular myomectomy) do not appear to have a significant effect on mortality ( Wigle et al., 1985 ), thus making the identification of at-risk patients and the timing for transplantation extremely problematic.

Relative Contraindications to Pediatric Heart Transplantation

A number of variables must be assessed before referring any patient for heart transplantation. The presence of increased pulmonary vascular resistance (PVR), active infection, irreversible organ damage, pulmonary emboli or infarction, other severe systemic disease, active malignancy, and significant psychosocial limitations are the major factors to be considered.

Particular attention is given to the degree of pulmonary hypertension, as it is a key determinant of function of the donor right ventricle after transplantation and hence of overall outcome. The incidence of increased pulmonary vascular resistance in children who are admitted for heart transplantation is probably greater than that in adults because of the number of congenital pediatric lesions that can be associated with increased pulmonary blood flow or raised left atrial pressure. Increased left atrial pressure can also be a frequent contributor to elevated PVR in patients with cardiomyopathy. In adults, PVR of greater than 6 Wood units is usually considered to be a relative contraindication for heart transplantation. The upper limit of PVR that precludes successful heart transplantation in children has not been firmly established ( Benson et al., 1991 ). It has been shown that right ventricular dysfunction or critical pulmonary hypertension after transplantation is unlikely in children whose preoperative PVR is less than 6 Wood units ( Addonizio and Rose, 1987 ). This same group suggests that PVR index (PVRI) rather than PVR be used, in that the former allows some correction for body size. Others suggest that the transpulmonary gradient (TPG) is a more accurate predictor of early trans-plant mortality than PVR and that a TPG of greater than 15 mm Hg is associated with an increased risk, at least in adults ( Murali et al., 1993 ). In the present era, most centers view increased PVR as only a relative contraindication, and successful heart transplantation has occurred in children with a PVRI between 7 and 15 Wood units. In such patients, one approach has been to attempt to distinguish a fixed, irreversible pulmonary vascular disease from pulmonary hypertension with a reactive component that resolves with insertion of a well-functioning heart. This distinction is frequently attempted on the basis of PVR response to vasodilators such as oxygen, nitroglycerin, prostaglandin (PG)E1, or inhaled nitric oxide in the catheterization laboratory.

Previously, children in whom the PVR was reduced to less than 8 Woods units after 1 to 2 weeks of prostaglandin therapy were also considered for transplantation ( Baum et al., 1991 ; Benson et al., 1991 ). Evidence suggests that long-term (months rather than weeks) continuous intravenous prostacyclin (PGI2) can significantly reduce PVR, thus reducing right ventricular afterload and allowing for heart transplantation in a previously excluded group ( Rosenzweig et al., 1999 ; Kao et al., 2001 ; Dandel et al., 2003 ). Another approach to transplantation in the presence of pulmonary hypertension in infants and children is to use an “oversize” donor heart (1.5 to 2 times the size of the recipient). The oversize gives the recipient a greater right ventricular mass to respond to the elevated PVR ( Addonizio et al., 1989 ). However, the usefulness of this approach has not been statistically confirmed.

Patients with truly fixed and overly severe pulmonary hypertension are not candidates for orthotopic heart transplantation. Options include either heterotopic transplantation (the recipient's heart remains in place to assist with right ventricular work) or heart-lung transplantation. Both alternatives are less desirable. The operative and long-term mortality rates of heterotopic transplantation are increased (5-year survival, 54%) compared with orthotopic transplantation (5-year survival, ≈75%) ( Kriett and Kaye, 1991 ). Survival after heterotopic transplantation is better compared with heart-lung transplantation.

Viral Infection

Cytomegalovirus (CMV) infection, in particular, is a significant cause of morbidity and mortality in transplant patients, as well as being a likely major contributor to the manifestations and severity of chronic heart transplant rejection (see later). However, the limited donor pool has made it impossible from a practical standpoint to exclude the transplantation of hearts from CMV-positive donors into CMV-negative recipients. Use of anti-CMV therapies such as ganciclovir has become a standard component of most transplantation regimens.

Whether hepatitis C viruses (HCVs) in the donor or recipient should be a contraindication remains undetermined. In a survey of 72 thoracic transplantation centers, 64% do list HCV-positive patients for heart transplantation and 74% use HCV-positive organs (albeit in either HCV-positive recipients or UNOS 1 recipients) ( Lake et al., 1997 ). Those in favor suggest that HCV acquisition is better than the alternative (i.e., death without transplantation). The argument against is that a significant proportion of infected posttransplant patients begin to have progressive liver dysfunction within 5 to 10 years after transplantation. In addition, antiviral therapy appears to be less reliable; there also is an increased incidence of hepatocellular carcinoma in this subgroup ( Fishman et al., 1996 ). A full evaluation of liver function should be conducted on a potential HCV-positive recipient before listing and the use of HCV-positive organs should follow the practice stated above ( Fricker et al., 1999 ). There is a limited number of case studies of heart transplant patients with preexisting or acquired HIV infection, making definitive recommendations problematic. Despite the fact that these individuals may be immunocompromised and be more susceptible to opportunistic infections than other candidates, results in HIV-positive recipients seem to be encouraging ( Calabrese et al., 2003 ; Morgan et al., 2003 ).

Psychosocial

Psychosocial problems and noncompliance are significant issues in the pediatric population, particularly in adolescents. Severe psychiatric disorders that cannot be controlled are a contraindication to the procedure. However, postoperative noncompliance can be difficult to predict and is an important risk factor for rejection and other complications. Reliable caretakers and a stable family structure are extremely important to the success of transplantation in infants and children because of the requirements for and stresses of frequent hospital visits, procedures, numerous medications, and chronic illness.

Donor Selection

Donors are matched largely according to blood type and body size. Typically, donor weight approximates that of the recipient. As mentioned previously, if the PVR is increased, a donor up to 2.5 times the weight of the recipient may be sought. Human lymphocyte antibody (HLA) typing and donor lymphocyte cross-matching are usually done retrospectively.

Most infant and pediatric donors are trauma victims (motor vehicle accidents, child abuse); occasionally they result from sudden infant death syndrome or intracranial hemorrhage. Hypotension requiring pressor support (catecholamines, vasopressin) is common in victims with severe brain injury or brain death; it should not be inferred that it indicates myocardial dysfunction. Significant myocardial damage can result directly from trauma or secondarily from hypotension, hemorrhage, or ischemia. Routine donor screening includes a chest radiograph, electrocardiogram, and echocardiogram; mild contractile dysfunction is usually not an absolute contraindication to donation. There is some evidence that increased blood concentrations of cardiomyocyte proteins such as the cardiac-specific isoform of troponin I in donor blood is predictive of graft failure ( Grant, 1994) . Many centers administer T3 (triiodothyronine) to the donor before harvest, based on evidence that it is associated with improved graft contractile function in the recipient ( Novitzky et al., 1990 ).

In an effort to expand the potential donor pool, some centers have extended the conventional limits for ischemic times. One study compared ischemic times of greater than 8 hours with less than 90 minutes in pediatric heart transplants. They found no difference in early or late recipient outcome between the two groups ( Scheule et al., 2002 ). Current practice recommendations suggest, limiting the ischemia time of the donor heart to less than 6 hours, and preferably to less than 4 hours, is likely to produce the least amount of myocardial preservation injury and acceptable graft function.

Infection, such as evidence of pneumonia, in the donor is relatively common. In general, rather than being a contraindication for the use of the organ, positive cultures in the donor are used to guide postoperative antibiotic management in the recipient.

Perioperative Management of the Pediatric Heart Transplant Recipients

Preoperative Considerations

In potential recipients, blood is typed to ensure ABO compatibility and a panel reactive antibody test (PRA [tests recipient reactivity to antigens in a panel of random, not donor, sera]) is conducted. In children with a negative PRA test, matching is done solely on the basis of blood typing. In children who react to more than 10% of random sera, a negative prospective lymphocyte crossmatch is ideal. However, this is not always possible, and strategies for the recipient with a highly reactive PRA include pretransplantation and posttransplantation plasmapheresis of the recipient, often in combination with intravenous pooled immunoglobulin ( Leech et al., 2003 ). In general, preoperative blood transfusions should be avoided whenever possible so as not to stimulate antibody production; and obviously, transfused blood should be CMV negative for CMV-negative recipients.

The approach to the perioperative management of patients with congenital heart disease for heart transplantation should be based on a comprehensive understanding of the patient's cardiovascular pathophysiology. Outflow obstruction is characterized by increased pressure work, chamber hypertrophy, and a reduced ability to increase output. Optimal function is achieved by ensuring adequate preload and controlling the heart rate to allow adequate time for chamber filling and ejection. Left ventricular outflow obstruction requires the maintenance of SVR in the face of fixed cardiac output and coronary blood flow. Right ventricular obstruction may also benefit from reducing the afterload (PVR) where possible. In the instance of significant hypertrophy of either ventricle (or both ventricles), it is important to maintain coronary perfusion pressure (and hence aortic blood pressure) and oxygen-carrying capacity (i.e., hematocrit) to ensure adequate myocardial oxygen delivery to the hypertrophied muscle mass.

Valvular regurgitation may occur as a result of congenital lesions or severe dilated cardiomyopathy. Increased ventricular volume loading is the end result. Contractile function is preserved by keeping the heart rate normal to somewhat increased, in order to decrease ventricular filling time and volume and to optimize cardiac output. Other possible maneuvers include afterload reduction and inotropic support (“inodilators” such as milrinone or dobutamine), which tend to decrease chamber size and wall tension, as well as increase forward flow, and reduce the regurgitant fraction.

Large left-to-right shunts impose both volume and pressure loads on the right ventricle and pulmonary circulation as well as a volume load on the left ventricle. Systemic hypoperfusion, ventricular dysfunction, acidosis, oliguria, and eventual circulatory collapse can be induced by maneuvers that increase the magnitude of the left-to-right shunt,    p/   s (i.e., decrease PVR and/or increase SVR). The increased pulmonary blood flow may also result in left atrial hypertension and pulmonary edema. Management involves the maintenance of PVR and preventing increased pulmonary flow with subsequent “steal” from the systemic circulation. Inotropic therapy may be required to maintain contractility and blood pressure.

Different principles apply to patients with cyanotic lesions associated with decreased pulmonary blood flow. Adequate oxygenation is dependent on the balance of PVR to SVR, as well as overall cardiac output. Increasing PVR or decreasing SVR can severely compromise pulmonary blood flow. A subset of children admitted for heart transplantation are dependent on surgical systemic-to-pulmonary shunts for pulmonary blood flow. The flow through these shunts may be marginal at the time of transplantation, either because of growth or due to partial occlusion or narrowing of the shunt. Under these circumstances, systemic oxygen saturation is increased by increased cardiac output and SVR; significant increases in PVR should be avoided. The approach to shunts that are large with substantial pulmonary blood flow (best indicated clinically by high systemic oxygen saturation for the lesion [typically >85% to 90%] and wide pulse pressure) follows that described above for large left-to-right shunt lesions.

Cardiac function in end-stage dilated cardiomyopathy occurs at the extremes of the LaPlace and Frank-Starling relation. This means that wall tension is maximal, subendocardial perfusion is easily compromised, and even minor changes in heart rate, contractility, preload, and afterload can lead to myocardial decompensation. The early addition of inotropic support may prevent bradycardia, augment contractility, augment myocardial blood flow, and minimize the negative inotropic effect of anesthetic agents. Positive-pressure ventilation can affect ventricular performance ( Badke, 1982 ; Kaul, 1986 ). High intrathoracic pressure and large lung volumes can compress alveolar capillaries and thus increase PVR and right ventricular afterload. These effects can decrease right ventricular function. By the mechanism of ventricular interdependence, left ventricular filling and function can also be compromised. Hypoventilation may also increase PVR by producing hypoxia, hypercarbia, and atelectasis ( West, 1974 ). At appropriate lung volumes, positive-pressure ventilation often improves function of the failing systemic ventricle by reducing afterload (ventricular transmural pressure is decreased by the increase in intrathoracic pressure, thereby reducing afterload as per LaPlace's law).

The management of the child with HLHS awaiting transplantation merits specific discussion (see Chapter 17 , Anesthesia for Cardiovascular Surgery). To maintain systemic perfusion via the ductus arteriosus, an infusion of PGE1 (0.05 to 0.10 mcg/kg per min) is usually begun shortly after birth. Systemic perfusion may require further augmentation with inotropes and volume replacement. Any metabolic acidosis is monitored and also treated aggressively. A balloon atrial septostomy may be performed to ensure unimpeded left-to-right atrial flow.

The major goals of preoperative management of HLHS are to maintain systemic perfusion, promote optimal systemic oxygen delivery, and prevent excessive pulmonary blood flow; large increases in PVR are also to be avoided. Thus, a careful balance must be maintained between the ratio of pulmonary-to-systemic blood flow (   p/   s). Hyperventilation, alkalosis, and hyperoxia all decrease PVR and increase pulmonary blood flow (   p), with a subsequent decrease in systemic blood flow (   s). Therapeutic efforts are directed to maintaining normocarbia, normal pH, and the arterial oxygen saturation at approximately 75% to 80%. This range of SpO2 is generally indicative of a “balanced circulation” (i.e., acceptable    p/   s ratio) and generally favors appropriate systemic oxygen delivery, adequate myocardial contractility and blood pressure. If excessive pulmonary blood flow arises, nitrogen is added to the inspired gas mixture (delivered via either endotracheal tube or head box) in order to provide a hypoxic gas mixture (<21%). Intubation, paralysis, and induced hypercarbia (usually via carbon dioxide added to the breathing circuit in conjunction with normal minute ventilation) can also be used to decrease excessive pulmonary blood flow while improving systemic oxygen delivery and cerebral oxygenation ( Tabbutt et al., 2001 ; Ramamoorthy et al., 2002 ).

Bridge to Heart Transplantation

A significant number of children die while awaiting heart transplantation. The number varies according to age, etiology, and degree of heart failure at the time of presentation but ranges from 23% to 70% (McGiffin et al., 1997 ; Morrow et al., 1997 ; Mital et al., 2003 ). Mechanical extracorporeal life support (ECLS) using either venoarterial extracorporeal membrane oxygenation (ECMO) or a paracorporeal ventricular assist device (VAD) has been proved to minimize myocardial oxygen consumption and permit myocardial recovery ( Kirshbom et al., 2002 ). In children with end-stage heart failure awaiting transplantation, the major problem is duration of mechanical support. In the setting of transplantation, these techniques have increasingly been successful in supporting the failing circulation as a bridge to transplantation ( Kanter et al., 1987 ; Delius et al., 1990 ; del Nido et al., 1992 ; Levi et al., 2002 ). Additional indications for ECLS include postoperative ventricular or pulmonary failure that prevents weaning from cardiopulmonary bypass, severe pulmonary arterial hypertension despite maximal medical support (alkalinization, inotropic agents, inhaled nitric oxide), and refractory postoperative ventricular or pulmonary dysfunction.

The selection of technique depends on patient size and site(s) of dysfunction (see later). When using mechanical support in the postoperative setting, care must be taken to exclude anatomic causes of graft dysfunction that require operative intervention. The ability of mechanical support to facilitate recovery also requires that organ dysfunction be reversible. These factors mandate both appropriate patient selection and the institution of mechanical support before irreversible organ injury occurs. The importance of the latter consideration was demonstrated in early studies of ECMO treatment of respiratory failure in adults, where prolonged mechanical ventilatory support before ECMO use was associated with pathologic evidence of irreversible lung injury, minimal improvement during ECMO, and poor outcome ( Gille and Bagniewski, 1976 ; Zapol et al., 1979 ).

Extracorporeal Membrane Oxygenation

ECMO reduces ventricular work by reducing wall tension and maintains systemic perfusion and oxygenation. It is the preferred means of mechanical support in very small infants with myocardial failure and in patients who require supported gas exchange. Arteriovenous cannulation is usually used, although venovenous bypass may be used in a patient only requiring ventilatory support. The most frequent cannulation sites are mediastinal, using single right atrial and ascending aortic cannulas, and in the neck, with cannulas in the internal jugular vein and carotid artery. Left atrial decompression is required in any patient in whom left ventricular ejection is inadequate and/or whose left atrium is not decompressed (i.e., via a patent foramen ovale or atrial septal defect). This can be achieved via a separate left submammary approach to the apex of the heart or right anterior thoracotomy to the left atrium if the chest is closed. The femoral and iliac vessels in infants and young children (<10 to 15 kg) cannot usually accommodate cannulas of sufficient size to permit complete circulatory support. ECMO should be instituted early before significant nonthoracic end-organ damage has occurred, and complications such as pulmonary edema and infection should be treated aggressively.

The minimal circuit volume is usually 300 to 400 mL, and the whole system consists of tubing, a reservoir, a membrane oxygenator, and heat exchanger. Before cannulation, heparin (100 to 200 units/kg) is administered intravenously with confirmation that systemic administration has occurred by measurement of the activated clotting time (ACT). The ACT is usually maintained between 180 and 200 seconds with a heparin infusion. Larger than usual doses of heparin, as well as other drugs that are lipophilic (such as fentanyl or midazolam), may be required because of binding to the circuit and oxygenator (Rosen et al., 1990 ). Perfusion flow rates range from 100 to 125 mL/kg per min for full circulatory support. An increased flow rate is required in the presence of a patent shunt, which also may need to be narrowed or occluded if systemic perfusion remains inadequate. Appropriate blood products are used to maintain the hematocrit between 35% and 45% and the platelet count greater than 100,00/mm3. Fresh-frozen plasma or cryoprecipitate may be needed to maintain adequate concentrations of clotting factors. If possible, the skin should be closed over the chest and cannulas, or a surgical membrane should be used instead. Echocardiography may be used frequently during ECMO to assess cardiac structure, global contractile function, and the need for left atrial venting or the evacuation of fluid and blood collections.

Once ECMO is established, levels of inotropic support are reduced. Ventilatory support and the FIO2 are also decreased, although infrequent lung expansion (4 to 6 breaths/min) and low levels of PEEP are used to stabilize lung volumes, prevent alveolar collapse, and limit inactivation of alveolar surfactant. Greater amounts of PEEP may be indicated in the presence of significant pulmonary disease ( Keszler et al., 1989 ). Mechanical ventilation of surfactant-deficient lungs may exacerbate lung injury ( Jobe et al., 1985 ). Exogenous surfactant administration may have a role in improving pulmonary function and facilitating weaning from ECMO in patients with lung injury ( Lewis and Jobe, 1993 ; McGowan et al., 1993 ).

ECMO has been used successfully as a bridge to cardiac transplantation, as well as a mechanism to permit recovery in instances of severe postcardiotomy myocardial failure, including acute cardiac allograft failure ( del Nido, 1994 ; Duncan, 1998) . In one study ( Delius et al., 1990 ), all (three of three) patients placed on ECMO while awaiting transplantation died. Del Nido (1996) reported on 14 children who were considered candidates for heart transplantation and were placed on ECMO as a bridge to transplantation. In this series, eight children had postcardiotomy myocardial dysfunction, three had dilated cardiomyopathy, and three had acute viral myocarditis. Five of the 14 patients were placed on ECMO during cardiopulmonary resuscitation. Nine patients underwent a heart transplant and seven patients had long-term survival. One patient with viral myocarditis recovered spontaneously. Four patients died of sepsis while on ECMO, and one late death occurred from PTLD.

Poor outcome associated with ECMO is usually due to the presence of significant coexisting disease or injury. Complications from ECMO include hemorrhage, renal dysfunction, neurologic injury, infection, dysrhythmias, and difficulties with maintaining adequate nutrition ( Kanter et al., 1987 ; Weinhaus et al., 1989 ; Delius et al., 1990 ; Pennington and Swartz, 1993 ).

ECMO may also be used to support the failing heart after transplantation. Delius and others (1990) reported on the early survival of two of three patients placed on ECMO postoperatively for acute rejection or graft dysfunction. In patients with congenital heart disease requiring postoperative ECMO support, overall survival was between 40% and 70% ( Kanter et al., 1987 ; Rogers et al., 1989 ; Weinhaus et al., 1989 ). Outcome appears to be substantially better in children who are placed on ECMO postoperatively after an initial period without circulatory support compared with those who require ECMO in the operating room to wean from CPB. This may reflect a more serious degree of irreversible cardiac injury in those patients requiring ECMO to wean from CPB. Major bleeding complications also appear to be less in this setting if the patient has some period off of CPB and before institution of ECMO. Sustained dysrhythmias are also likely to indicate severe myocardial injury and poor outcome. Left atrial decompression to reduce left ventricular end-diastolic pressure (LVEDP) and increase subendocardial perfusion may improve myocardial and pulmonary function in these patients.

ECMO is not designed for long-term use, and after a period of greater than 6 weeks, the risk of bleeding, sepsis, and end-organ dysfunction becomes prohibitive. VADs have been demonstrated in the adult population to be capable of supporting patients for many months without end-organ damage ( Farrar et al., 1994) . Both systems are not exclusive of one another and many children may be placed on ECMO in the emergent situation and converted to a VAD on an elective basis. Despite the successful use of small-size adult VADs in children ( Helman et al., 2000 ; Reinhartz et al., 2001 ), until recently, the only choice for mechanical support in neonates was ECMO. However, the development of miniature pediatric-sized VADs has permitted the use of pulsatile mechanical support in neonates and children, and the number and types of these devices that are available for long-term ventricular support of infants and children is increasing ( Hetzer et al., 1998 ; Schindler, 2003) . In an outcome study following transplantation, Stiller and others (2003) noted no significant difference in short- or long-term mortality, neurologic outcome or acute rejection in those patients who had a VAD device placed compared with those who did not.

Partial Ventriculectomy

Another method that deserves mention as a bridge to transplantation is the use of partial ventriculectomy and mitral valve repair. This method has been used successfully to provide a biological rather than mechanical bridge in the period before transplantation in the child with dilated, end-stage cardiomyopathy ( Hsu et al., 2002 ).

Anesthetic Management

The anesthetic management of the pediatric heart transplant recipient requires a thorough understanding of the pathophysiology of the particular condition. One begins with an analysis of the patient's anatomy and assessment of cardiopulmonary function. It is useful to then outline the events that will improve or destabilize contractile function, pulmonary blood flow, and systemic perfusion. One can then formulate an anesthetic plan based on these variables and the predicted responses to anesthetic agents, cardiovascular drugs, and ventilatory manipulations.

Premedication

Most children coming for heart transplantation, regardless of whether they have fasted, should probably be considered to have full stomachs because of their debilitated state and poor perfusion. Therefore, the administration of nonparticulate antacids or H2 antagonists and metoclopramide may be advisable. Sedative premedication is avoided or administered cautiously in those patients with severe ventricular dysfunction. In addition to limiting anxiety, reoperative sedation can decrease PVR and myocardial oxygen demand and increase systemic saturations.

Monitoring

Standard noninvasive monitors, including a precordial stethoscope, pulse oximeter, three-lead ECG, and a noninvasive automated blood pressure monitor, are placed before induction. Arterial and central venous catheters and temperature monitors are generally placed after the induction of anesthesia and intubation of the patient's trachea. If the child has significant ventricular dysfunction, the arterial catheter may be placed using local anesthesia before induction. The avoidance of right internal jugular cannulation to preserve the vessel for subsequent endomyocardial biopsies is advocated by some. Routine pulmonary arterial catheterization before CPB has not been found to be beneficial ( Martin et al., 1989 ). In those patients in whom such monitoring may be warranted (e.g., those with a potential for increased PVR), one practice is to insert the vascular sheath after induction. A thermodilution/oximetric catheter (4 Fr or greater) can then be passed into the pulmonary artery with surgical assistance before terminating CPB.

Induction and Maintenance of Anesthesia

Agents should be selected according to their effects on heart rate, contractility, and vascular resistance (see Chapter 3 , Cardiovascular Physiology in Infants and Children, and Chapter 6 , Pharmacology). Intravenous induction agents are generally preferred. Among intravenous agents, ketamine, etomidate, and high-dose synthetic opioids have all been used in pediatric patients. Ketamine or etomidate can be combined with succinylcholine or high-dose rocuronium/vecuronium if a rapid sequence induction is required. Ketamine will effectively preserve myocardial contractility and SVR in patients with relatively normal myocardial function and adrenergic tone. In patients with severe cardiomyopathy, the ability to increase stroke volume is absent, adrenergic receptors are downregulated as a result of increased circulating catecholamines, and sympathetic tone is already maximal. Ketamine may then reduce cardiac output as a result of its direct negative inotropic effects; if ketamine administration is accompanied by increased SVR, stroke volume, particularly by the myopathic heart, may be reduced further ( Gutzke et al., 1989 ). Etomidate probably produces minimal effects on contractility and vascular resistances at standard induction doses, although Pagel and others (1998) noted in experimental animals that etomidate-induced increases in aortic impedance could potentially reduce the contractility of the failing systemic ventricle. The opioids fentanyl and sufentanil are generally well tolerated in children. A delay in the time to peak effect of fentanyl and perhaps increased sensitivity to the drug are apparent in patients with severely reduced ventricular function ( Benowitz and Meister, 1976 ; Wynands et al., 1983 ). These factors mandate slow administration and careful titration in children with congestive heart failure. Larger doses of fentanyl (25 to 75 mcg/kg) and sufentanil (5 to 10 mcg/kg) can effectively blunt increases in PVR and provide extended hemodynamic stability.

Pancuronium may be a useful muscle relaxant to offset the vagotonic and bradycardic effects of fentanyl and sufentanil. Vecuronium or rocuronium may be used in patients in whom minimal effects on heart rate and blood pressure are preferred. Severe bradycardia and even asystole have been reported from the use of vecuronium and sufentanil in combination ( Starr et al., 1986 ).

Scopolamine may be useful for providing amnesia if a narcotic technique is used. Benzodiazepines can cause significant reductions in myocardial contractility and SVR when given in combination with potent opioids ( Tomichek et al., 1983) . Barbiturates decrease SVR and myocardial contractility. They should be avoided unless ventricular function is known to be preserved.

Inhalation induction is used infrequently in this group of patients because of the hemodynamic side effects of myocardial depression and hypotension as well as the increased risk of aspiration ( Borland, 1985 ; Demas et al., 1986 ). An inhalation induction with sevoflurane and careful airway management can be a satisfactory approach for the infant with congenital heart disease and preserved ventricular function. Nitrous oxide is usually avoided in older children with cardiomyopathy or increased PVR because of potentially significant reductions in myocardial contractility and uncertain effects on PVR (Lappas et al., 1975 ; Schulte-Sasse et al., 1982 ). However, in infants, Hickey and others (1986) showed that N2O does not produce the elevations in PAP and pulmonary artery resistance seen in adults.

A right-to-left shunt will slow the rate of inhalation induction because less anesthetic is taken up from the lungs. The magnitude of slowing is less when using more soluble agents because rapid uptake of soluble agents makes alveolar delivery the rate-limiting step. For insoluble agents such as nitrous oxide and sevoflurane, right-to-left shunts slow induction appreciably (see Chapter 6 , Pharmacology). Of note, anesthetic removal rates and the ability to change anesthetic depth are similarly slowed, and thus inhaled anesthetic excess will be difficult to reverse in patients with significant right-to-left shunts. Left-to-right shunts do not affect the rate of inhaled induction in an appreciable manner ( Tanner et al., 1985 ).

In summary, the potential for circulatory collapse during induction of anesthesia and conversion to positive-pressure ventilation should be anticipated in the patient with severely compromised ventricular function or circulatory instability, regardless of the chosen anesthetic technique. In patients with relatively severe contractile dysfunction, it may be helpful to institute inotropic support before induction. Response to volume expansion, inotropic support, defibrillation, and other resuscitative measures is infrequent when it occurs in this setting in the severely compromised heart. The ability to proceed immediately to CPB should be available.

Operative Management

The surgical technique of pediatric heart transplantation is similar to that used in adults (Figs. 28-2 and 28-3 [2] [3]). Increased technical difficulty and risk of hemorrhage before bypass should be expected in children who have had previous heart surgery. Hypothermic CPB is standard. A period of deep hypothermia with circulatory arrest is often required in young infants (e.g., HLHS) and those requiring extensive aortic or other vascular reconstruction ( Mavroudis et al., 1988 ; Bailey et al., 1989 ). The usual duration of circulatory arrest is less than 1 hour; longer periods increase the risk for some degree of irreversible cerebral insult.

 
 

FIGURE 28-2  Cardiac implantation after recipient cardiectomy. The venous cannulas are shown entering the superior and inferior vena cavae with retained cuffs of the right and left atrial tissue. The pulmonary artery (PA) is transected and the aorta is cross-clamped with aortic (Ao) cannula out of the field of view. The inset details the first atrial anastomosis along the inferior margin of the left atrium (LA), showing the mitral valve of the donor heart. The aortic perfusion cannula is not shown. RA, right atrium.  (From the Handbook of Cardiac Transplantation, 1995, with permission of the American College of Cardiology Foundation.)

 

 

 

 
 

FIGURE 28-3  Anastomosis of the right atrial suture line. The upper panel shows the right atrial anastomosis following which, in the lower panel, the heart is swung over into position to complete the atrial free wall suture. The great artery anastomoses are made, after which the heart is de-aired and the cross clamp is removed. The aortic perfusion cannula is not shown. PA, pulmonary artery; Ao, aorta; RA, right atrium; LA, left atrium.  (From the Handbook of Cardiac Transplantation, 1995, with permission of the American College of Cardiology Foundation.)

 

 

 

For infants with HLHS, the pulmonary artery is cannulated as the arterial inflow site for CPB (systemic blood flow occurs via the ductus arteriosus). Complicated repairs with extensive suture lines and anastomoses may be necessary in infants with HLHS (because of aortic hypoplasia), abnormalities of the pulmonary arteries (because of pulmonary atresia, truncus arteriosus, previous banding, or Fontan procedures), or abnormalities of the superior vena cava (after a Glenn anastomosis). Such reconstruction increases the overall risk of the procedure by prolonging the duration of bypass and circulatory arrest and also increasing the severity of postbypass bleeding.

Acute right ventricular dysfunction is one of the major problems in the transplanted heart immediately after CPB. The initial approach is to minimize PVR in order to reduce right ventricular afterload. Ventilatory manipulations are initially used to reduce PVR and optimize right ventricular (and consequently, left ventricular) performance. Before termination of CPB, the endotracheal tube is suctioned and several vital capacity inflations are performed to expand atelectatic lungs. Moderate hyperventilation with 100% oxygen is then used to maximize alveolar and arterial oxygen tension and achieve a PaCO2in the range of 25 to 30 mm Hg. While no specific mode of ventilation can be universally recommended, in general the use of larger tidal volumes (e.g., >10 mL/kg) and slower respiratory rates frequently appears to provide the best balance between minute ventilation and deleterious effects on right ventricular filling and function. The use of PEEP to improve gas exchange usually does not adversely affect PVR. In addition to hyperoxia and alkalinization (via both ventilation and supplemental sodium bicarbonate), inhaled nitric oxide can be a valuable therapy in the transplant patient at risk for post-CPB pulmonary hypertension. Other maneuvers to support the failing right ventricle include ensuring adequate coronary perfusion pressure, preload, and use of inotropes and inodilators (see Chapter 17 , Anesthesia for Cardiovascular Surgery).

Usually, a modest level of inotropic support (e.g., 5 to 10 mcg/kg per min of dopamine) is sufficient, unless there has been more extensive preservation and/or reperfusion injury, RV failure, or technical problems with the graft. Typically, right and left atrial filling pressures are similar; filling pressures in the range of 10-15 cm H2O are necessary to support cardiac output. Higher values and/or significant discrepancies between right and left atrial pressures should arouse suspicions of pulmonary hypertension, right ventricular failure (increased right atrial pressure), or severe left ventricular dysfunction (increased left atrial pressure).

A situation peculiar to infant and pediatric transplantation is the occasional use of hearts from donors of relatively smaller body size than the recipient. Such “undersizing” of the donor may be associated with apparent graft insufficiency or failure, manifested as low cardiac output and systemic perfusion despite optimal or maximal filling pressures and inotropic support. Pulmonary hypertension and significant preservation injury exacerbate the hemodynamic instability. ECMO may be needed to permit a period of myocardial recovery in this setting of acute postoperative graft dysfunction.

In addition to having ischemia-reperfusion injury, the donor heart is also denervated. In the absence of sinus rhythm or if the chronotropic response to vasoactive drugs is insufficient, atrial or atrioventricular sequential pacing is often needed in the immediate postbypass period to facilitate adequate heart rate, cardiac output, and control of ventricular filling. It is unusual for pacing to be required for more than several days posttransplantation. The continued need for pacing suggests more significant damage to the organ.

Postoperative bleeding is another frequent problem. The potential causes are multiple. Extensive scarring and adhesions from previous palliative procedures are common. Pediatric patients may require some degree of aortic or pulmonary artery reconstruction at the time of transplantation, creating potentially extensive high-pressure suture lines that are not found in other heart transplantation settings. Chronic cyanosis may be associated with coagulation factor deficiencies, accelerated fibrinolysis, platelet function abnormalities, and an increased number and size of collateral vessels. Abnormalities in a variety of coagulation proteins also have been found in patients with single-ventricle physiology (Odegard, 2002, 2003 [449] [451]). Many patients receive chronic anticoagulant therapy (aspirin, warfarin [Coumadin], etc.), which cannot be discontinued in sufficient time to allow recovery of the coagulation profile before transplantation. Significant hemodynamic shear stress (e.g., aortic stenosis) can result in an acquired form of von Willebrand disease by promoting degradation of active, high molecular weight von Willebrand multimers into inactive monomers. Cardiopulmonary bypass induces bleeding in infants and small children. The causes for bleeding are multifactorial and include hemodilution of coagulation factors, higher flow rates, higher shear stress (resulting in increased activation and consumption of platelets and coagulation and fibrinolytic proteins), greater blood trauma, use of colder temperatures, and an increased systemic inflammatory response.

In general, after protamine has been given to neutralize the heparin, platelets are given and are followed by cryoprecipitate ( Miller, 1997) . Specific patients, such as those receiving warfarin preoperatively or with clinically significant preoperative coagulopathy due to hepatic dysfunction or malabsorption/protein-losing enteropathy, may also benefit from the administration of fresh frozen plasma. Use of antifibrinolytic agents such as tranexamic acid or aprotinin may also be beneficial, particularly in small infants and patients with a history of one or more prior thoracic procedures. Aprotinin may also have some beneficial effects on inflammation and reperfusion injury.

Immunosuppression in Heart Transplantation

In brief, the rejection process begins when recipient CD4 T cells recognize foreign antigen in the donor heart. Recognition leads to activation of the larger T-cell pool, with subsequent IL-2 secretion, thereby triggering activation of monocytes/macrophages, B cells, and cytotoxic CD8 cells.

Induction of immunotherapy is targeted toward the prevention of T-cell activation. This can occur by depleting the T-cell pool with monoclonal or polyclonal antibodies or by using monoclonal antibodies to prevent IL-2 secretion. OKT3 is a murine monoclonal antibody used in clinical practice. This agent binds to the CD3 molecule on the T-cell surface. This complex is closely linked to the antigenic recognition site of the T-cell receptor. Within minutes of the commencement of OKT3, the T-cell population decreases dramatically ( Delmonico and Cosimi, 1988 ). T-cells reappear within 3 to 5 days, but without the CD3 molecule. Although OKT3 was originally used in the context of acute rejection, its current use also includes induction of immunosuppression. When OKT3 is used in this fashion, the administration of cyclosporine or tacrolimus may be delayed by 5 to 7 days. This is particularly useful in the context of patients with borderline renal function where calcineurin inhibitors and their nephrotoxic properties can further compromise renal function. Other side effects of OKT3 include chills, fever, diarrhea, dyspnea, and wheezing. Pulmonary edema and cardiac arrest have also been reported ( Thistlethwaite et al., 1988 ).

ATG and ALG are polyclonal antibodies prepared from thymocytes and lymphoblasts, respectively. They are both IgG antibodies, and while the precise mechanism of action has yet to be elucidated, their administration causes profound lymphocytolysis. Side effects include chills, febrile reactions, erythema, and pruritus. Thrombocytopenia occurs in over 50% of patients, and serum sickness and Steven Johnson syndrome have also occurred secondary to ATG or ALG therapy.

Basiliximab and daclizumab are both monoclonal antibodies to the alpha chain of the IL-2 receptor. The receptor has three noncovalently bound chains. The alpha chain is specific for IL-2 and once activated by IL-2, the T cell begins its rejection amplification cascade ( Kovalik et al., 1999) . The binding of these monoclonal antibodies effectively and rapidly prevents activation of the cascade. Furthermore, the alpha chain is not present in inactivated T cells, and thus only activated T cells are targeted ( Denton et al., 1999 ). There is some concern that these agents may be associated with an increased incidence of superimposed infections such as CMV and possibly the development of PTLD.

Maintenance of Immunosuppression

Three classes of drugs are available for maintenance immunosuppression. Corticosteroids are nonspecific anti-inflammatory agents. Their effects are numerous and include inhibiting cytokine and cell surface molecule gene transcription in monocytes, inhibiting phospholipase A2 enzyme activity and thus reducing the inflammatory cell activation, signaling, and inflammatory molecule production. Steroids also inhibit the nuclear transcription factor NF-κB, thus reducing IL-2 gene transcription and the production of several other proinflammatory cytokines and signaling and recognition molecules (Auphan et al., 1995 ).

Antiproliferative agents prevent the expansion of activated T-cell and B-cell clones. The original agent used for this purpose, azathioprine, is being replaced by newer agents such as mycophenolate mofetil (MMF) and sirolimus (rapamycin). The toxic effects of azathioprine include bone marrow depression leading to marked leukopenia, possible liver damage, and the development of pancreatitis.

MMF is a selective inhibitor of the de novo pathway of purine biosynthesis, thus inhibiting cell proliferation. It is administered as a morpholinoethylester prodrug of mycophenolic acid, which is metabolized to the active compound. Its mechanism of action is the result of reversible noncompetitive inhibition of inosine-monophosphate-dehydrogenase activity (IMDPH). It thereby targets proliferating lymphocytes, which are dependent on the availability of guanine nucleotides, which are no longer generated ( Allison et al., 1993 ; Brazelton et al., 1996 ; Shaw et al., 1999 ). Side effects of MMF include nausea and vomiting; but it lacks significant bone marrow and renal toxicity. There is a concern, however, about the possible development of invasive CMV infection during the use of MMF.

Rapamycin (sirolimus) is a newer antiproliferative agent that, despite binding to FK506-binding protein 12, confers its action by inhibiting cellular proliferation without inhibiting calcineurin. Side effects appear to be dose-dependent elevation of triglyceride levels and dose-dependent bone marrow suppression.

Calcineurin Inhibitors.

Calne's first published use of cyclosporine as an immunosuppressive agent was in 1979, and it continues to be one of the primary drugs used for the prevention of rejection in many transplant programs (Calne et al., 1979) . The mechanism of action of cyclosporine involves binding to cyclophilin in the T-cell cytosol. This cyclosporine/cyclophilin complex then binds to calcineurin and prevents calcineurin from promoting transcription of the IL-2 gene, thus preventing further IL-2 production ( Liu et al., 1991 ; Flanagan et al., 1991 ; Schreiber et al., 1992 ; Schreier et al., 1993 ). The most significant side effect of cyclosporine therapy is nephrotoxicity; other significant side effects include liver dysfunction, hypertension, hyperlipidemia, and PTLD.

Tacrolimus (FK506) is a macrolide that also acts as a calcineurin inhibitor. It forms a complex with an immunophilin, FK-binding protein, and this complex subsequently binds to calcineurin to prevent IL-2 gene transcription ( Sigal et al., 1992 ; Liu et al., 1991 ). Side effects include nephrotoxicity, glucose intolerance, and an increased incidence of PTLD.

Calcineurin inhibitors, antimetabolites, and corticosteroids are the mainstays of antirejection therapies. While the use of cyclosporine still predominates, tacrolimus use is increasing. The nephrotoxicity of both drugs is significant. Use of azathioprine appears to be decreasing in favor of MMF or sirolimus. The use of sirolimus will increase further if suggestions of reduced transplant vasculopathy associated with its use are confirmed ( Mancini et al., 2003 ). The use of steroids remains at fairly constant levels, but increased acceptance of the newer agents is likely to lead to more rapid weaning and lower dosing of corticosteroids and thereby limit the side effects of growth retardation, hypertension, and glucose intolerance.

Data from the International Society for Heart and Lung Transplantation suggest that fewer than 40% of children receive induction immunotherapy. The most common induction therapy includes either ATG or ALG followed by a specific IL-2 receptor antagonist. A small proportion of children also receive OKT3. There are as yet no randomized multicenter studies to determine the benefits of induction therapy, but one retrospective multicenter's study determined that children given polyclonal ATG had lower mortality than those given no induction agent or OKT3 ( Boucek et al., 1999 ). In general, the use of induction therapy allows the initiation of calcineurin inhibitors to be delayed for a few days postoperatively, which may be most beneficial in those patients with some degree of renal dysfunction.

Complications

Complications following heart transplantation can be divided into those associated with rejection and those arising from other causes. Acute rejection generally occurs in the first year posttransplantation and is the most frequent cause of death during this time period. Late-onset acute rejection also occurs in a significant number of children beyond the first posttransplant year. Acute rejection remains a source of morbidity and correlates with the ongoing need for immunosuppression. Although risk factors for acute rejection have been sought, results have been conflicting ( Kirklin et al., 1992 ; Chartrand et al., 2001 ; Webber, 2003 ). Overall, it would appear that an older age at the time of transplantation increases the risk of acute rejection and that an episode of acute rejection in the first year increases the risk of subsequent episodes ( Webber et al., 2003) .

Clinical detection of rejection remains difficult, as signs and symptoms are subtle and nonspecific; these include general malaise, fever, change in activity or appetite, tachycardia, and conduction or voltage changes on the surface ECG. More severe bouts may be accompanied by symptomatic reductions in graft function. Other relatively noninvasive tests, such as various myocardial or inflammatory markers in blood, echocardiography, and cardiac magnetic resonance imaging, continue to be investigated, but none of the tests have shown the necessary sensitivity and specificity. As a result, endomyocardial biopsy remains the gold standard for diagnosis of rejection ( Boucek, 2000 ; Wagner et al., 2000 ). It is performed at scheduled intervals as a surveillance tool, to guide immunosuppression regimens and dosing, and to diagnose acute rejection episodes.

Chronic rejection and associated posttransplantation coronary artery disease are the leading causes of death among late survivors of heart transplantation. According to data from the International Society for Heart and Lung Transplantation, approximately 20% of all pediatric transplant patients have some degree of posttransplantation coronary artery disease at 5 years posttransplantation. This accelerated vasculopathy can affect infants, children, and adults alike. The mortality following diagnosis is substantial. The histologic appearance is that of concentric myointimal proliferation that ultimately results in luminal occlusion. In addition to repeated bouts of rejection, CMV infection is likely to be a contributing risk factor. Efforts have been made to more aggressively control other etiologic factors present in these patients that can contribute to the development of atherosclerosis, such as hypertension, hyperlipidemia, and glucose intolerance. At present, the effects of these efforts are uncertain.

As the transplanted heart is denervated, chest pain caused by myocardial ischemia is a rare presenting complaint; progressive deterioration in graft function, heart failure, or sudden death are the primary presentations for rejection. For this reason, transplant recipients are routinely screened (usually on a yearly basis) for this development. Although coronary angiography was long thought to be the most sensitive means of detecting the development of graft vasculopathy, it underestimates the presence of early or mild disease. As a result, many centers have begun to use dobutamine stress echocardiography as the primary means of screening for coronary artery disease in transplant recipients. Intracoronary ultrasound may also be useful ( Dent et al., 2000 ; Pahl et al., 1999 ; Costello et al., 2003 ).

Treatment of posttransplant coronary artery disease is palliative coronary artery stenting (which is of limited benefit given the diffuse nature and involvement of distal vessels) or retransplantation. Rapamycin, which appears to slow the progression of transplant vasculopathy, has shown some benefit, either as an additional immunosuppressive treatment or in the form of rapamycin-coated coronary stents ( Mancini et al., 2003 ; Morice et al., 2002 ). Retransplantation for graft vasculopathy and resulting graft failure is associated with greater risk and diminished success.

Infection following heart transplantation is usually caused by bacterial pathogens that do not cause disease in the immunocompetent host. Immunosuppression makes the severity of infection much worse, and even with early aggressive therapy, such infections are a significant cause of morbidity and mortality in the transplant patient. In addition to bacterial pathogens, other opportunistic pathogens such as fungi and viruses (CMV, Ebstein-Barr, and adenovirus), cause significant morbidity. Infection with Ebstein-Barr virus has been associated with the development of PTLD ( Webber et al., 2003) . This may be treated initially with reduction in immunosuppressive therapy and, failing this, with chemotherapeutic agents. Other complications in heart transplant patients are mostly secondary to immunosuppressive regimens and include diabetes, growth retardation, hypertension, and renal dysfunction.

Outcome After Pediatric Heart Transplantation

Data from the International Society for Heart and Lung Transplantation show the actuarial 10-year survival for all pediatric heart recipients exceeds 50% ( Boucek et al., 2002 ). The mortality rate is higher in infants in the first year of life but is followed by a slightly lower mortality rate of less than 2% per year in the 4- to 10-year period. If one excludes first-year mortality, the conditional actuarial survival in infants exceeds 80%. Adolescents have a slightly higher average mortality of 4% per year. In comparing the actuarial survival in the first 4 years posttransplant by era, significant progress has occurred. During the period 1982 through 1987, the actuarial 4-year survival was just below 60%, whereas in the current era (1998 through 2001), the 4-year actuarial survival approaches 80%.

The greatest risk factor for first-year mortality was the diagnosis of congenital heart disease. Other risk factors for poor first-year outcome included ventilatory support before transplantation, hospitalization before transplantation, and the need for retransplantation. Recipient age was also found to be a risk factor. Those patients younger than 6 years and older than 12 years were at increased risk.

Recipient factors not associated with increased risk during the first year include the need for inotropic support, use of prostaglandin, use of ECMO, prior sternotomy, height, the need for dialysis, recent infection, or a history of malignancy. Although age did affect first-year mortality risk, weight as an independent factor posed no additional risk.

Overall, the leading cause of death in transplant recipients under the age of 3 is acute rejection, and over 3 years of age is coronary artery vasculopathy ( Boucek et al., 2002 ). Among survivors, over 95% of patients report no limitation of activity at the 5-year follow-up. However, with formal exercise testing, as many as 50% may have mild to moderate limitations in exercise and aerobic capacity. In the absence of rejection, in general myocardial and somatic growth are normal in most pediatric transplant recipients ( de Broux et al., 2001 ).

▪ LUNG TRANSPLANTATION

Demographics and Indications

At present, more than 1200 pediatric lung transplantations have been performed ( Boucek, 2002) . As with pediatric heart transplantation, available data suggest that the annual number of pediatric lung transplants conducted since the late 1980s has decreased, since a peak in the late 1990s. Waiting times have increased overall; adolescents may wait as long as 1 or 2 years for cadaveric lungs (average waiting time, 20 months), while younger children aged 1 to 10 years wait an average of approximately 6 to 12 months. Organ donation and viability continue to be major limitations ( Sweet, 2003 ; Burch and Aurora, 2004 ).

Early pediatric transplantation efforts emerged directly from adult experience, and the majority of the recipients were older children with cystic fibrosis (CF), primary pulmonary hypertension, secondary pulmonary hypertension (e.g., from congenital heart disease), and pulmonary fibrosis. With increasing experience and the development of pediatric lung transplant centers, transplantation in infants and younger children has grown, and children younger than 2 to 3 years may now comprise 10% to 20% of lung transplant recipients. In infants and young children, the most common diagnoses include interstitial lung disease, primary pulmonary hypertension, severe pulmonary vein obstruction, and alveolar proteinoses.

Contraindications

Absolute contraindications to pediatric lung transplantation include hepatitis B or C virus infection, HIV infection, active malignancy within the past 1 to 2 years, and irreversible neurologic or neuromuscular disorders. Significant liver, heart, or renal dysfunction (requiring dialysis) is also an absolute contraindication; lung-liver or heart-lung transplantation may be considered with the first two of these conditions. Some issues such as prior thoracotomies or pleurodeses, steroid dependence, or colonization with a variety of organisms (especially in patients with CF) are no longer absolute contraindications in many centers. Relative contraindications can include significant musculoskeletal disease, invasive ventilation (which has been linked to increased risk in older patients, potentially less so in infants and young children), colonization with various fungi or atypical mycobacteria, poor nutritional status (<70% or >130% of ideal body weight), and an inability to wean from or significantly reduce dependency on systemic corticosteroids. As with heart transplantation, significant psychological and behavioral disturbances in the potential recipient, or social and familial circumstances that could hinder access to care and/or compliance with complex medical regimens, may also preclude transplantation.

Organ Preservation

Achieving successful lung preservation continues to be a difficult problem. Lung ischemic time is a major factor in the development of posttransplant lung injury. The optimal duration of preservation is between 3 and 4 hours, although lungs with ischemic times as long as 9 hours have been implanted successfully ( Kaiser et al., 1991 ). During organ harvest, the lungs and pericardium are exposed and a prostaglandin infusion is begun. Prostaglandin is believed to cause pulmonary dilation and thereby improves the distribution of preservation solution. The vena cavae are then transected, the left atrial appendage is incised, and then the aorta is cross-clamped. This harvesting sequence prevents any left atrial hypertension, and thus reduces the risk of pulmonary edema. A cold crystalloid preservation solution (Euro-Collins) with a high potassium concentration is infused into the pulmonary artery while cardioplegia is administered into the aortic root. Ventilation is discontinued and the lungs are allowed to deflate. For single- or sequential double-lung transplantation, the left atrium is divided such that a cuff of atrial tissue surrounds the right and left pulmonary veins. The pulmonary veins may be excised in a single atrial cuff for double-lung transplantation. If both the heart and lung(s) are to be used (but in different recipients), adequate segments of the left atrium and pulmonary artery must be allocated to each ( Griffith and Zenati, 1990 ). During transportation, the lungs are generally kept deflated, although there is some experimental evidence that intermittent inflation prolongs the allowable ischemic time (Toledo-Pereyra, 1977) . In addition, some centers believe that donor cooling with CPB also extends the permissible ischemic time ( Heritier et al., 1992 ).

Single-Lung Transplantation

Single-lung transplantation is performed infrequently in pediatric patients. One general reason is that the ability of the transplanted lung to grow remains uncertain. Most practitioners believe it is wise to implant as much “normal” lung tissue as possible to meet the demands of future somatic growth in children. Second, the most frequent indication for pediatric lung transplantation is CF, and there is great concern about the transplanted lung being contaminated by the chronically infected native lung.

When a single-lung transplant is performed, the most important decision is the determination of laterality, usually determined by chest radiograph, chest computed tomography, and/or scans. The side that appears to have the less affected lung and/or that has better ventilation/perfusion scan is kept; the opposite side is transplanted. If possible, implantation is done on the side opposite to any previous thoracotomy. Typically, a more emphysematous lung is removed (or volume reduced) so as not to compress the allograft on the opposite side. A more fibrotic lung might remain, so as to favor ventilation and blood flow distribution to the transplanted lung.

Omentum may be fashioned to provide a “vascular cuff” around the bronchial anastomosis in order to improve bronchial blood supply. In such cases, a midline laparotomy is performed first, in order to mobilize omentum with an attached pedicle. This is tunneled through the diaphragm and the incision is closed ( Fig. 28-4 ). Single-lung ventilation is then instituted (see later). A thoracotomy is performed, and the pulmonary artery, pulmonary veins, and mainstem bronchus are exposed. The pulmonary artery is then test-occluded while gas exchange, PAP, and hemodynamic status are observed. The lung is removed if the patient tolerates this procedure. Allograft implantation involves connecting the donor atrial flap containing the pulmonary vein orifices to an area of recipient left atrial tissue that is isolated within a clamp. The pulmonary artery anastomosis is completed. The technique of telescoping bronchial anastomosis is used more frequently ( Calhoon et al., 1991 ). To perform this, the smaller of the two bronchial ends is placed inside the other one to a depth of one cartilaginous ring, and then the connection is oversewn. This method provides sufficient blood flow for high-quality bronchial healing and precludes the need for an omental cuff. The lung is then gently inflated. Air within the vascular spaces is removed either via the pulmonary artery (with the left atrium partially occluded, the proximal end of the pulmonary artery clamped, and its distal end vented) or via the left atrial cuff (with the pulmonary artery unclamped and the left atrial cuff vented). Pulmonary blood flow and ventilation are then established simultaneously.

 
 

FIGURE 28-4  The bronchial anastomosis is first completed, followed by the vascular anastomoses. The vessel is reconstructed from posterior to anterior with the suture untied, allowing for de-airing through the anastomosis later.  (From Kirby TJ, Birnbaum PL: Technique of single-lung transplantation. In Patterson GA and Couraud L (eds): Current topics is general thoracic surgery, Vol. 3, Lung Transplantation, Amsterdam, 1995, Elsevier Science B.V.)

 



Double-Lung Transplantation

Double-lung transplantation is the type of lung transplant operation performed most frequently in pediatric patients. The technique most often used involves sequentially implanting each lung. This method has several advantages compared with en bloc implantation, which was done previously by some ( Pasque et al., 1990 ; Kaiser et al., 1991 ). The lungs are harvested individually, each with a separate pulmonary artery, mainstem bronchus, and two pulmonary veins encompassed within a cuff of the donor's left atrium. A bilateral anterior thoracosternotomy is performed extending across the midline by transverse sternotomy. This approach (“clamshell” incision) allows the anterior thoracic cage to be swiveled upward, providing full access to the bilateral hilar structures ( Fig. 28-5 ). Each set of pulmonary arteries and mainstem bronchi are anastomosed end to end, and each left atrial cuff is anastomosed to the recipient's left atrium. CPB is almost always used in pediatric patients, although it is possible to perform bilateral sequential lung transplantation without CPB. Omental flaps may be mobilized for each bronchial connection, although most current techniques use telescoping bronchial anastomoses ( de Hoyos and Mauer, 1992) . Both methods appear to result in improved healing of the airway connections, compared with tracheal anastomoses (as are used with the en bloc method). This is presumably due to enhanced blood flow ( Pinsker et al., 1979 ).

 
 

FIGURE 28-5  Clam shell position with the arms at 90 degrees.

 

 

Living Donor Lung Transplantation

The shortage of donor organs has led to the development of living donor lobar lung transplantation, which requires that two separate donors each undergo lobectomies to provide right and left lower lobes. Outcomes of living donor lung transplants have been comparable to cadaveric lung transplants ( Starnes, 1999) . The technique of living related lung transplants also overcomes some of the inherent difficulties of attempting to predict the clinical course of various types of lung disease and the appropriate timing for listing the patient for transplantation. Size limitations can be problematic: adult lobes are usually too large for children under 5 years, and, conversely, the amount of lung tissue may be insufficient for well-grown adolescents. The various anastomoses, particularly those of the pulmonary veins, can be technically difficult and prone to stenosis. The operation obviously poses more than minimal risk to the donors, and truly informed consent may be difficult to determine in such an emotionally difficult situation. The ethical issues are therefore complex, and this procedure is infrequently performed.

▪ HEART-LUNG TRANSPLANTATION

Because of early problems with the integrity of bronchial anastomoses, many patients with terminal lung disease received heart-lung transplants, with the possibility of their (normal) heart going to a heart transplant recipient in a “domino” procedure. Since the development of techniques to promote healing of bronchial anastomoses, the frequency of heart-lung transplantation has decreased substantially. At present, in pediatric patients it is only considered for patients with pulmonary hypertension or other end-stage lung disease when there is also congenital heart disease that cannot be repaired and in patients with end-stage lung disease and severe left ventricular or right ventricular dysfunction. Pulmonary hypertension with right heart dysfunction is no longer considered an indication, unless the right ventricular dysfunction is severe, as it often improves after successful lung transplantation.

Anesthetic Management

It should be noted that these patients are often critically ill by the time they come for lung transplantation. This is due to several factors, including the nature of the underlying disease, and reticence on the part of both physicians and patients/families to undergo such a procedure, as well as the long waiting time required for cadaveric organs. For example, the clinical course of CF is very unpredictable. Most centers initiate the transplantation process when a CF patient's FEV1 falls below 30% to 40% of predicted value; however, most centers would not actually transplant patients at this point if the patient thinks that his or her quality of life is acceptable (Yankaskas, 2002). Thus, the CF patient is likely to be quite compromised (pulmonary, nutrition, etc.) by the time of actual transplantation. In children with pulmonary hypertension, survival has been inversely related to right atrial and pulmonary artery pressures, as well as to the product of right atrial pressure and PVR ( Clabby, 1997) . However, it is likely that prostacyclin therapy (and perhaps newer agents such as endothelin receptor antagonists) will improve survival and prevent or at least delay the need for lung transplantation in some children with pulmonary hypertension ( McLaughlin, 2002 ).

Patients with end-stage COPD or restrictive lung disease are often hypoxic and hypercarbic and may be dependent on supplemental oxygen. Their ventilatory effort is at least partially sustained by increased circulating catecholamine concentrations. Sedation can reduce ventilatory drive and cause hypotension and is best avoided. If necessary, small increments of midazolam may be titrated until the desired effect is achieved. Although sedative medication may be useful as an adjunct to control pulmonary vascular responses during induction, this should only be given in the immediate preoperative period with full monitoring in situ. If undertaken, small increments of midazolam are administered until the desired effect is achieved.

The preoperative assessment of the patients is focused on the cardiopulmonary status as well as dysfunction in other organ systems. The CF patient undergoing lung transplantation is usually already on maximal medical therapy. This may include oral or inhaled bronchodilators, supplemental oxygen, nebulized antibiotics, N-acetylcysteine or DNase, and chest physiotherapy. These are continued through the time of surgery. It is important to have recent information about right ventricular function and PAP (both usually with echocardiography). Baseline liver and renal function, as well as coagulation status (potentially compromised by malabsorption), should also be determined.

Monitoring and Vascular Access

Noninvasive monitoring is instituted before induction. An arterial catheter may also be inserted under local anesthesia before induction. However, this is usually performed following induction in young children. Although cannulation of the central venous circulation may be difficult in the patient with severe obstruction or fibrosis, due to the large negative intrathoracic pressures generated during spontaneous ventilation, it is usually possible before induction. Pulmonary artery catheterization before pneumonectomy is essential if assessing the response to pulmonary arterial cross-clamping is required (i.e., single-lung transplantation or bilateral sequential transplantation without cardiopulmonary bypass). The catheter may either be floated into the appropriate artery using transesophageal echocardiography (TEE) guidance, or the surgeon may place the tip by palpation. It is essential to withdraw the catheter tip into the main pulmonary artery before pneumonectomy in patients undergoing bilateral lung transplantation. If present, TEE may be used to visualize the effects of pulmonary artery occlusion and mechanical ventilation on ventricular function ( Triantafillou and Heerdt, 1991 ). TEE can also provide valuable information about ventricular function and volume status after transplantation.

Intraoperative and postoperative bleeding can be significant. This may be exacerbated by extensive adhesions, especially in patients with long-standing lung inflammation (e.g., CF) or those who have undergone prior thoracic surgery. Thus, it is important to have large-bore vascular access to facilitate rapid volume resuscitation. Often, the use of a rapid infusion device is quite helpful. Almost all pediatric lung transplantations are performed with the patient supine and the patient's arms raised over the head and flexed at the elbows (see Fig. 28-5 ). This position may occlude catheters placed in the antecubital fossae, and thus other sites are recommended. Epidural catheters can provide excellent postoperative analgesia and facilitate ventilatory effort and pulmonary toilet. Although the use of both lumbar or thoracic approaches are adequate, the decision to place the catheter while the child is awake or after induction remains unresolved. In addition, the placement of an epidural catheter for a child who is to undergo lung transplantation using CPB is also contentious. An alternative approach is to place the epidural catheter on the first or second postoperative day, before extubation, when the coagulation status has normalized.

Induction and Maintenance of Anesthesia

A child who is to undergo lung transplantation has precarious physiology and minimal reserve and is usually frightened and thus has elevated levels of circulating endogenous catecholamines. Thus it is important that the anesthetic induction have minimal effects on the pulmonary and cardiovascular systems. Myocardial depression and increased pulmonary vascular tone should be avoided, whereas bronchodilation and pulmonary vascular dilation are desirable. Etomidate, ketamine, propofol, and thiopental have all been used successfully for intravenous induction ( Triantafillou and Heerdt, 1991 ). However, should a rapid sequence induction be required, etomidate may provide the best overall combination of hemodynamic stability and rapid airway control. Ketamine is useful in those patients prone to airway reactivity. The effect of ketamine on PVR is controversial; it probably does not increase PVR if hypoxia and hypercarbia are avoided ( Hickey et al., 1985 ). Ketamine does, however, have some direct negative inotropic effects, and it should be avoided in patients with severe pulmonary hypertension or significant right ventricular dysfunction.

Potent synthetic opioids such as fentanyl are frequently used for both induction and maintenance of anesthesia. In addition to providing relative hemodynamic stability, opioids are effective in attenuating sympathetic stimulation in those patients prone to pulmonary hypertensive crises. In order to avoid the chest wall rigidity (and limitation to ventilation) that may occur with these agents, it is usually preferable to perform an intravenous induction with etomidate, establish neuromuscular blockade, and then titrate the opioids to achieve the desired effect. Although the vagolytic effects of pancuronium may be useful in conjunction with synthetic opioid administration, vecuronium or rocuronium also may be used.

There is some evidence that nitrous oxide may increase PVR and impair hypoxic pulmonary vasoconstriction ( Sykes et al., 1977 ; Schulte-Sasse et al., 1982 ), and thus it is probably best avoided. Inhaled anesthetics are usually used in moderate concentrations as anesthetic adjuncts and to provide amnesia; bronchodilation and perhaps some degree of pulmonary vasodilation secondary to abolishment of pulmonary vascular vasoconstriction may be other benefits. All volatile anesthetics are likely to impair hypoxic pulmonary vasoconstriction to some degree, which may be a particular problem if single-lung ventilation is used and also in patients with significant lung disease,    /   mismatch, and/or intrapulmonary shunting ( Benumof, 1985 ).

A standard single-lumen endotracheal tube of an appropriate size is used for lung transplantation with CPB. An appropriate double-lumen endotracheal tube is inserted after induction for single-lung transplantation or bilateral sequential transplantation without CPB. It is placed to provide differential lung isolation, and its position may be confirmed by flexible bronchoscopic examination ( Benumof, 1985 ). At all times, the possibility of tube obstruction due to inspirated secretions and blood clots must be kept in mind. If a double-lumen endotracheal tube is used, it is exchanged for a standard endotracheal tube at the completion of the procedure.

Usually the initial inspiratory oxygen concentration is set at 100%. This can then be adjusted according to pulse oximetry and blood gases. Ventilatory parameters are set according to the pathophysiology of the disease involved. The patient with restrictive lung disease is best ventilated with higher rates and lower-than-normal tidal volumes to minimize peak airway pressures, whereas the patient with obstructive lung disease may benefit from longer expiratory times to allow complete expiration and to prevent “stacking” of breaths. In some situations it may be necessary to manually ventilate the patient in order to establish the optimal ventilatory pattern. The addition of PEEP may improve gas exchange. It should be remembered that excessive PEEP may compromise the patient's cardiovascular status. Volume resuscitation and inotropic support may be necessary to counter the negative hemodynamic effects of PEEP. In patients with CF, frequent suctioning of the endotracheal tube should be performed to keep it clear of copious and tenacious secretions.

Intraoperative Concerns

The group of patients undergoing lung transplantation have, by definition, severely compromised cardiorespiratory function. If the intention is to conduct either a single-lung or sequential bilateral lung transplantation without using CPB, there needs to be constant reassessment of the patient's underlying cardiorespiratory status, because single-lung ventilation frequently leads to unacceptable levels of CO2and cardiac instability ( Triantafillou and Heerd, 1991) . If at any point the situation becomes untenable, the patient is placed on CPB in order to complete the procedure.

There are two events that must be critically evaluated. First, with the onset of single-lung ventilation, an immediate increase in airways resistance occurs in all patients. In those patients with restrictive lung disease, these changes are more pronounced. High airway pressure will both inhibit venous return and reduce pulmonary blood flow. The initial respiratory management is an adjustment of the ventilatory setting and the possible addition of inotropic agents to augment support for right ventricular function. If gas exchange and hemodynamic status are not improved, then it is important to reinstitute two-lung ventilation while plans for CPB are instituted.

The second intervention that needs to be evaluated is when the pulmonary artery is occluded during single-lung ventilation. Occlusion of the pulmonary artery during one-lung ventilation leads to an improvement in gas exchange. This occurs because the shunt passing through the collapsed lung is removed and the    /   matching in the perfused lung is improved by minimizing physiologic dead space. However, PAP is increased, with a concomitant increase in afterload. This increased afterload is best treated with pulmonary vasodilation using agents such as prostaglandin, milrinone, or nitric oxide. Maintaining coronary perfusion of the hypertensive right ventricle is essential to preserving its function. Thus, adequate preload and inotropic support (alone or in combination with α-adrenergic agonists) may also be necessary. If right ventricular failure cannot be managed with preload and inotropic support, then the pulmonary artery should be unclamped and CPB instituted.

Double sequential lung transplantation performed on CPB does not have these physiologic difficulties. The lungs are reperfused individually as soon as the anastomoses are complete. Following the implantation of the first lung, there is often a “honeymoon” period of excellent gas exchange. However, this may be short-lived. Gas exchange may worsen due to factors that include reperfusion injury, pulmonary edema, and reduced compliance. Pulmonary hypertension may also occur due to hyperinflation in an open thoracic cavity. These two problems can usually be resolved with ventilatory adjustment and the use of moderate levels of PEEP. Inotropic support is frequently required. Blood products, including platelets and clotting factors, may be required (occasionally in quite substantial amounts) to correct for ongoing bleeding at surgical sites, adhesions as a result of CPB, and/or preexisting coagulation abnormalities. Use of antifibrinolytic agents, particularly aprotinin, may have beneficial effects with regard to the inflammatory response and the reperfusion injury.

Patients with “septic lungs” (e.g., CF patients) can occasionally develop sepsis or a syndrome resembling septic shock, probably from bacteremia and/or release of inflammatory mediators during removal of their native lungs, in the early postbypass period. The outcome is frequently poor, despite intensive therapy with inotropes, antibiotics, etc.

Early Postoperative Complications

Acute Graft Dysfunction

Acute dysfunction of the transplanted lung immediately after implantation or over the ensuing several hours continues to be a significant problem, occurring in up to 30% to 40% of recipients. The primary mechanism is believed to be related to ischemia-reperfusion injury, and in fact its appearance and severity are generally associated with a longer duration of ischemia. The contribution of other factors, such as duration of donor support and occult lung injury (e.g., trauma, infection, multiple transfusions), or recipient factors, such as chronic infection/colonization or use of CPB, is unclear. Acute graft dysfunction typically resembles an acute respiratory distress syndrome or noncardiogenic pulmonary edema, with key features that include markedly decreased lung compliance and impaired gas exchange (especially oxygenation).

The primary treatment is preventive, aiming to keep lung ischemic times less than 5 to 6 hours whenever possible. The other major focus is mechanical ventilation, with appropriate use of airway pressures and PEEP. In general, ventilatory parameters should be adjusted to maintain normocarbia or mild hypocarbia with adequate but not excessive lung expansion. Peak and mean airway pressures are kept at the minimum required to maintain gas exchange while protecting the bronchial anastomoses and limiting the possibility of volutrauma. Inspired oxygen concentration is kept as low as practical such that PaO2 is below 120 mm Hg in order to limit oxygen toxicity and reperfusion injury. In the case of single-lung transplantation, the two differing cardiorespiratory requirements make hypoxia due to    /   mismatching more likely ( Triantafillou and Heerd, 1991) . It may, on occasion, be necessary to use differential lung ventilation in order to address the ventilatory requirements of the two lungs independently ( Smiley et al., 1991 ; Todd, 1990 ). Fluid and blood product administrations are limited as much as possible. Inhaled nitric oxide may be beneficial in some circumstances to improve the matching of ventilation to perfusion and to reduce PVR. ECMO has been used successfully in some cases of acute graft failure ( Meyers et al., 2000 ).

Infection

Infection is a significant problem in the immediate postoperative period. There are multiple risk factors. In addition to extensive surgical sites and invasive catheters, the patient is often nutritionally compromised and has begun receiving high-potency immunosuppressive agents. The transplanted lung is denervated. The cough reflex is therefore lost below the level of the anastomosis. Airway ciliary function is also likely to be severely impaired in the posttransplant period. It is essential that chest physiotherapy and tracheobronchial suction be performed routinely to prevent accumulation of blood and secretions, which can obstruct the endotracheal tube or airways and contribute to infection. Bronchoscopy may be necessary at times to clear the airway of the debris. An absence of lymphatic drainage from the donor lung(s) contributes to the tendency to accumulate lung water and develop infection and acute graft dysfunction ( Montefusco and Veith, 1986 ; Todd, 1990 ).

Use of prophylactic antibiotics is routine and is guided by the donor's and recipient's colonization status and by subsequent surveillance cultures in the recipient. Ganciclovir (for CMV) and antifungal agents are given when these pathogens exist in either donor or recipient. Infection with parainfluenza, adenovirus, and herpesvirus can be life threatening in pediatric lung transplant recipients ( Bridges, 1996) .

Postoperative hemorrhage is one of the most frequent major complications, with the surgical anastomoses and adhesions within the chest being the most common sites. A high degree of suspicion must be maintained to quickly diagnose anastomotic obstruction or ischemia (bronchial anastomoses). Echocardiography and nuclear medicine perfusion scans can be effective in detecting obstruction of the pulmonary arterial or venous connections (the latter may be a particular problem in lobar transplantation, and in either setting can be heralded by copious amounts of pink, frothy secretions after reperfusion). The bronchial anastomoses are usually inspected toward the end of the procedure using flexible bronchoscopy. Airway necrosis and dehiscence are frequently fatal. Increasing scarring and stenosis can also occur. Therefore, regular fiberoptic bronchoscopy is also conducted after surgery to screen for these problems ( Todd et al., 1990 ; de Hoyos et al., 1992) .

Rarely, recurrent laryngeal or phrenic nerve damage can become apparent in the postoperative period, most likely as a consequence of the surgical procedure. These are often transient, although permanent vocal cord or hemidiaphragmatic paralysis can occur; the latter may require plication of the diaphragm.

Later Complications

Although the principal cause of death during the first 30 days after transplantation is graft failure, infection in the setting of sustained immunosuppression is a leading cause of death in the first year; it continues to be a significant cause of mortality after that period ( Boucek, 2002) . Symptoms of infection in the transplant patient are often difficult to distinguish from those of rejection. Both can present with fever, dyspnea, decreased oxygenation, and pulmonary infiltrates. Definitive diagnosis for most entities requires bronchial lavage and culture; some patients may need a lung biopsy to rule out infection or rejection. Prevention of infection is a primary goal in the management of lung transplant recipients.

Cytomegalovirus (CMV) is one of the most frequent causes of infection in the transplant patient, especially in the CMV-negative recipients who have received organs from CMV-positive recipients. CMV infection may be asymptomatic or symptomatic and may cause pneumonitis (where it is associated with fever, respiratory distress, decreased pulmonary function, hypoxemia, and patchy interstitial infiltrates), gastrointestinal disease (abdominal pain, fevers, and increased liver function enzymes), or viremia. It may also present a sepsis-like picture that can progress to multiple organ failure. CMV infection has been associated with acute cellular rejection and also an increased frequency and severity of chronic rejection ( Duncan et al., 1992 ). Aggressive treatment with antiviral agents, with possible reduction in immunosuppressive therapy, is usually successful. Diagnosis is usually based on positive antibody staining in lung tissue specimens, although newer assays that detect antigenemia may allow for earlier and less invasive diagnosis ( Kusne, 1999) . The use of ganciclovir has decreased the incidence and severity of CMV-related disease in these patients. Prophylactic treatment is usually used in patients where either the donor or recipient is CMV positive.

Overall, patients are constantly at risk for bacterial lung infection. Patients with CF are more susceptible to bacterial infection with agents such as Pseudomonas aeruginosa or fungal organisms such asAspergillus. These infectious agents should be actively sought (using bronchoalveolar lavage and transbronchial lung biopsy), especially in patients who do not respond to empiric therapy. Infection with Ebstein-Barr virus is of note because of its association with malignancy (see later).

Another significant and often insidious complication is the development of airway obstruction due to scarring and granuloma formation, usually at the bronchial anastomosis suture line. The lesion can progress over several months and typically presents as wheezing and shortness of breath. Flow-volume loops and large airway flow rates are usually reduced. The diagnosis is confirmed by bronchoscopy and is treated with dilation and/or stenting.

Delayed gastric emptying and gastroparesis may frequently follow lung transplantation, perhaps due to surgical injury to the vagus nerve. In addition to the obvious aspiration risk at the time of subsequent surgeries, gastroesophageal reflux has been linked to occult (or overt) aspiration, lung injury, graft failure, and bronchiolitis obliterans ( Berkowitz et al., 1995 ; Huddleston, 1996 ).

Acute Rejection

Acute rejection is most frequent in the first year and particularly the first several months after transplantation, declining substantially thereafter (Sweet, 1997, 2003 [604] [605]). It is often initially asymptomatic; symptoms include fever, dyspnea, and desaturation. Positive laboratory tests can include pleural effusions and/or perihilar infiltrates on chest radiography, and lower airway obstruction with decreased FVC and FEV1 on spirometry. The diagnosis is made (and attempts to differentiate from infection) using bronchoalveolar lavage and transbronchial biopsy. The diagnosis of acute rejection requires the presence of lymphocytic bronchitis or bronchiolitis with associated perivascular mononuclear infiltrates. Acute rejection is most often treated with high-dose steroids, to which patients usually respond rapidly with improvements in symptoms and pulmonary function tests. More persistent or severe episodes are typically treated with OKT3 or ATG. Although most lung transplant patients will experience at least one episode of rejection in the first year, additional episodes should prompt reevaluation of the immunosuppressive regimen. Acute rejection episodes are believed to be a major risk factor for the later development of bronchiolitis obliterans.

Bronchiolitis Obliterans

The major manifestation of chronic rejection is obliterative bronchiolitis (bronchiolitis obliterans). Bronchiolitis obliterans syndrome affects greater than 50% of all pediatric recipients more than 5 years posttransplantation, and bronchiolitis obliterans is the most common cause of death after 1 year. As with patients following heart transplantation, all lung transplant patients are followed with transbronchial biopsies, initially every 3 months and with increasing intervals to evaluate the presence of rejection. Pulmonary function tests are also performed to rule out or follow the progression of bronchiolitis obliterans. Respiratory symptoms of bronchiolitis obliterans are not dissimilar to those of asthma involving small airways; it sometimes responds mildly to bronchodilators even though the transplanted lungs are denervated. However, as time progresses, the airway obstruction becomes irreversible. Histologic examination confirms the diagnosis, although progressive reductions in FEV1 and maximum expiratory flow rates (FEF25-75, FEF75) are sufficient to make the diagnosis without histologic evidence. An association has been shown of bronchiolitis obliterans with increased episodes of acute rejection and/or infection (particularly CMV) and the onset of chronic rejection. The primary therapy is aimed at immunosuppressive prevention of acute rejection and prompt treatment of CMV ( Sharples et al., 1996 ).

Although increased immunosuppressive therapy has been used to attempt to halt the progress of the disease, no solution except retransplantation has been shown to be beneficial. Unfortunately, the 1-year survival rate for a retransplanted lung recipient is only 26% ( Sharples et al., 1996 ).

Immunosuppression for Lung Transplantation

There is substantial variability among pediatric lung transplant centers in terms of standard immunosuppressive regimens for preventing rejection. Induction immunosuppression is used in approximately 40% of patients, typically with an IL-2 receptor antagonist or ATG. All centers use combination therapy for chronic immunosuppression, typically a steroid, a calcineurin inhibitor (cyclosporine or tacrolimus), and an inhibitor of T-cell proliferation (mycophenolate mofetil or azathioprine). Complications arising from the use of these agents have been largely summarized earlier and, as with heart transplantation, significant morbidity is associated with the use of these drugs. Hypertension, hyperlipidemia, diabetes, and renal dysfunction are all present to varying extents. Diabetes is a particular problem in CF patients who have undergone a lung transplant, most likely due to pancreatic injury as a result of their underlying disease; as noted earlier, steroids (which cause insulin resistance) and tacrolimus (postulated to have a direct pancreatic effect) are additional risk factors. In addition, PTLD affects up to 15% of patients ( Armitage et al., 1995 ). Those treated with tacrolimus may have an even higher incidence of PTLD.

Outcome

The overall actuarial survival for single-lung transplants approximates to 25% at 5 years compared with 40% at 5 years with a double-lung transport. This difference reflects the better pulmonary reserve and larger pulmonary vascular bed in double-lung transplants compared with single-lung transplants ( UNOS/OPTN, 2005 ).

When survival is compared by age group, children less than 1 year of age have an actuarial survival at 7 years of greater than 40%, whereas those greater than 1 year have an actuarial 7-year survival of less than 35%. Unfortunately, the actuarial survival in the current era of transplantation shows no significant improvement compared with the past decade. Mortality in the first month posttransplantation is usually secondary to graft failure, whereas mortality in the first year beyond the first month is predominantly due to infection.

Chronic rejection in the form of bronchiolitis obliterans affects more than 50% of transplant recipients after the first year and becomes the main cause of death. On a slightly more optimistic note, of those patients who survive, more than 80% show no limitation of activity at 1, 3, and 5 years.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ LIVER TRANSPLANTATION

The first successful pediatric liver transplant was performed in 1967 ( Starzl et al., 1968 ). Between 1989 and 2004, almost 1000 pediatric patients have successfully undergone liver, pancreas, or intestinal transplantation in the United States. Before 1980, with the use of the immunosuppressive agents azathioprine and prednisone, the 5-year survival in the pediatric patient following liver transplantation was a dismal 20% ( Gordon and Bismuth, 1991 ; Gordon et al., 1991 ). After the introduction of cyclosporine in 1980, long-term survival after liver transplantation became a reality. For the first time, 5-year patient survival began to exceed that of the life expectancy related to the specific disease process. Graft survival has progressively improved since 1992, with, for example, a 1-year graft survival of 81% in 2001 (6- to 10-year recipient age) compared with 68% a decade ago ( UNOS/OPTN, 2005 ). Patient survival for this age group is estimated at 1 year at 90.5%; 3 years, 85.9%; and 5 years, 83.8%. Patient survival in the first year after transplant is similar for all age groups except children younger than 1 year, who have the highest annual death rate. For these infant recipients transplanted in 2001 and 2002, there was a marked decline in 1-year death rate, which is also seen as a trend for children aged 1 to 5 years and those aged 11 to 17 years. Improvements in patient and graft survival rates have been attributed to new immunosuppressive regimens consisting of tacrolimus (FK506, Prograf), MMF, and rapamycin with diminished use of cyclosporine, azathioprine, and corticosteroids and improved access to the donor pool using reduced grafts, living donors, and a new UNOS scoring system (Pediatric End-Stage Liver Disease [PELD] scale) for estimating medical urgency.

The age distribution in pediatric patients varies, with the majority of liver transplants performed in patients 5 years of age or younger. In the pediatric patient population to date, 28% of grafts have been given to patients less than 1 year old, 37% transplanted in patients 1 to 5 years old, and the remaining 35% in children 6 to 17 years old. From 1988 to 2004, a total of 8951 pediatric liver transplants have been performed in the United States ( UNOS/OPTN, 2005 ).

Liver transplantation, as well as multivisceral and small bowel transplantation, has become a widely accepted therapy for organ failure of the abdominal viscera. Although small bowel transplantation is still in its infancy, it has gained recognition as an acceptable therapy for intestinal dysfunction of various etiologies. For all ages, 126 intestinal transplantations were performed in 2004, of which 77 patients were less than 18 years old.

General Indications and Contraindications

The recognition of orthotopic liver transplantation (OLT) as a viable alternative for pediatric patients with liver failure has increased the number of potential recipients. By the same token, the past decade has also revealed diseases now considered absolute contraindications to OLT, having failed to provide demonstrable improvement in patient survival.

The indications for OLT can be classified in general as follows:

  

1.   

End-stage liver disease (ESLD) expected to progress to death

  

2.   

Secondary disease not confined to the liver

  

3.   

Prevention of the complications of major metabolic disorders

  

4.   

Nonprogressive liver disease in which mortality is greater than the risk of OLT

  

5.   

Fulminant hepatic failure

Disease-specific indications for OLT are shown in Box 28-3 .

BOX 28-3 

Disease-Specific Indications for Orthotopic Liver Transplantation (Percent of UNOS Pediatric Recipients 1995–1999)

  

 

Biliary atresia (46%)

  

 

Biliary hypoplasia

  

 

Alagille's syndrome

  

 

Extrahepatic

  

 

Metabolic diseases (12%)

  

 

Tyrosinemia

  

 

Glycogen storage disease types I and II

  

 

α1-Antitrypsin deficiency

  

 

Wilson's disease

  

 

Primary oxalosis/oxaluria

  

 

Hemochromatosis-hemosiderosis

  

 

Hyperlipidemia-II-homozygous

  

 

Cystic fibrosis

  

 

Cholestatic and noncholestatic cirrhosis (14%)

  

 

Malignant neoplasms and benign tumors

  

 

Acute hepatic necrosis (14%)

  

 

Miscellaneous

  

 

Budd-Chiari syndrome

  

 

TPN/hyperalimentation-induced liver disease

  

 

Neonatal hepatitis

  

 

Congenital hepatic fibrosis

  

 

Familial cholestasis

  

 

Trauma

  

 

Graft-versus-host disease secondary to nonliver transplant

With improvements in surgical and medical expertise the absolute and relative contraindications to pediatric OLT continue to evolve. There are very few absolute contraindications to OLT: the presence of any active, untreated bacterial, fungal, or viral infection at the time of transplantation; cancer outside the liver or those liver tumors not meeting cure criteria; actively replicating HBV infection; AIDS; or technically not feasible. The relative contraindications are more variable and tend to be transplant center specific. Examples include a child with ESLD and advanced cardiopulmonary disease, epilepsy, or multisystem organ failure and with HIV-positive serology.

▪ PATHOPHYSIOLOGY OF END-STAGELIVER DISEASE

ESLD is an irreversible process that results in diffuse fibrosis and cirrhosis with loss of functional hepatocytes. The clinical manifestations are independent of the etiology but are primarily related to the degree of liver dysfunction. This dysfunction is secondary to structural changes that the liver undergoes after it sustains any type of significant damage. Irrespective of the cause of the hepatic insult, there is cell necrosis followed by an attempt at regeneration by the liver. If the damage is of a chronic nature, this regeneration leads ultimately to fibrosis, further necrosis, and micronodular and/or macronodular cirrhosis. Interestingly, the liver is the only solid organ in the body that can fully regenerate after sustaining up to 80% destruction of its functional capacity or similarly a resection of up to 80% of the organ.

There are two main mechanisms through which structural changes lead to hepatic failure: cellular dysfunction and portal hypertension. In cellular dysfunction, liver cell mass decreases as hepatocytes become necrotic. As the liver attempts to regenerate, fibrosis develops, with the eventual disruption of the portal triads. The end result is formation of intrahepatic shunts, sinusoidal thickening, and an overall increase in the resistance to blood flow. This constellation of abnormalities results in the development of portal hypertension and varices. Similarly, biliary drainage becomes abnormal, leading to the intracellular accumulation of byproducts that are normally secreted (proteins, bile). Altogether these changes lead to abnormal hepatocyte energy metabolism, defects in protein and lipid synthesis, and alterations in substrate clearance.

Portal hypertension develops as a result of the increased resistance to blood flow through the disrupted sinusoids. In addition to this increase in resistance, there is an increase in splanchnic arterial blood flow caused by the development of arteriovenous shunts and vasodilatation as liver failure progresses. Worsening portal hypertension is manifested by ascites, splenomegaly, and portasystemic shunts (varices, hemorrhoids, telangiectasia). These portasystemic shunts lead to decreased clearance of previously metabolized substrates by the liver. Cellular function is further compromised as oxygen is shunted away, leading to a potentially dysoxic environment ( Dishart et al., 1998 ). Irrespective of the cause of liver failure, the pathophysiologic derangements are manifested in a similar fashion in the cardiovascular, pulmonary, renal, neurologic, and hematologic systems.

Child-Pugh Classification

The Child-Pugh classification is a universal scoring system of the degree of liver failure in patients with cirrhosis. Traditionally assigning patients to Child-Pugh class A, B, or C has been used as a predictive index for operative mortality rate in adult patients undergoing portosystemic shunting procedures. The estimated 1- and 5-year survival rates are 95% and 75% for patients with Child-Pugh class B and 85% and 50% for patients with Child-Pugh class C, respectively. After the onset of the first major medical complication (ascites, variceal bleeding, jaundice, or encephalopathy), survival rates for these patients are significantly reduced. Variables measured by this system include ascites, encephalopathy, serum albumin, serum bilirubin, and prothrombin time. Points are subsequently assigned to different degrees of each variable, and the total points are used to assign a grade within the Child-Pugh scoring system ( Table 28-3 ). Although a liver biopsy is often helpful in assessing histologic activity and the amount of fibrosis in patients with chronic hepatitis, it is not a criterion for the determination of the Child-Pugh class. Until February 2002, the Child-Pugh score was used by transplant centers to group patients into one of four medical urgency categories: blood type, patient size, medical urgency, and waiting time determined liver allocation.

TABLE 28-3   -- Child-Pugh scoring system for cirrhosis

Score

Bilirubin (mg/dL)

Albumin (g/dL)

PT (sec > control)

Hepatic Encephalopathy

Ascites (grade)

1

<2

>3.5

<4

None

None

2

2 to 3

2.8 to 3.5

4 to 6

1 to 2

Mild

3

>3

<2.8

>6

3 to 4

Severe

Child class: A = 5 to 6; B = 7 to 9; C = 10 to 15 points.

 

 

 

Pediatric End-Stage Liver Disease (PELD) Scale

The PELD numerical scale is currently used by UNOS for liver allocation for ages less than 12 years. PELD replaced the previous status 2B and 3 for pediatric patients, while status 1 is not affected by PELD. PELD is based on bilirubin, INR, albumin, growth failure, and age when patients are listed for transplantation, and it is used to calculate a value on a numerical scale, which is an accurate predictor of 3-month mortality, independent of the complications of portal hypertension and the etiology of the liver disease. The MELD (Model for End-stage Liver Disease) is a similar numerical scale ranging from 6 (less ill) to 40 (gravely ill) that is used for ages 12 and older ( UNOS/OPTN, 2005 ). The score indicates how urgently the patient needs a transplant in the next three months. The number is calculated from three routine laboratory test results: bilirubin, INR, and creatinine (Edwards and Harper, 2001, 2002 [163] [164]; Kremers et al., 2004 ).

▪ SYSTEMIC MANIFESTATIONS OF END-STAGE LIVER DISEASE

ESLD is associated with unique systemic physiologic alterations ( Robertson, 1998 ) ( Table 28-4 ).


TABLE 28-4   -- Cardiovascular, pulmonary, and renal complications of advanced cirrhosis

Cardiovascular

“Hyperdynamic circulation”
Increased cardiac index and stroke volume
Decreased systemic vascular resistance
Low to normal mean arterial pressure (widened pulse pressure)
Increased heart rate
Central hypovolemia
Increased circulating blood volume
Decreased effective plasma volume
Increased sympathetic tone
Hyporesponsiveness of the vasculature to pressor therapy
Flow-dependent oxygen consumption
Hepatic and splanchnic vasculature
Portal hypertension
Portal-systemic collateral circulation
Decreased hepatic blood flow
Alcoholic cardiomyopathy (reduced LVEF)
Cirrhotic cardiomyopathy (impaired cardiac contractility defective excitation contraction coupling, systolic and diastolic function, prolonged QTc interval, autonomie dysfunction, impaired β-adrenergic function and postreceptor defect, decreased responsiveness to catecholamines, conductance abnormalities)
Arrhythmias

Pulmonary

Arterial hypoxemia (PaO2 <70 mm Hg)
Hepatopulmonary syndrome
Portopulmonary hypertension
Impaired hypoxic pulmonary vasoconstriction
Increased pulmonary blood flow
Parenchymal abnormalities
Restrictive ventilatory pattern due to ascites limiting diaphragmatic excursion, pleural effusions, or chest wall deformity due to osteoporosis
Obstructive airway disease, emphysema, bronchkis-bronchiectasis
Interstitial lung disease (infection, pneumonias, pulmonary edema)

Renal

Renin-angiotensin-aldosterone activation: impaired sodium handling, water excretion, potassium metabolism, and concentrating ability
Impaired renal acidification
Prerenal insufficiency (ascites or diuretics)
Acute renal failure (acute liver failure, biliary obstruction, sepsis)
Hepatorenal syndrome
Glomerulopathies

 

 

Cardiovascular System

Progressive liver failure is characterized by a hyperdynamic circulation with a left ventricular ejection fraction greater than 65%, fixed low total peripheral resistance, and a compensatory increase in cardiac output, impaired circulatory reserve, and diminished response to catecholamines. High-risk patients are those with cardiomyopathy and dysrhythmias, congestive heart failure from fluid and reverse electrolyte imbalances, and moderate to severe pulmonary hypertension.

Systemic vascular resistance (SVR) is low because of peripheral vasodilatation and shunting (cutaneous, intrapulmonary, portopulmonary, and pleural). This profound vasodilatation may result from abnormal levels of vasodilator substances, possibly originating in the splanchnic circulation, that would otherwise be cleared by the liver. The most likely mediators include nitric oxide, tumor necrosis factor-α, and endothelium-derived relaxing factor. Activation of the renin-aldosterone-angiotensin system causes an increase in extracellular fluid volume through salt and water retention, and release of AVP results in a decrease in free water excretion, despite an overall central hypovolemia. Similarly, the sympathetic nervous system is activated in an attempt to cause peripheral vasoconstriction to maintain adequate circulating volume. Mixed venous oxygen saturation (SVO2) is elevated in the pulmonary artery (blood blended in the right ventricle from the IVC and SVC and coronary circulation) and is dependent on SaO2, cardiac output, hemoglobin, and oxygen consumption. The increase in SVO2 results from poor oxygen extraction and correlates somewhat with cardiac index ( Jugan et al., 1992 ; Steib et al., 1993 ).

Of the metabolic or inherited disorders, several have associated cardiovascular malformations. For example, Alagille's syndrome is an autosomal dominant disorder characterized by chronic cholestasis and cardiac anomalies, including, most commonly, peripheral pulmonary stenosis, tetralogy of Fallot, coarctation of the aorta, atrial or ventricular septal defect, patent ductus arteriosus, or pulmonary atresia.

Respiratory System

Cirrhotic patients are predisposed to arterial hypoxemia from intrapulmonary shunting due to capillary vasodilatation, restrictive lung disease caused by ascites or pleural effusions, impaired hypoxic pulmonary vasoconstriction, increased pulmonary blood flow and a rightward shift in the oxygen-dissociation curve due to decreased levels of 2,3-diphosphoglycerate (2,3-DPG). Respiratory compromise may also result from the hepatopulmonary syndrome, portopulmonary hypertension, defects in alveolar oxygen diffusion or pulmonary manifestations of systemic disease (e.g., CF, autoimmune disease, or α1-antitrypsin deficiency). These defects are compensated for by an increase in mixed venous oxygen saturation and resting cardiac output ( Schott et al., 1999 ; Teramoto et al., 2000 ). Arterial hypoxemia usually responds to supplemental oxygen and positive-pressure ventilation. Depressed airway reflexes, delayed gastric emptying, hiatus hernia, and massive ascites increase the risk of aspiration. Pulmonary edema, atelectasis, and pneumonia are not uncommon.

The frequency of hepatopulmonary syndrome (chronic liver disease, increased alveolar-arterial gradient A–aDO2 while breathing room air, and intrapulmonary vasodilatation) is reported between 4% and 29% ( Naeije, 2003 ; Mazzeo et al., 2004 ). Patients with liver disease may develop progressive and refractory hypoxemia due to abnormal intrapulmonary vascular dilatation causing anatomic shunting and diffusion-perfusion abnormalities ( Hoeper et al., 2004 ). These patients are at risk for systemic arterioembolization causing stroke, intracranial hemorrhage, or brain abscess. The prognosis of the hepatopulmonary syndrome is poor, and a mortality rate of 41% within 2 to 5 years has been reported ( Krowka et al., 1993 ). In contrast, up to 20% of cirrhotic patients are at risk of developing portopulmonary hypertension (portal hypertension and increased pulmonary vascular resistance). Severe pulmonary hypertension may cause acute right ventricular failure and sudden cardiac death. Preoperative therapy with epoprostenol, nitric oxide, and sildenafil may improve outcome in this group if right ventricular function is preserved and treatment results in a decrease in pulmonary pressures and vascular remodeling. ( Ghofrani et al., 2002 ; Makisalo et al., 2004 )

Renal System

Renal dysfunction is common in patients with ESLD, and the kidneys are very susceptible to insult and prone to failure. Fluid and electrolyte imbalances are secondary to diuretic therapy, hypoalbuminemia, and portal hypertension causing generalized ascites, progressive edema, hypovolemia, dilutional hyponatremia, and hypokalemic metabolic alkalosis. Three main mechanisms singularly or in combination contribute to renal insufficiency: prerenal causes, acute tubular necrosis (ATN), and hepatorenal syndrome. Renal insufficiency not only complicates the management of liver failure patients but, more importantly, may contribute to mortality. Thus it is important to aggressively evaluate and treat reversible causes of renal insufficiency ( Table 28-5 ). Renal function is often difficult to assess in these patients because reduced muscle mass and hepatic synthesis of creatine reduces the serum creatinine. Creatinine clearance will overestimate the glomerular filtration rate.


TABLE 28-5   -- Strategic plan for optimizing renal function and prevention of hepatorenal syndrome

Initial Management

Homeostatic environment (electrolytes, acid-base status, hematocrk)
Cardiovascular stability (euvolemia, mean arterial pressure >60 mm Hg)
Identify intrinsic renal parenchymal disease
Treat bacterial infections and complications related to liver disease, i.e., ascites, dilutional hyponatremia, and variceal bleeding
Avoidance of nephrotoxic agents (e.g., NSAIDs or aminoglycosides)

Optimize Renal Perfusion

Intravascular volume expansion
Drug therapy (splanchnic vasoconstriction or renal vasodilators): vasopressin analogues, α-adrenergic agonists, endothelin antagonists, antioxidants

Strategies

Transjugular intrahepatic portosystemic shunt
Spontaneous bacterial peritonitis: albumin and antibiotic therapy

Modified from Gines P, Guevara M, Arroyo V, Rodes J: Hepatorenal syndrome. Lancet 362:1819–1827, 2003.

 

 

 

Prerenal azotemia is most commonly associated with aggressive use of diuretic therapy in the treatment of ascites. With a decreased effective blood volume, patients are more susceptible to the volume-depletion effects of diuretics and large volume paracentesis without adequate intravascular volume replacement. As with other types of prerenal azotemia, the urine sodium level will be low (<15 mEq/L) with a fractional excretion of sodium (FENa) of less than 1%. This type of renal failure is amenable to careful volume replacement.

The kidneys in patients with liver failure are also at increased risk for developing ATN as a result of decreased renal perfusion. This decreased perfusion is a consequence of a relative decrease in central blood volume due to splanchnic pooling, which activates secretion of vasopressin, in combination with other compensatory mechanisms attempting to restore mean arterial pressure such as increased sympathetic tone and renin-angiotensin activity. Renal perfusion is further compromised because prostaglandin synthesis is reduced in advanced liver disease. Prostaglandins are the most potent renal arteriolar vasodilators ( Govindarajan et al., 1987 ; Claria and Arroyo, 2003 ). Hence, tubular function is much closer to an ischemic threshold in liver failure patients. This low ischemic threshold renders the kidneys more susceptible to nephrotoxic drugs such as intravenous contrast dye or aminoglycosides used to treat infectious complications. Additionally, in the patient with “tense” ascites, renal cortical perfusion may also be diminished due to an abdominal compartment syndrome. Urine sodium in this setting is usually greater than 20 mEq/L with an FENa of greater than 1% ( Epstein, 1985 ). Treatment should be directed at minimizing additional renal injury, optimizing renal perfusion, and maintaining urine output, with some form of dialysis possibly introduced until the ATN resolves. This usually occurs within 10 to 14 days. It is not uncommon, however, for the hepatorenal syndrome to become superimposed once the patient develops ATN.

The most consequential form of renal dysfunction with a very poor prognosis is the hepatorenal syndrome. This syndrome is characterized by a rapid deterioration in renal function associated with profound sodium retention and low urinary sodium excretion. It is usually precipitated by a major physiologic event, such as gastrointestinal hemorrhage, sepsis, or surgery. It is differentiated from prerenal azotemia by the lack of responsiveness to volume expansion. The pathogenesis is severe renal vasoconstriction with absence of cortical blood flow. Interestingly, this vasoconstriction is reversible if the kidney is transplanted into a host with normal hepatic function ( Koppel et al., 1969 ). This form of renal failure requires dialysis to sustain life but may be reversible with liver transplantation ( Iwatsuki et al., 1973 ).

Hematologic Complications

Anemia, thrombocytopenia, and coagulopathy are the expected findings in the patient with liver failure. Anemia is usually a result of bone marrow suppression, vitamin deficiency, hemorrhage, and diminished erythropoietin production caused by renal insufficiency. Thrombocytopenia (platelet count <100,000/mm3) is seen in 70% ( Kang et al., 1985 ) of patients with liver disease and is primarily a result of portal hypertension with platelet sequestration in the spleen; however, bone marrow suppression, abnormalities in platelet metabolism, inadequate production of thrombopoietin, or autoimmune causes may also be contributing factors ( Peck-Radosavljevic, 2000) . Impaired platelet aggregation and clot retraction due to qualitative platelet defects are also seen in patients with liver disease and renal failure.

The tissue factor pathway of coagulation is classically assessed by measuring the partial thromboplastin time (PTT) and the prothrombin time (PT). The liver is the main site of synthesis of all coagulation factors except von Willebrand's factor, which is produced primarily in the vascular endothelium. Failure of bile salt secretion results in poor absorption of vitamin K, which is a cofactor necessary for the posttranscriptional γ-carboxylation and activation of factors II, VII, IX, and X. In cirrhotic patients the levels of fibrinogen and factor VIII are usually supranormal with the production of all other clotting factors diminished. Additionally, approximately 80% of patients with liver failure also produce an abnormal fibrinogen molecule (dysfibrinogenemia) ( Martinez et al., 1978 ; Cunningham et al., 2002 ). Control of coagulation therefore depends on the balance of hepatic synthesis of clotting factors and its clearance of activated clotting factors, plasminogen activators, and fibrinolytic proteins.

Neurologic Complications

Hepatic encephalopathy is a frequent metabolic complication of acute or chronic liver disease. The neuropsychiatric abnormalities are often reversible with the clinical presentation ranging from subtle personality changes to frank coma. Neuromuscular symptoms include tremor, hyperreflexia, and decerebrate posturing. There are three theories regarding the pathogenesis of hepatic encephalopathy: (1) ammonia toxicity with accumulation of toxins in the brain, (2) alteration in plasma amino acid composition with accumulation of false neurotransmitters, and (3) increase in neuroinhibitory substances, manganese, monoamines, or endogenous opiates. Various studies have supported aspects of each hypothesis, yet none has been conclusively established. In patients who have died in hepatic coma, neuropathologic findings occur in the astrocytes, rather than neuronal changes. Positron emission tomography studies show decreased glucose utilization in the cerebral cortex, which may explain the neuropsychiatric abnormalities. ( Butterworth, 1996 ).

Forty percent of ammonia is generated in the intestine from ingested nitrogenous substances and subsequently metabolized in the liver into urea, which is excreted through the kidneys and into the colon. With liver failure and portosystemic shunting, ammonia, which is a known neurotoxin, accumulates and readily diffuses into the brain, where it exerts its neurotoxicity. The lack of a strong correlation between blood ammonia levels and the degree of hepatic encephalopathy, the presence of this condition in the absence of elevated ammonia levels, and the neuroexcitatory effects of low ammonia concentration have been used as arguments against ammonia being the sole factor in the pathogenesis. Other metabolic byproducts, such as mercaptans and short-chain fatty acids, have also been implicated.

With progressive liver failure, the ratio of branched-chain amino acids to aromatic amino acids decreases. These aromatic amino acids cross the blood-brain barrier and may competitively inhibit “normal” neurotransmitters and favor the generation of false neurotransmitters (octopamine), which have an inhibitory effect on cerebral function.

GABA is a major inhibitory neurotransmitter in the central nervous system that regulates the chloride channel. It has been suggested that elevated ammonia levels enhance GABAergic neurotransmission and synergistically augment the action of benzodiazepine receptor agonists ( Basile and Jones, 1997 ). This theory is supported by the fact that hepatic encephalopathy can at times be improved by the benzodiazepine receptor antagonist flumazenil.

Among the multiple precipitating factors in hepatic encephalopathy are azotemia, drugs (sedatives, tranquilizers, analgesics), gastrointestinal bleeding, excess dietary protein, metabolic alkalosis, infection, and constipation ( Abou-Assi and Vlahcevic, 2001) . Treatment consists of reducing dietary protein, avoiding sedatives, administering lactulose (converts ammonia to nonabsorbable ammonium and modifies the colonic flora), correction of hypokalemia, discontinuation of diuretics, treating infection, and volume expansion.

Endocrine dysfunction is common in ESLD. Oversecretion of growth hormone and glucagon leads to peripheral and hepatic insulin resistance and impaired glucose metabolism, with lipid utilization as a preferred energy substrate. Hypoglycemia is an ominous sign indicative of depletion of glycogen stores in the liver and survival limited to days without intravenous glucose supplementation and transplantation.

Fulminant Hepatic Failure

Fulminant hepatic failure (FHF) is the most severe, life-threatening complication of liver failure. The differentiation of acute fulminant liver failure versus an acute exacerbation of chronic liver disease is important with regard to therapeutic and prognostic implications, as not all acute liver failure patients are the same. Fulminant hepatic failure is usually defined as rapidly progressive liver failure with the onset of encephalopathy within 8 weeks of the onset of jaundice in patients without a previous history of liver disease. However, no uniform definition of FHF in children has been established. One definition that is widely accepted is the sudden onset of liver failure with altered mental status and coagulopathy in an otherwise healthy child ( Nazer and Nazer, 2004 ). In the pediatric age group, the incidence of FHF is estimated to be 50 cases per year in the United States. FHF was the primary diagnosis in 15% of pediatric patients transplanted from 1995 to 2000.). Viral hepatitis and drug-induced hepatotoxity are the two most common causes, but in most cases, the exact etiology remains unidentified. For the majority of fulminant failure patients, survival ultimately depends on medical stabilization and urgent liver transplantation, as mortality rates may reach 80% to 90%.

The etiology of FHF is quite varied. In approximately 50% of patients FHF is caused by acute viral hepatitis (A, B, C, D, E, and non A-E). Of note, HCV infection is not a significant cause of FHF in children. Many other viruses are also recognized, including Epstein-Barr virus (EBV), CMV, paramyxovirus, varicella-zoster virus, herpesvirus types 1, 2, and 6, parvovirus, and adenovirus. Less common causes include hepatotoxic drugs (acetaminophen, salicylates, chlorinated hydrocarbons, halothane, isoniazid, intravenous tetracycline, sodium valproate, methanol, Amanita mushroom poisoning), ischemia, vascular obstruction (Budd-Chiari syndrome), massive steatosis (Reye's syndrome), and metabolic causes (Wilson's disease in older children; in neonates: inborn errors of metabolism and hemochromatosis).

Jaundice is the most common presenting symptom, with mental changes occurring over the next 2 weeks in most patients. The condition then progresses in as many as 80% of patients to coma, with development of ascites, cerebral edema, decorticate and decerebrate posturing, severe coagulopathy, gastrointestinal bleeding, and hemodynamic instability.

Cerebral edema appears to be the major cause of morbidity in patients with FHF and contributes to the high mortality rates. Early signs and symptoms include increased muscle tone, arterial hypertension, seizures, agitation, and sluggish papillary response to light. Infants may present with poor feeding, irritability, and altered sleep patterns. The mechanism of cerebral edema is unknown, although both vasogenic and cytotoxic etiologies have been proposed. Whatever the cause, cerebral edema ultimately leads to intracranial hypertension, impairment of cerebral perfusion, irreversible neurologic brain injury, uncal herniation, and death ( Hanid et al., 1979 ). Encephalopathy may be classified according to the scheme in Table 28-6 . This is useful to judge the effects of treatment and assess the progression of the disease process.


TABLE 28-6   -- Staging (grading) of hepatic encephalopathy

Stage

Mental Status

Tremor (Asterixis)

Electroencephalogram

I

Euphoria, altered sleep, slurred speech

Slight

Δ and α irregularities

II

Drowsiness, incontinence

Marked

Slow α and Δ

III

Arousable from sleep, confused

Diminished

τ wave prevalent

IV

Responsive to painful stimuli

Absent

Slow Δ to flat

V

Unresponsive to pain

Absent

Flat

 

 

Medical treatment is generally supportive until either recovery with hepatocyte regeneration, liver transplantation (cadaveric, split, or living related donor), or death. Experimental approaches have been tried using liver-assist devices. Supportive measures are directed at minimizing morbidity and mortality from serious complications. This includes monitoring in a critical care unit; endotracheal intubation for airway protection; an infusion of 10% to 20% glucose to prevent hypoglycemia and replacement of calcium phosphorous and magnesium; antibiotic treatment of infections, peritonitis, and pneumonia; maintaining urine output and avoidance of nephrotoxic drugs with surveillance for renal insufficiency; H2-blockers for stress ulcer prophylaxis; correction of coagulopathy with vitamin K, plasmapheresis, and platelets, with fresh frozen plasma reserved for patients with active bleeding, as normalization of PT is often used as a prognostic indicator for recovery of synthetic function; avoidance of volume overload; and, most important, management of intracranial hypertension. Protein intake is restricted, with lactulose enemas and oral neomycin given to decrease enteric bacteria that produce ammonia and evacuate the bowels. If a causative agent is identified, then specific treatment should be initiated early: N-acetylcysteine for acetaminophen overdose.

Initial management of cerebral edema should begin with a computed tomography (CT) scan of the brain to assess cerebral blood flow ( Aggarwal et al., 1994 ). If there is evidence of cerebral edema and compromise of cerebral blood flow without carbon dioxide responsiveness, continuous monitoring of ICP is vital, especially in stage 3 or 4 encephalopathy. Therapeutic measures to reduce ICP include head-up positioning, ventilatory support with moderate hyperventilation and mannitol for a documented ICP greater than 30 mm Hg with progressive edema (Aggarwal et al., 2005). It may be efficacious to place a jugular bulb catheter so that adequate assessment of cerebral metabolism is possible ( Lassen and Lane, 1961 ). The important parameters that aid in management are the arteriovenous oxygen content difference (AVDO2), glucose, and lactate across the brain (Aggarwal et al., 1993, 1994, 2005 [12] [14]). Mild hypothermia to 34°C and barbiturate coma remain controversial topics with respect to the management of the patient with hepatic coma. Barbiturate coma should be reserved until all therapeutic interventions have failed to reduce ICP. Continuous electroencephalographic (EEG) monitoring is advisable in this instance, since the goal is to achieve EEG silence. Proceeding to liver transplantation will be inherent on the likelihood of neurologic recovery.

Serial abdominal computed tomography scans may be useful in assessing the hepatic size and morphology. A transjugular liver biopsy is invaluable but may not provide a definitive diagnosis and results correlate poorly with prognosis. Histologic findings are of two types: extensive necrosis of the peripheral hepatocytes with little or no regeneration (drugs and viral hepatitis) and microvesicular steatosis and centrilobular necrosis (Reye's syndrome and metabolic disorders). Serum levels of liver enzymes do not correlate with the severity of the disease. Typically, conjugated hyperbilirubinemia is present, with hyponatremia, hyperkalemia, respiratory alkalosis, and metabolic acidosis.

Prognostic criteria include the patient's age, cause of liver disease, onset and degree of encephalopathy relative to the appearance of jaundice, serum bilirubin level, PT/INR, serum creatinine, factor V level, and arterial pH. A sensitive predictor of outcome is the INR value. With an INR of 4 or greater, the mortality rate reaches 86%; with an INR of less than 4, it may be as low as 27% ( Nazer and Nazer, 2004).

▪ PREOPERATIVE EVALUATION

Risk assessment of the patient scheduled for OLT is still in its evolutionary stage. The primary focus for the anesthesiologist is to evaluate the whole patient for systemic manifestations of ESLD as well as predictable disease-specific extrahepatic manifestations (such as pulmonary involvement with CF).

Cardiovascular Evaluation

Cardiac evaluations of pediatric candidates for OLT should be tailored according to the underlying cause of cirrhosis. Inherited metabolic liver disorders rank second behind biliary atresia as an indication of OLT in children; as such, possible myocardial involvement should be considered in patients with oxalosis, glycogen storage disease type III, Gaucher's disease, Niemann-Pick disease, Wilson's disease, neonatal iron storage disease, and amyloidosis. The physical examination and diagnostic work-up should focus on cardiac auscultation, the presence or absence of cyanosis (arterial oxygen saturation SpO2and PaO2) or clubbing, and transthoracic echocardiography. Detection of a cardiac anomaly may then require cardiac catheterization.

Cardiac function in adults with cirrhosis has been extensively investigated, but there is little information available on children. A study of 22 children with cirrhosis compared with a control-group of healthy age- and sex-matched children (mean age, 4.1 ± 3.5 years) reported that pediatric OLT candidates have normal left ventricular systolic function unless their hearts were primarily involved in the underlying disease. In advanced liver failure, left ventricular systolic function may be impaired. These children also had increased systolic LVPWT (left ventricular posterior wall thickness), which may reflect left ventricular hypertrophy and impaired diastolic function. Left ventricular ejection fraction is usually normal or increased at rest in adults with cirrhosis unaccompanied by ascites ( Grose et al., 1995 ; Laffi et al., 1997 ). The presence of ascites adversely affects cardiac function in adults ( Valeriano et al., 2000 ). In contrast, most pediatric patients with ascites have normal left ventricular systolic function. Cyanosis is not a reliable sign of hypoxemia in children because of changes due to crying, anemia, and jaundice. Clubbing in patients with chronic liver disease is a common finding, with a prevalence ranging from 23% to 32% ( Ozcay et al., 2002 ). Given the physiologic stresses inherent in liver transplant surgery, cardiac problems may emerge perioperatively that contribute to significant morbidity and mortality in patients with cirrhosis and mild or latent cardiomyopathy ( Myers and Lee, 2000 ).

Pulmonary Evaluation

Patients have various degrees of pulmonary impairment, including normal PaO2 and reduced DLCO, significant arterial hypoxemia, hepatopulmonary syndrome, portopulmonary hypertension, and preexisting lung disease. The question that has not been definitively answered is, “What values of FEV1, DLCO, and PaO2 identify the high-risk pediatric patient scheduled for liver transplant surgery?” Investigative studies include chest radiography, pulmonary function studies, high-resolution computed tomography studies of the lung, contrast transthoracic echocardiography with saline, and arterial blood gas measurements.

Cirrhosis affects the pulmonary circulation, lung parenchyma, and pleural spaces. Reduced alveolar-capillary diffusion may be seen in the absence of significant hypoxemia, especially in patients with HCV cirrhosis. This anatomic derangement of the alveolar-capillary membrane worsens with disease progression with DLCO abnormal at less than 80% predicted value. A reduced diffusion capacity may persist up to 15 months after transplantation ( Ewert et al., 1999 ). Of interest, the Hepatitis C Association is supporting a no-smoking policy for teens and adults, as smoking has been determined to be an independent risk factor associated with elevated ALT levels among anti-HCV-seropositive patients ( Wang et al., 2002 ; Hezode et al., 2003 ).

Mild arterial hypoxemia is common in patients with cirrhosis and, primarily caused by a decrease in FRC and total lung capacity (ascites, pleural effusions), impaired diffusion capacity, and pulmonary arteriovenous shunting ( Liu and Lee, 1999 ). In advanced liver diseases, ventilation/perfusion (   /   ) defect is an important cause of hypoxemia. The arterial blood gas analysis while standing and breathing 100% FIO2 is of particular importance because severe hypoxemia patients with at least a moderate response to breathing 100% oxygen on standing (PaO2 >150 mm Hg) are thought to have an adequate pulmonary reserve and may be safely oxygenated intraoperatively ( Krowka et al., 1997 ; Mohamed et al., 2002 ). Nonresponsive individuals should be suspected of having a fixed shunt, and transplantation should be delayed pending further evaluation.

Hepatopulmonary syndrome (HPS) was once considered a contraindication to transplantation, but now it is considered an indication for early liver transplantation, as there is no successful long-term medical treatment. Patients typically present with progressive exertional dyspnea and hypoxemia. HPS is characterized by the triad of chronic liver disease, hypoxemia, and intrapulmonary shunting in the absence of primary cardiac or pulmonary disease. The exact incidence in the pediatric patient population is unknown. The pathoanatomic defects causing arterial hypoxemia include intrapulmonary vascular dilatation due to dilated precapillaries, direct arteriovenous communications, and engorged pleural blood vessels. This results in decreased oxygen diffusion into the dilated vessels (diffusion-perfusion impairment) along with decreased intrapulmonary transit time and decreased hypoxic pulmonary vasoconstriction. This is actually not a true “anatomic” shunt, as the patient with the more common type I lesions will demonstrate a significant PaO2 response to 100% oxygen.

Appropriate preoperative evaluation should include a chest radiograph, an arterial blood gas level measurement with the patient breathing room air and then 100% FIO2, and one of several imaging techniques: perfusion lung scanning, contrast-enhanced (microbubble) transthoracic echocardiography, lung scintiscan, or pulmonary angiography (identifies type I O2 reactive versus type II O2 nonreactive lesions). With liver transplantation, HPS is reversible ( Liang et al., 2001 ), but regression of vascular abnormalities in patients with true anatomic shunts and those with marked precapillary dilatation and evidence of poor response to supplemental oxygenation is not predictable ( Lange and Stoller, 1995 ). Treatment of HPS type II presents a dilemma, although liver transplantation with concomitant lung transplantation is a possible choice ( Yuan et al., 2003 ).

Pulmonary arterial hypertension as a consequence of liver dysfunction is termed portopulmonary hypertension (PPH). This is a pulmonary vasoproliferative and vasoconstrictive process leading to pulmonary hypertension (increased PVR and normal PCWP or LVEDP) and right heart failure frequently not reversible by liver transplantation. This disorder is uncommon (up to 20% of patients with cirrhosis of the liver), and its existence in the pediatric population is not well described. How rapidly PPH can develop varies, as reports indicate anywhere from 3 weeks to 5 years. Remarkably, a review of published PPH cases through 1999 documented that 65% of diagnoses were first recognized during the liver transplant procedure ( Krowka et al., 2004 ). The clinical presentation is subtle and includes exertional dyspnea, fatigue, ankle edema, chest pain, and syncope. Arterial hypoxemia is reported in 80% of patients with moderate to severe disease, with an increased alveolar-arterial oxygen gradient A–aDO2, reduced diffusion capacity, and accentuated respiratory alkalosis ( Kuo et al., 1997 ; Cotton et al., 2002 ). Transthoracic contrast-enhanced echocardiography is the screening procedure of choice, with right heart catheterization the gold standard for making the diagnosis and assessing right ventricular function. The best prognosis is in patients with mild symptoms, preserved heart function, and pulmonary arteries responsive to vasodilator therapy.

Treatment options include inhaled nitric oxide, calcium channel blockers, anticoagulation, digoxin, diuretics, supplemental oxygen, and intravenous prostacyclin. The significance of this disease entity is its high perioperative morbidity and mortality in patients undergoing OLT. The data available to date indicate a perioperative mortality of greater than 70% with an mPAP of 45 mm Hg or higher and up to 100% if the mean pressure is greater than 50 mm Hg at the time of transplant. There is no increase in mortality risk if the mPAP is 35 mm Hg. The national liver transplant database reports an overall mortality perioperatively of 36%. The key to survival is good right ventricular function. Even after OLT, the pulmonary vascular abnormalities may progress unless long-term pulmonary vasodilator therapy is instituted.

Pulmonary involvement in the patient with α1-antitrypsin deficiency or CF is not uncommon in the pediatric patient. α1-antitrypsin has a reported incidence of liver involvement in 10% to 20% of patients, primarily those who are PIZZ homozygotic ( Psacharopoulos et al., 1983 ). The incidence of this phenotype is 1:7000 in the United States and 1:2000 in Scandinavia ( Schwarzenberg and Sharp, 1990 ). Males are affected more frequently than females. About 10% to 20% of PIZZ individuals develop neonatal cholestasis, and jaundice is often the first presentation of this disease. α1-antitrypsin deficiency is also associated with cirrhosis and primary liver cancer and may be associated with coexisting obstructive lung disease. Appropriate assessment should be obtained in this particular group of patients with liver failure.

Renal Evaluation

Renal dysfunction in conjunction with worsening hepatic function is common. Acute renal failure requiring hemodialysis is a strong predictor of mortality in these patients. Bartosh and others (1997)reported abnormal renal function in one third of children following liver transplantation, with acute renal failure requiring dialysis (6.2%) a predictor of a high mortality rate (85%). The etiology of renal insufficiency in the patient with ESLD is usually multifactorial. Possible causes include hepatorenal syndrome, disturbances of salt and water clearance, ATN, renal pathology associated with the underlying liver diseases, and diminished intravascular volume causing prerenal azotemia. Exposure to nephrotoxic drugs such as intravenous contrast dyes, aminoglycosides, and nonsteroidal anti-inflammatory agents may also contribute to ATN.

Urine sodium handling is an important variable during evaluations. Both prerenal azotemia and hepatorenal syndrome are characterized by normal urinary sediment, very low urine sodium concentrations (<10 mEq/L), azotemia, and oliguria; it is important to exclude hypovolemia. Specifically, hepatorenal syndrome does not respond to a fluid change with diuresis, whereas the expected response in the patient with prerenal azotemia is diuresis and a subsequent decrease in the serum creatinine and urea nitrogen levels. ATN tends to be salt wasting at its initial presentation, with urine sodium concentrations characteristically greater than 30 mEq/L. An important diagnostic test is the FENa, which also aids in the distinction between these two disease processes. Obtaining an accurate GFR using creatinine clearance in patients with cirrhosis and ascites may give spurious results, as GFR measurements may range from high values to those diagnostic of end-stage renal disease despite the presence of a normal serum creatinine ( Papadakis and Arieff, 1987 ).

Renal ultrasonography is a simple (noninvasive), useful adjunct in the evaluation of azotemia. Kidney size and structural abnormalities should be ascertained for evidence of obstructive uropathy. If a renal biopsy demonstrates irreversible renal disease, then a combined liver and kidney transplant should be considered. Prerenal azotemia due to hypovolemia usually resolves with judicious volume replacement. ATN is usually self-limited and runs a 7- to 14-day course with appropriate support. However, the hepatorenal syndrome is usually not reversible without liver transplantation ( Gonwa et al., 1989 ).

Biliary atresia is the main indication for liver transplantation in infants and children. A palliative surgical hepatoportoenterostomy (Kasai procedure), as opposed to a primary curative OLT, may be performed preferably in the first 60 days of life to restore biliary flow. The natural progression of this disease to cirrhosis and death may then be markedly delayed, with survival reported up to 20 or 30 years. Portal hypertension occurs in at least two thirds of children after portoenterostomy even with complete restoration of biliary flow and return of the serum bilirubin to normal values. In addition, the subsequent development HPS or pulmonary hypertension has been reported.

▪ SURGICAL TECHNIQUE

There are a few significant differences between the surgical techniques for liver transplantation between children and adults. Size discrepancies affect the choice of donor liver, biliary drainage procedure, primary or delayed abdominal closure, the feasibility of using venovenous bypass, and the incidence of hepatic artery thrombosis and other vascular thrombotic complications.

Previous surgery for biliary atresia (Kasai procedure) or open liver biopsy or the use of segmental grafts increases the risk of perioperative bleeding. Donor-recipient size mismatch, especially for children younger than 2 years, has necessitated the utilization of reduced-size and split-liver cadaveric/deceased donors grafts (in situ or ex vivo) and segmental grafts from living donors. Blood loss must be kept to a minimum, given the small total blood volume of the child. The arterial anastomosis is a major challenge because of its small diameter, so there must be creative use of vascular grafts (iliac, carotid, and aortic conduits), which requires partial cross-clamping of the abdominal aorta. Two basic liver transplant techniques are described.

Classic OLT requires placing clamps on the portal vein and suprahepatic and infrahepatic vena cava, and the diseased liver is then removed en bloc ( Starzl et al., 1984 ; Starzl and Iwatsuki, 1987 ) ( Fig. 28-6 ). In most cases, with sufficient collateral circulation and preload and pressor support, the patient tolerates 90 minutes of cross-clamping. Otherwise, hemodynamic stability is maintained in larger children and adults with venovenous bypass. The new liver is placed starting with the vascular outflow anastomosis first, which includes the suprahepatic vena cava and infrahepatic vena cava, followed by the vascular inflow of the portal vein and finally the hepatic artery. Biliary reconstruction depends on the underlying diagnosis and size discrepancy of the recipient and donor bile ducts. A Roux-en-Y (hepaticojejunostomy) with or without a stent is most common.

 
 

FIGURE 28-6  Biliary tract reconstruction with choledochojejunostomy, using a Roux limb.  (From Starzl TE, Iwatsuki S, VanThiel DH, et al.: Hepatology 2:614, 1982; with permission of the American Association for the Study of Liver Diseases.)

 

 

 

The second approach is referred to as the “piggyback hepatectomy technique.” The liver is dissected away from the retrohepatic vena cava, which eliminates the need for total caval clamping and facilitates the use of different size-matched grafts. This has become the preferred technique in pediatric liver transplantation. The diseased liver is mobilized with sequential ligation of the portal vein, short hepatic veins from the IVC to the liver, and the left/right/middle hepatic veins. In this technique, there are only two vascular anastomoses that need to be completed before the reestablishment of blood flow to the donor liver: the suprahepatic cava of the donor liver to the native hepatic veins (end-to-side) or the donor IVC to the recipient IVC (end-to-side) with partial clamping of the IVC and the portal vein anastomosis ( Tzakis et al., 1989 ) ( Fig. 28-7 ). The piggyback technique requires a longer operative time but offers the advantages of greater hemodynamic stability and reduced red blood cell transfusion, intraoperative fluids, and requirement for vasoactive drugs ( Moreno-Gonzalez et al., 2003 ).

 
 

FIGURE 28-7  The native liver is dissected away from the IVC and the vascular pedicle of the hepatic veins is isolated. The native liver, after being devascularized, may then be transected to allow intraparenchymal exposure of the hepatic veins (A and B). The final appearance of the recipient liver is illustrated with the native IVC intact and the confluence of the recipient's hepatic veins at the suprahepatic cava, being anastomosed to the donor's intact IVC (C).  (From Tzakis A, Todo S, Starzl TE: Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 210:649–652, 1989.)

 

 

 

The surgical procedure is divided into four distinct stages. Stage I, the liver dissection phase, occurs from induction of anesthesia to devascularization of the diseased liver. Stage II, the anhepatic phase,begins with removal of the native liver and ends when the IVC and portal vein anastomoses are complete. Stage III, the reperfusion phase, occurs with reperfusion of the donor liver by release of the clamps on the portal vein and IVC. Hepatic arterial reconstruction is performed after portal reperfusion, surgical hemostasis, and hemodynamic stability are established. Stage IV is biliary reconstruction with either a duct-to-duct anastomosis or choledochojejunostomy to a Roux-en-Y limb.

The routine use of venovenous bypass during the anhepatic phase of OLT with or without preservation of the cava remains controversial. In early experiments of OLT in a noncirrhotic dog model, it was discovered that clamping of the portal vein or IVC resulted in death of the animal within 30 minutes ( Shaw et al., 1985 ). Although it was later found that most patients can tolerate caval and portal vein clamping remarkably well, Shaw and others (1984) reported in 1984 a 10% intraoperative mortality due to hemodynamic instability in adults during the anhepatic phase. Because of this, a bypass system was developed consisting of heparin-bonded tubing and a centripetal-force pump, allowing cannulation of the femoral and portal veins and diversion of mesenteric and IVC blood to the SVC through the subclavian or axillary veins ( Griffith et al., 1985 ) ( Fig. 28-8 ). Over the years the technique of veno-venous bypass (VVB) has undergone simplification, but unfortunately, there are no published randomized clinical trials of specific outcomes to evaluate its potential benefits. VVB is not without associated morbidity, and Kuo and others (1995) demonstrated that omission of VVB saved 3 hours of operative time, perfusion charges, and circuit costs.

 
 

FIGURE 28-8  This technique was developed to augment cardiac output and diminish vascular congestion during the anhepatic stage of the surgery. Note the placement of the cannulas, joined by a connector, into the portal vein and the femoral veins. Blood drained from the splanchnic and systemic venous systems is then returned to the right heart through the axillary vein with the aid of a pump.  (From Kang Y, Gelman S: Liver transplantation. In Gelman S, editor: Anesthesia and organ transplantation, Philadelphia, 1987, WB Saunders.)

 



Results from a survey conducted in 1998 of 50 major liver transplant centers indicated that the use of VVB in North America was decreasing, with 91% routinely using VVB in 1987 and 42% of the same programs in 1997 ( Chari et al., 1998 ). Children have a high tolerance to caval cross-clamping. This is a great advantage because it is very inconvenient or impossible to use VVB in patients weighing less than 25 kg (Shaw et al., 1984, 1985 [552] [551]). The prerequisite VVB blood flow is usually 20% to 40% of the cardiac output or greater than 1 L/min ( Griffith et al., 1985 ). As these children are not heparinized, the extremely low-flow states that result in children less than 20 kg would predispose to almost certain formation of emboli.

▪ ANESTHETIC MANAGEMENT

Most liver transplantation centers develop their own practice of intraoperative care and utilization of clinical resources. A survey of intraoperative resource utilization in anesthesia for liver transplantation in the United States during 2002 indicated that pediatric only programs were distinctly different in personnel, equipment, monitoring, and VVB utilization when compared with adult or mixed-age programs (Schumann, 2003 ). Pediatric only programs always monitored platelets and traditional coagulation studies (PT, INR, PTT, fibrinogen, D-dimer), with less than 30% of these programs using ACT and TEG to monitor coagulation. Intraoperative metabolic monitoring included ionized calcium in all pediatric programs; magnesium, 46.2%; phosphate, 30.8%; and lactate, none. Measuring arterial blood gases, electrolytes (sodium, potassium), and blood glucose level took place in all programs primarily using operating room satellite laboratories with a turnaround time of less than 5 minutes. The majority of pediatric only programs deployed two anesthesia personnel per case. Anesthesia fellows were used significantly more often and ancillary personnel significantly less often than at mixed-age centers. This observation may be explained by a reduced need for VVB and rapid large-volume infusion: rapid infusion system in 15.4%, level 1 in 46.2%, and no rapid infusion device in 38.5%. This is a significant deviation that is practiced from adult-only or mixed-age centers. None of the 11.3% of centers using transesophageal echocardiography were pediatric only centers. Only a small number used continuous cardiac output monitoring (7.7%), bispectral index (BIS) (15.4%), VVB (7.7%), and more than one arterial catheter (15.4%).

Anesthetic management can be compartmentalized into four distinct stages corresponding to the four surgical stages previously described. An understanding of the pathophysiologic changes that occur in each stage of the surgery allows the anesthesiologist to anticipate and appropriately diagnose, manage, and treat the cardiovascular, hematologic, metabolic, and other derangements encountered throughout the surgery ( Borland et al., 1985 ; Carlier et al., 1987 ; Kang and Gelman, 1987 ; Lindop and Farman, 1983 ; Carton et al., 1994a, 1994b [98] [99]). Liver transplantation in the pediatric patient is very similar to adults from a technical point of view, but there are distinct differences in transfusion requirements and strategies for minimizing blood loss, perioperative coagulation, hemodynamic consequences of caval clamping and reperfusion of the liver, monitoring, vascular access, incidence of thrombosis of the hepatic artery, retransplantation rate, and postoperative pain relief.

Induction and Maintenance of Anesthesia

Liver transplantation has essentially become a semiurgent or elective procedure. The recipient is premedicated with oral, intravenous, or intranasal midazolam. In the operating room, standard monitors are placed and the patient is preoxygenated. Patients without serious cardiac disease or multisystem organ failure will tolerate routine induction of anesthesia followed by endotracheal intubation. Rapid-sequence intravenous induction includes atropine (0.01 to 0.02 mg/kg); a sedative/hypnotic agent using thiopental (3 to 5 mg/kg), propofol (2 mg/kg), etomidate (0.2 to 0.3 mg/kg), or ketamine (1 to 2 mg/kg); fentanyl (2 to 3 mcg/kg); rocuronium (1.0 mg/kg); or succinylcholine (2 mg/kg). The airway is secured with an oral endotracheal tube (preferably cuffed), which is then anchored to the face with tincture of benzoin and adhesive tape. Choosing the appropriate size of endotracheal tube and proper positioning is especially important. Placement of an uncuffed tracheal tube of insufficient diameter may result in inadequate alveolar ventilation, especially as chest compliance is reduced during surgery by upper abdominal retraction, tissue edema of the lung parenchyma, surgeons leaning on the chest wall, and placement of a large liver graft. In anticipation of these factors, a tracheal tube with a leak at an inflating pressure greater than 15 to 20 cm H2O should be placed with the tip approximately 2 cm proximal to the carina.

Succinylcholine has been used traditionally for intubation in pediatric patients at risk for aspiration. Today, this practice is a controversial issue. The “black box warning” indicates that there are rare reports of ventricular dysrhythmias and cardiac arrest secondary to acute rhabdomyolysis with hyperkalemia in apparently healthy children who received succinylcholine. Many of these children were subsequently found to have a skeletal muscle myopathy whose clinical signs were not obvious. Because it is difficult to identify which patients are at risk, it is recommended that the use of succinylcholine in children should be reserved for emergency intubation or where immediate securing of an airway is necessary as succinylcholine has the fastest onset (30 to 60 seconds) compared with other muscle relaxants (seeChapter 6 , Pharmacology; Chapter 10 , Induction of Anesthesia).

Alternatively, using a relatively large dose of a nondepolarizing muscle relaxant permits securing the airway rapidly without placing the patient at risk for hyperkalemia. The ideal drug in patients with end-stage liver or kidney disease is cis atracurium, as it undergoes spontaneous breakdown at physiologic temperature and pH (Hoffmann elimination), as well as ester hydrolysis. In patients with hepatorenal syndrome, nondepolarizing muscle relaxants should be administered cautiously and titrated to effect. Muscle relaxants requiring significant renal excretion include pancuronium (40%), metocurine (43%), tubocurarine (45%), doxacurium (30%), and pipecuronium (38%). Vecuronium and pancuronium also have 3-OH metabolites, which accumulate in renal failure. The 3-OH metabolite of vecuronium is 50% as potent as the parent compound, and that of pancuronium has two thirds the potency of the parent compound. Muscle relaxants that are metabolized in the liver include pancuronium, vecuronium, rocuronium, and pipecuronium. Vecuronium and rocuronium also have significant biliary excretion. Pancuronium has an increased volume of distribution, prolonged elimination half-life, and decreased plasma clearance in patients with cirrhosis. These patients may need more pancuronium initially to achieve muscle relaxation, and they have a prolonged recovery of blockade between doses ( Duvaldestin et al., 1978 ). In patients with biliary obstruction, the initial dose of pancuronium required is unchanged, whereas the duration of action of each dose is similarly prolonged ( Duvaldestin et al., 1978 ). This may be advantageous because the operative procedure is lengthy and ventilation is usually required for at least 24 hours postoperatively.

The patient is positioned on the operating table supine with the arms abducted and elbows flexed. It is essential to keep the patient covered, warm, and dry. Strategies include warming blanket, heated humidified gases, intravenous fluid warmers, wrapping extremities, Mylar foil wrapping, and using a thick cotton mattress pad below with a U-shaped surround Bair Hugger (Arizant Inc., Eden Prairie, MN) forced-air warming device. Care should be taken to avoid stretch injury of the brachial plexus or pressure necrosis of the occiput, ears, heels, sacrum, or elbows. After the induction of anesthesia, additional monitoring is established: end-tidal CO2, rectal and esophageal temperature probes, an esophageal stethoscope, an indwelling urinary catheter, a peripheral nerve stimulator, and systemic arterial and central venous pressure cannulas. Access to arterial pressure monitoring above the diaphragm is essential because cross-clamping of the abdominal aorta may be necessary during the hepatic arterial anastomosis.

A radial and femoral (or brachial) arterial line is often used during surgery if there is concern about the accuracy of the radial arterial blood pressure compared with central blood pressure during hemodynamic instability ( Kamath et al., 2001) , as well as the need for frequent blood sampling necessitating interruption of the pressure tracing. One or two additional large intravenous cannulas (preferably 18-gauge or larger) are then inserted in the upper extremities, either percutaneously or by surgical cutdown. Routine use of VVB in larger children will preclude use of the left arm for venous access. If placement of vascular access in the arms is difficult, the lower extremities may be used, with the understanding that during the anhepatic stage venous return to the heart depends on collateral flow or VVB. A central venous catheter is placed in the external or internal jugular vein. In smaller children, the surgeon will often insert a Hickman catheter (large-bore double-lumen central venous line). The use of a sheath-type catheter in larger children will allow for the rapid infusion of large volumes of blood components and the insertion of a flow-directed balloon-tipped pulmonary artery catheter. Technical difficulties in placing a pulmonary artery catheter and subsequent displacement or migration by surgical maneuvers may preclude its routine use in pediatric patients.

The patient is ventilated with a tidal volume and respiratory rate adjusted to maintain a normal end-tidal CO2 and arterial carbon dioxide level of 35 to 40 mm Hg. Tidal volume and minute ventilation may be improved using a pressure-limited mode. Air-oxygen is used with an inspiratory oxygen concentration sufficient to maintain adequate oxygenation. PEEP of 5 cm H2O is routinely added because progressive atelectasis is common. Nitrous oxide is avoided because of its sympathomimetic effects; propensity to cause bowel distention, which may make surgical exposure and closure of the abdomen difficult; and limiting effect on increasing the inspiratory concentration of oxygen.

During anesthesia, all factors inducing arterial hypotension should be avoided. General anesthesia and surgery decrease hepatic blood flow and jeopardize oxygen supply to the liver. Intraoperative reductions in the arterial blood pressure and cardiac output decrease portal blood flow. Contributing factors include anesthetic drugs (inhalational anesthetics, vasodilators, β-blockers, α1-agonists, H2-blockers, and vasopressin), hypovolemia, ventilatory mode, hypoxemia, hypercarbia, and acidosis. Surgical manipulation in the right upper quadrant can reduce hepatic blood flow up to 60% from sympathetic activation or direct compression of the vena cava and splanchnic vessels. Compensatory vasodilatation of the hepatic artery in response to decreased portal inflow is diminished by volatile anesthetic agents in a dose-related manner (and absent in a denervated liver), and consequently blood flow becomes pressure dependent. Isoflurane has the least detrimental effect on liver blood flow. A simultaneous decrease in the liver's metabolic demand tends to balance the oxygen supply-uptake ratio. A study of hepatic circulation in pigs during surgical stress and anesthesia suggested that fentanyl and light isoflurane provided adequate hepatic oxygen supply, whereas anesthesia with higher concentrations of isoflurane (which decrease blood pressure >30%) or with halothane in any concentrations studied resulted in inadequate hepatic oxygen supply ( Gelman et al., 1987 ).

When administering drugs to patients with chronic liver disease, all drug dosages should be decreased and carefully titrated until the desired effect is achieved. Experts currently recommend that isoflurane alone or in combination with small doses of fentanyl be used as the method of choice provided adequate pulmonary ventilation, cardiac output, and arterial pressure are maintained. Anesthetic management problems during the four stages of surgery are listed in Box 28-4 .

BOX 28-4 

Anesthetic Management Problems During the Four Stages of Surgery

  

 

Stage I: Recipient Hepatectomy

  

 

Blood loss, anemia, coagulation abnormalities

  

 

Hypotension

  

 

Hypoxemia

  

 

Hypothermia

  

 

Hyperkalemia, hypocalcemia, acidosis

  

 

Encephalopathy with raised intracranial pressure

  

 

Stage II: Anhepatic Stage

  

 

Hemodynamic changes with caval clamping and total hepatic vascular exclusion

  

 

Acidosis, hypocalcemia, hypothermia, hypoglycemia

  

 

VVB

  

 

Urine output and renal function

  

 

Backwashing of the liver

  

 

Stage III: Reperfusion

  

 

Reperfusion syndrome

  

 

Postreperfusion hyperkalemia

  

 

Fibrinolysis

  

 

Pulmonary thromboembolism

  

 

Pulmonary hypertension

  

 

Fluid overload, ventricular dysfunction, pulmonary edema

  

 

Systemic hypotension

  

 

Hypothermia

  

 

Stage IV: Biliary Reconstruction

  

 

Primary nonfunction or delayed primary function of the graft

  

 

Abdominal closure

  

 

Hypokalemia

  

 

Coagulation status, bleeding

  

 

Renal dysfunction

  

 

Hyperglycemia, metabolic alkalosis, hypomagnesemia

Cardiovascular Changes

During stage I, hypotension is secondary to major fluid shifts, bleeding, and ionized hypocalcemia ( Jawan et al., 2003 ). Transient decreases in mean arterial pressure are not unusual in this stage from surgical manipulation of the liver and compression of the IVC transiently precluding venous return to the heart. Drainage of ascites may result in hypotension if the patient is not adequately hydrated before incision of the peritoneum. Factors contributing to blood loss include adhesions from prior operations, coagulopathy (factor deficiency, low platelets, abnormal fibrinogen, or disseminated intravascular coagulopathy), portal hypertension and collateral venous circulation, and lack of surgical hemostasis (especially a hole in the IVC). Placement of the suprahepatic caval clamp may be associated with arrhythmia, and in one instance I have witnessed hypotension and hypoxemia due to acute right ventricular outflow tract obstruction, as the pericardium and a portion of the right ventricle were included in the clamp. Hypotension that is unresponsive to intravenous pressors should raise suspicions of absolute or relative hypovolemia (limited preload due to vascular clotting or torsion of the liver on its vascular pedicle), acidosis, sepsis, or vasoparesis.

During stage II, classic OLT requires a trial of portal vein and IVC clamping. The hemodynamic response is characterized by a decrease in cardiac output, CVP, and PAP and compensatory increase in heart rate and SVR ( Eyraud et al., 2002 ). Hemodynamic instability may result from decreased venous return (modified by VVB or piggyback technique) and insufficient physiologic compensation by the patient for this acute change. Therapeutic strategies then polarize into the “flooders” and the “squeezers,” each with associated morbidity for the patient. Colloid or crystalloid boluses are administered, followed by dopamine or norepinephrine (phenylephrine or epinephrine) for pressor support. The goal is to maintain the lowest filling pressures compatible with an acceptable mean arterial pressure in anticipation of an increase in PAP with removal of the caval and portal vein clamps. Pulmonary hypertension may result due to an increase in venous return from the gut and lower extremities and reactive changes in pulmonary vascular resistance with the release of vasoactive hormones which are recirculated systemically. The donor liver is flushed either with crystalloid or colloid or by backwashing the liver. The procedure for backwashing involves insertion of a red rubber cannula into the recipient/donor IVC, and the clamp is removed from the portal vein, allowing washing of the liver with autologous blood retrograde from the portal vein through the donor liver, exiting through the cannula into a stainless steel graduated cylinder.

Communication with the surgeon at this point is imperative as one does not hear the sound of the suction or observe blood filling the canisters, but the patient becomes immediately and dramatically hypotensive. Hypotension associated with this maneuver can be ameliorated with the prophylactic administration of phenylephrine or epinephrine boluses, gentle fluid administration, or transfusion of packed red blood cells if the hematocrit is low. The elimination of air bubbles, hyperkalemic preservation solution, hormones, or other “evil humors” has been credited for decreasing the incidence of subsequent reperfusion syndrome in adult patients that may occur with reperfusion of the liver ( Fukuzawa et al., 1994 ). The goal for warm ischemia time (time from liver up into the surgical field until reperfusion in the recipient) is usually less than 60 minutes, so managing hypotension and preparing for reperfusion occur over a relatively short period. Reactivation of HCV has been shown to be less if the warm ischemia time can be kept under 35 minutes, which shortens the target time for completing this portion of the operation even further ( Clavien et al., 2004 ).

During stage III, severe hemodynamic instability may occur immediately after reperfusion of the transplanted liver, including severe hypotension, bradycardia, supraventricular and ventricular arrhythmias, variable cardiac output, and occasionally cardiac arrest (0% to 5%). These changes are due to recirculation of the residual hyperkalemic preservation solution from the donor liver directly to the recipient's heart or the postreperfusion syndrome (defined as a decrease in mean arterial pressure >30% from baseline for at least 1 minute within 5 minutes of reperfusion). The incidence of this postreperfusion syndrome in adults may be as high as 30%, and epinephrine boluses are usually required to prevent cardiovascular collapse ( Aggarwal et al., 1987 ). Immediately after reperfusion left ventricular function may be impaired and pulmonary capillary wedge pressure, CVP, and PAP usually increase with a major decrease in SVR, while TEE monitoring shows a stable or even decreased left ventricular end-diastolic volume. These contradictory findings may be due to a period of deteriorated left ventricular compliance or “cardioplegia” on reperfusion ( Suriani et al., 1996 ; De Wolf, 1999) .

The etiology of postreperfusion syndrome remains unclear, but it may be caused by the release of vasoactive mediators from the ischemic liver or decompressed portal circulation, changes in the rate of venous return (volume overload), and perhaps an increase in serum potassium. Possible mediators that are highly suspect include nitric oxide and TNF-α with demonstrable increased levels after graft reperfusion ( Nishimura et al., 1993 ) and xanthine oxidase, a generator of cytotoxic oxygen radicals that may produce myocardial dysfunction and cellular damage. Vasoactive drugs for pressor support (norepinephrine, epinephrine, dopamine) may be required, and a balance is reached between a lowered mean arterial pressure and often very low SVR, permitting increased flow to perfusable organs at a lower perfusion pressure. Prophylactic use of aprotinin has been reported to ameliorate the postreperfusion syndrome in liver transplantation, as reflected by a significant reduction in vasopressor requirements ( Milroy et al., 1995 ; Molenaar et al., 2001 ). High filling pressures should be avoided that may cause congestion of the donor liver, bleeding from surgical sites, and biventricular dysfunction with pulmonary edema. Therapies for reducing filling pressures include limiting intravenous infusions, furosemide-induced diuresis, vasodilatation (intravenous nitroglycerin or morphine), nitric oxide, or PGE1.

Blood Loss, Coagulation, and Hemostasis

During liver transplant surgery, the effects of fibrinolysis, thrombocytopenia, coagulation factor, and fibrinogen deficiency on clinical bleeding are not always predictable and transfusion requirements are variable. Portal hypertension with fragile venous collaterals, adhesions from prior operations, and lack of surgical hemostasis contribute to the complexity of massive blood loss and hemostatic management. Independent predictors of increased transfusion requirements include the severity of liver disease or Child-Pugh classification (especially those hospitalized for inpatient support), preoperative PT, history of abdominal operations, preoperative hematocrit and factor V levels, portal vein hypoplasia, reduced-size liver graft, and operative time as a marker for more difficult surgery ( Ozier et al, 1995 ; Maurer and Spence, 2004) . Usually, the greatest operative blood loss occurs during vascular dissection and the hepatectomy phase. During this stage, there is a progressive degradation of the coagulation cascade. A dilutional coagulopathy results along with progressive thrombocytopenia. The range of blood loss may be from 0.5 to 25 times the blood volume ( Borland et al., 1985 ).

Alterations of coagulation in the pediatric patient during OLT have been studied ( Kang et al., 1989 ). Classic hourly monitoring of the prothrombin time, activated partial thromboplastin time (aPTT), and platelet counts demonstrates a progressive prolongation of the PT and PTT, as well as a significant decrease of all clotting factors. On graft reperfusion, there may be profound prolongation of the PTT, usually to greater than 100 seconds. Besides the standard coagulation tests (PT, aPTT, fibrinogen, platelets, and D-dimer), the TEG (thromboelastogram) and Sonoclot (coagulation and platelet function analyzer) are used in the evaluation of coagulation. The TEG is performed using whole blood; it assesses clot formation until an end point of clot lysis or retraction is determined. TEG findings have correlated with clinical bleeding and can assist in treating intraoperative hemorrhage by identifying the cause of the bleeding diathesis (factor deficiency, fibrinolysis, heparin effect, thrombocytopenia, or platelet dysfunction) ( Kang, 1986 ; Zuckerman et al., 1981 ) ( Fig. 28-9 ). Abnormalities of the reaction time (r), the alpha angle (a), or the maximum amplitude (MA) may indicate decreased clotting factors, diminished factor VIII and fibrinogen, or diminished platelet function or number, respectively ( Kang et al., 1989 ). Conversely, a short reaction time is indicative of a hypercoagulable state. This has occasionally been observed in patients who have developed thrombosis after graft reperfusion ( Kang, 1995 ; Gologorsky et al., 2001 ; Planinsic et al., 2004 ).

 
 

FIGURE 28-9  Thromboelastogram (TEG). A, This is a representation of the normal parameters that are measured and analyzed for interpretation of the TEG. B, This figure illustrates the coagulation alterations that are noted during OLT. Note the elements of low platelets that improve the MA after administration of platelets, the development of fibrinolysis, which is treated by EACA and detected early on the TEG at the time of graft reperfusion. In addition, the diminished alpha angle in stage 3 is treated with administration of cryoprecipitate, with noted improvement of coagulation.  (From Kang Y, Gelman S: Liver transplantation. In Gelman S, editor: Anesthesia and organ transplantation. Philadelphia, 1987, WB Saunders.)

 



Increased fibrinolytic activity is observed in patients with ESLD as a result of increased tissue plasminogen activator (TPA) activity and reduced synthesis of fibrinolysis inhibitors. TPA further increases during the anhepatic stages and peaks immediately after graft reperfusion. Various antifibrinolytic agents have been used to counter this accelerated fibrinolysis evident immediately on graft reperfusion in up to 80% of patients, but their precise role remains undefined. These include aprotinin, ε-aminocaproic acid (EACA), and tranexamic acid. Aprotinin is a serine protease inhibitor that prevents the lysis of fibrinogen by inhibiting plasmin, kallikrein, and leukocyte elastase. Studies have reported a significant reduction in blood loss (60%) and packed red blood cell transfusion requirements compared with control subjects, with no increase in thrombotic complications ( Porte et al., 2000 ; Dalmau et al., 2003 ; Porte, 2004 ). Other studies have not reported a benefit with aprotinin use. EACA ( Kang et al., 1987) and tranexamic acid prevent fibrinolysis by inhibiting plasminogen and plasmin, thus preventing the eventual degradation of fibrin. In addition, a significant heparin effect may be seen immediately on graft reperfusion for up to 30 minutes. This effect is caused by the release of endogenous heparinoids from the liver, as well as residual heparin from the preservation solution. Calcium is an important coenzyme in the coagulation cascade. During the dissection and anhepatic phases of liver transplantation, hypocalcemia may develop, especially when large amounts of fresh frozen plasma have been given. In many transplant centers, continuous calcium infusions and magnesium supplements are routine therapy.

The approach to blood product replacement differs in children from adults because of two important concerns: thrombosis of the hepatic artery and postoperative hypercoagulability. Thrombosis of the hepatic artery is the most common serious complication after liver transplantation in children and as such, less fresh frozen plasma and platelets are routinely administered. Following reperfusion, ideally the hematocrit should be maintained at 20% to 30% to minimize the increase in blood viscosity and to limit the risk of thrombotic complications ( Tisone et al., 1988 ). Children have been reported to be at greater risk for hepatic artery thrombosis compared with adults due to small arterial size, no use of intraoperative microscope, and postoperative hypercoagulable state ( Heffron et al., 2003 ). The incidence of hepatic artery thrombosis has been reported in 15% of the mixed-ages pediatric series ( Otte et al., 1990) ; however, it appears to be directly related to the size of the hepatic artery (smaller arteries and livers from neonates or infants having the highest incidence of this complication) ( Mazzaferro et al., 1989 ; Jurim et al., 1995 ; Mas et al., 2003 ; Martin et al., 2004 ) and technical complications during the vascular reconstruction. When a split liver is used, thrombosis is relatively rare (5% to 8%) and similar to the adult rate ( Gridelli et al., 2003 ). Thus, in some institutions, aggressive correction of coagulation is pursued only when there is diffuse bleeding after graft reperfusion or if monitoring reveals fibrinolysis that was not reversed by the new liver. Many transplant centers use the normalization of the PT and platelet count as indicators of recovery of donor liver graft function. Persistent hypothermia, coagulopathy with bleeding, hypocapnia, hyperkalemia, acidosis, absence of bile duct production, hyperglycemia, renal insufficiency, and hemodynamic instability may suggest suboptimal graft function.

Following liver transplantation in children, a decrease occurs in protein C and antithrombin III levels to below 50% of normal values and persists for 10 days. This prolonged decrease is not seen in adults. Immediately after surgery, a 10-fold increase in plasminogen activator inhibitor occurs, with a further increase 6 to 9 days later. Therefore, in the immediate postoperative period between days 4 and 10, children are at an increased risk of thrombosis ( Harper et al., 1988 ). An attempt to minimize this occurrence has resulted in administration of anticoagulation therapy: intravenous heparin, dextran 40, aspirin, and antithrombin III ( Abengochea et al., 1995 ). There are also differences in coagulation between the infant and adult. In the normal neonate, there is a deficiency of vitamin K-dependent clotting factors for several weeks. Protein C is significantly reduced for at least 6 months ( Andrew et al., 1987 ), and protein S concentrations do not increase to within the normal adult range until 3 months of age (Donaldson et al., 1991) . Protein C inhibits the function of factors VIII and V and enhances fibrinolysis, which is enhanced by protein S.

In the child whose body weight is greater than 20 kg, use of the rapid infusion system (RIS) facilitates the rapid replacement of blood products. In this instance, however, blood product replacement is similar to that for an adult. A unit each of red blood cells, fresh frozen plasma, and 250 mL of either normal saline solution or neutral pH-balanced salt solution (Plasmalyte) is mixed in the cardiotomy reservoir of the RIS. This mixture mimics whole blood with a hematocrit of 28% to 30%. Blood replacement may occur at a rate of up to 1500 mL/min if needed.

Hypothermia and hypocalcemia are known to contribute to coagulopathy ( Kang, 1995 ). Altered platelet function and an increased incidence of fibrinolysis are recognized consequences. Thus temperatures below 35°C are best avoided. Finally, cell salvage may be beneficial in the patient undergoing OLT. Blood recovery of up to 30% is expected, but the need for rapid volume replacement limits its use. In addition, the use of the cell saver is contraindicated in patients with viral or bacterial infections, tumors, or FHF without an identifiable cause of the liver failure. Massive blood transfusion has an associated morbidity of more frequent bouts of sepsis, a prolonged stay in the intensive care unit, a higher rate of severe CMV infection, and higher rates of graft failure and patient mortality ( Maurer and Spence, 2004) .

Metabolic Function

Hepatic failure can result in impairment of numerous complex metabolic functions that may significantly impact anesthetic care. The liver plays a critical role in maintaining a normal blood glucose level; hypoglycemia frequently results from failure of gluconeogenesis, insufficient insulin degradation, and a depletion of glycogen stores. Most patients with chronic liver disease are undernourished and fat stores are diminished with impairment of lipid transport and the integrity of cellular membranes.

Altered Glucose Metabolism

Hypoglycemia is rarely seen unless the patient presents with acute FHF or has exhausted their liver glycogen stores. Patients may also be at risk during catecholamine infusions or those requiring insulin for the management of hyperkalemia. During the anhepatic phase, there are several sources of glucose available to the patient such as a significant amount of free glucose (84 mg/dL by day 35 of storage) contained in packed red blood cells ( Miller, 2000 ), 5% dextrose in water (D5W) solution used as a carrier for drug infusions, and the administration of intravenous methylprednisolone for induction of immunosuppression during the portal anastomosis. Hyperglycemia after graft reperfusion is common due to glucose release from ischemic hepatocytes, steroid-induced insulin resistance, and decreased glucose metabolism in hypothermic patients ( DeWolf et al., 1987 ). As such, hourly monitoring of blood glucose levels is essential ( Fig. 28-10 ).

 
 

FIGURE 28-10  Glucose versus time. Mean and SD values are represented. Shaded area represents the anhepatic phase.  (Reprinted with permission from International Anesthesia Research Society from Anesthesia for Pediatric Orthotopic Liver Transplantation by Borland LM, Roule M, Cook DR: Anesth Analg 64:117, 1985.)

 

 

 

Acute Ionized Hypocalcemia and Magnesium

Ionized hypocalcemia results from the rapid transfusion of large volumes of blood products containing citrate, especially during periods of hypothermia and acidosis. Citrate chelates both calcium and magnesium and other divalent cations. Hypotension is usually not significant until an ionized calcium level of 0.56 mmol/L ( Marquez et al., 1986 , Martin et al., 1990 ). The consequence of acute ionized hypomagnesemia ( Scott et al., 1996 ) is not yet apparent, although it may result in a higher incidence of atrial arrhythmias and decreased myocardial contractility. Replacement of calcium with either calcium chloride or gluconate in equivalent calcium doses is equally effective. Administration of calcium chloride in the central line may result in transient arrhythmia, but deposition into tissues from an extravasated peripheral line will result in severe tissue necrosis. The recipient routinely receives sodium bicarbonate and calcium chloride about 1 minute before reperfusion to counteract anticipated hyperkalemia and hypotension.

Hypokalemia is the norm in chronic liver failure. It results from the use of diuretics, altered aldosterone metabolism, and metabolic alkalosis. If ventricular arrhythmias are noted during stages I and II, magnesium replacement is recommended. Potassium replacement is avoided because there is an expected transient twofold to threefold increase in potassium concentration immediately on graft reperfusion. Hypokalemia is common after graft reperfusion, usually as a result of diuresis, receptor stimulation with the use of epinephrine, and uptake of potassium by the new liver. Cautious replacement during the biliary reconstruction phase is appropriate if the patient has no preexisting renal insufficiency and evidence of adequate urine output.

Hyperkalemia should be treated aggressively at any point during the surgery. This electrolyte disturbance usually results from massive transfusion of red blood cells that have an estimated potassium content of 76 mEq/L by day 35 of cold storage or from renal failure ( Miller, 2000 ). The judicious use of diuretics as well as an infusion of glucose and insulin may be of benefit in reducing the potassium load ( De Wolf et al., 1993) . This is most crucial before revascularization of the donor liver. Postreperfusion hyperkalemia (7 to 12 mEq/L) is transitory, with redistribution occurring in 1 to 2 minutes, which seldom needs pharmacologic intervention other than prophylactic sodium bicarbonate and calcium intravenously ( Nakasuji and Bookallil, 2000 ). Washed red blood cells prevent the further development of this problem. When hyperkalemia is life threatening, the use of venovenous hemofiltration or removal of part of the patient's blood volume and washing by the cell saver may be beneficial.

Metabolic acidosis is progressive during OLT and peaks during graft reperfusion. It results from transfusion of blood products and becomes accentuated during the anhepatic stage when liver metabolism of citrate, lactate, and other acids is absent. Whether tissue hypoperfusion is a contributing factor remains unclear; however, this should be balanced by the fact that overall body oxygen consumption is reduced during the anhepatic stage. The threshold for bicarbonate administration is a base deficit of -5 mEq/L. Associated morbidity includes hypernatremia, hypercarbia, and hyperosmolality. Acidosis usually resolves after reperfusion of the graft. Sodium bicarbonate should be administered as indicated and any ongoing problem identified (poor perfusion with lactic acidosis or delayed primary/nonfunction of the graft). Metabolic alkalosis is common postoperatively due to potassium and diuretic therapy and metabolism of citrate or lactate. This may delay weaning of the patient from mechanical ventilation.

Hyponatremia and Hyperosmolarity

Dilutional hyponatremia is common and worrisome at serum sodium levels less than 125 mEq/L. Central pontine myelinolysis (CPM) is a frequently symmetric noninflammatory demyelinating disorder within the brainstem pons. In at least 10% of patients, demyelination also occurs in extrapontine areas. Clinical manifestations are characterized by postoperative confusion and/or weakness or a “locked-in” syndrome after transplantation ( Estol et al., 1989 ; Wszolek et al., 1989 ). The most frequent findings are delirium, pseudobulbar palsy, and spastic quadriplegia, which may result in permanent neurologic deficits. CPM occurs inconsistently as a complication of severe and prolonged hyponatremia, particularly when the sodium is corrected too rapidly. A study by Singh and others (1994) demonstrated that CPM was present in 29% of postmortem examinations of adult liver transplant patients. Risk factors included serum sodium less than 120 mEq/L for more than 48 hours, aggressive intravenous fluid therapy with hypertonic saline solutions, and hypernatremia during treatment.

Empirical data show that CPM is likely to occur when the total perioperative increase in sodium concentration is above 15 to 20 mEq/L ( Estol et al., 1989 ; Yu et al., 2004 ). In these patients, the choice of crystalloid should be Plasmalyte or 0.45% NaCl. Hyperosmolality has also been considered as a contributor to the development of CPM. In the presence of either of these metabolic derangements, the judicious use of THAM is recommended because the osmolality of THAM is 308 mOsm/L, whereas that of sodium bicarbonate is 2000 mOsm/L. In addition, the sodium content of bicarbonate buffer is 8.4% compared with 0.9% NaCl in intravenous solutions.

Temperature Regulation

 

The most effective means of cooling a man is to give him an anesthetic….—Pickering, 1958

 

Surgical procedures that place these patients at risk for unintentional hypothermia are those involving exposure of large skin, serosal, and mucosal surfaces during lengthy procedures under general anesthesia in a cold operating room, especially with no humidification of gases and infusion of cold intravenous fluids. Disruption of the hypothalamic thermoregulatory center causes the patient to become poikilothermic. The most significant contributors to hypothermia in the pediatric patient undergoing OLT are radiant and evaporative heat losses. In addition, the use of venovenous bypass may result in a 0.5° to 1.0°C temperature loss when a heat exchanger is not used. Preservation of the donor liver is inherent on rendering the organ metabolically inert by reducing the core temperature to 4°C through cold preservation techniques. To further extend this cooling period while performing the vascular anastomosis in the recipient, the liver may be wrapped in cold compresses or ice, which will further reduce the core temperature of the patient. With reperfusion, a hypothermia-induced cardiac arrhythmia and arrest may result if the perfusate of the liver is allowed to further cool the sinus node. Modest hypothermia to 35°C is well tolerated with minimal effects on coagulation, but platelet dysfunction, fibrinolysis, and bleeding begin to increase in a linear fashion as the core temperature decreases. Mild hypothermia may be beneficial as a reduction in metabolic oxygen requirements may limit warm ischemia and cerebral and myocardial injury. In pediatric patients, the detrimental physiologic effects of mild hypothermia (32° to 35°C) and the increased risk of infection clearly outweigh these minimal benefits.

Attention should be directed to aggressively maintaining a normal body temperature. This may be achieved by using forced air warming (Bair Hugger) or raising the ambient temperature of the operating theater. In addition, protective barriers should be strategically placed to prevent the operating room table from becoming wet, because this will result in conductive cooling of the patient. Heating of the humidified gases is also an important maneuver.

Pulmonary Function

Hypoxemia is common in pediatric patients with ESLD due to ascites and pleural effusions causing a decrease in FRC and total lung capacity, impaired diffusion capacity, and pulmonary arteriovenous shunting. After the induction of anesthesia, difficulties in ventilation and oxygenation may occur with diaphragmatic paralysis resulting in an acute restrictive lung effect. The increased A–aDO2 usually improves after the abdominal cavity is opened. If relative hypoxemia persists, other causes of venous admixture should be sought.

Factors that may worsen oxygenation during the surgical procedure include clot or air emboli, progression of acute respiratory distress syndrome, transfusion-related acute lung injury, HPS, and pulmonary edema from excessive fluid administration. Finally, extubation of the patient at the end of the procedure is not recommended no matter how short the surgery because 50% to 55% ( McAlister et al., 1993 ) of patients will develop right diaphragmatic paralysis postoperatively, and 25% will have pleural effusions, which compromise pulmonary function. The fast-track approach to anesthetic care may reduce the requirement for postoperative mechanical ventilation but does not reduce the intensive care unit stay after liver transplantation ( Gurakar et al., 1995 ; Findlay et al., 2002 ).

Renal Function

Renal insufficiency is a common finding in patients undergoing OLT and contributes significantly to postoperative morbidity, as well as being an independent predictor of postoperative mortality ( Gonwa, 2005 ). The patient who comes to the operating room with hepatorenal syndrome or ATN should not be expected to show improvement of renal function until after the graft functions ( McCauley et al., 1990). Information collected by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database support the conclusion that renal insufficiency in fulminant hepatic failure and those patients requiring preoperative dialysis or liver-kidney transplantation in cirrhosis predicts lower posttransplant patient and graft survival rates ( Brown et al., 1996 ).

A progressive decline in urine output is expected, with little or none during the anhepatic portion of the surgery without preservation of the IVC or use of VVB. This physiologic alteration has been thought to be secondary to congestion of the kidney from increased renal venous pressures with total cross-clamping of the infrahepatic IVC ( Gunning et al., 1991 ). Whether the incidence of postoperative renal insufficiency is as frequent in the patient in whom the piggyback technique is used remains unclear. The judicious use of the diuretics (mannitol and furosemide) is recommended in the patient who develops oliguria ( Polson et al., 1987 ). If furosemide is used, it should be noted that it may be ineffective in the patient with a low albumin level (average albumin in the patient with liver failure for OLT is 1.8 to 2.5 mg/dL). Although a renal dose of dopamine not exceeding 1.5 mcg/kg per min is often recommended, there is no clear benefit from its use as a renal protective agent ( Polson et al., 1987 ; Gray et al., 1991 ; Swygert et al., 1991 ; Kellum and Decker, 2001) . The incidence of renal complications postoperatively in all patients undergoing OLT remains the same with or without the use of venovenous bypass and/or diuretic therapy ( Schwarz et al., 2001 ; Cabezuelo et al., 2003 ). Acute renal insufficiency is estimated to occur after liver transplantation in up to 67% of recipients ( Rimola et al., 1987 ). Contributing factors include preexisting renal insufficiency, intraoperative complications (suboptimal renal perfusion associated with hypotension, massive transfusion, increased caval pressures), early graft dysfunction, sepsis, and administration of cyclosporine or tacrolimus in the immediate posttransplant period.

▪ GRAFT REDUCTION AND SPLIT-LIVER TRANSPLANTATION

With the plateau in organ availability in the past 5 years and the increased indications for OLT, newer creative techniques have been developed to increase organ availability to pediatric patients. These three techniques—living-related, split livers, and graft reduction—account for up to 30% of all pediatric OLT in some centers. Living related organ transplantation has been discussed earlier.

Reduced-size liver transplantation (graft reduction) was first performed by Bismuth and Houssin (1984) and Broelsch and others (1991) . This procedure involves the dissection of the graft at the back table with preparation of either the right lobe, left lobe, or left lateral segment graft, depending on the size of the recipient. The choice of lobe is related to the size of the recipient. With a recipient-to-donor size discrepancy of 1:2, a right lobe graft is chosen. Similarly, if the recipient-to-donor size discrepancy is 1:4 or 1:8 ( Thistlethwaite et al., 1991 ), a left lobe graft or a left lateral segment graft is chosen, respectively. Because this technique, as with split livers, requires the preparation of the graft at the back table, it lends itself to an increased cold ischemic time of the liver. Vascular anastomoses for this procedure are usually end-to-end with the occasional need for a piggyback technique or the direct anastomosis of the hepatic veins to the vena cava.

In split-liver transplantation, the liver is divided into left and right lobes and transplanted into two recipients ( Emond et al., 1990 ; Otte et al., 1990 ; Renz et al., 2004 ) ( Fig. 28-11 ). The division results in the right lobe containing the portal vein, hepatic artery, IVC, and common bile duct, while the left lobe includes the left lobar branches of the vessels and the left hepatic duct. Transplantation of the left lobe may necessitate the use of interposition vascular grafts, whereas the right lobe is transplanted in a fashion similar to that used for the whole organ. Most frequently, biliary reconstruction is by the Roux-en-Y technique because of the size discrepancy of the donor and recipient bile ducts.

 
 

FIGURE 28-11  Split liver transplantation. Demonstrated here is the use of either a right or left hepatic lobe. Note that the right lobe retains the native donor IVC whereas the left lobe is connected to the recipient IVC by the use of the left hepatic vein.  (A from Broelsch CE, et al.: Liver transplantation in children from living-related donors. Ann Surg 214:428, 1991; B from Broelsch CE, Emond JC, Thistlewaite JR, et al.: Liver transplantation, including the concept of reduced-size liver transplants in children. Ann Surg 208:410–420, 1988.)

 



Living-related liver transplantation from parent to child was described in 1991 by Brolesch, Whitington and others (1991) and has the potential advantages of increasing the availability of organs, reducing the waiting times and deaths on the recipient waiting list, allowing medical optimization of the recipient while minimizing the risk of clinical deterioration, and limiting immunosuppressive therapy by decreasing the immunogenicity of the transplanted organ. In addition, societies in which the criteria for death differ from those previously described ( Tanaka et al., 1993 ) are now able to offer organ transplantation in a socially acceptable manner. Until 1998, the majority of all living donor grafts in the United States went to children under 1 year of age. Living donation is not without risk. Mortality among healthy donors is low, but complications in the donor are relatively common.

These findings then raise the issues of safety and ethics. Potential risks to the donor include transfusion, biliary complications, negative psychosocial aspects (out-of-pocket expenses, loss of income, stress on the donor and donor family, change in body image, inability to work for at least 4 to 8 weeks after donation, and poor recipient outcome), and death. Up to 20% of donors may experience complications related to major abdominal surgery, including pneumonia, atelectasis, wound infection, small-bowel obstruction, incisional hernia, pressure ulcers, phlebitis, neuropraxia or peroneal nerve palsy, and reoperation. Until 1994, all living-donor liver transplants were performed with a left-lateral segmentectomy of one or more lobes or left lobectomy (20% of liver) from parent-to-child or adult-to-small adult. Adult-to-adult transplantation of the right hepatic lobe (60% of liver) was first reported in Japan in 1994, and in the United States a total of 62 live donor liver transplants were completed in 1996, peaking at 506 in 2001, then 355 in 2002, 315 in 2003, and 244 in 2004, for a total of 2518 living liver donors from 1989 to present ( UNOS/OPTN, 2005 ). An estimated 5% of patients on the transplant waiting list would be able to identify a suitable donor, resulting in approximately 750 living-donor liver cases in the United States each year. Adult-sized pediatric patients undergoing A2ALDLT may require a right hepatic lobe to provide sufficient liver mass for the recipient. In 1999, increasing numbers of older children (aged 11 to 17 years) began to receive living donor grafts, which by 2001 accounted for 18 of 107 pediatric living-donor recipients. This change paralleled the increasing number of adult living donor recipients. The donor is left with approximately half or less of their hepatic mass following hepatectomy, but due to the large functional reserve of the liver and its regenerative capacity, clinical evidence of hepatic insufficiency is rare.

Prolonged prothrombin time, elevated serum aminotransferase levels, and increased bilirubin level normalize after 1 week. The donor's native liver can regenerate to its original size within several weeks. The greatest concern for donor safety is the risk for donor death, which has been estimated at 0.28% to 2% to 3%, with 10 reported cases due to technical errors, sepsis, and pulmonary embolism ( Hayashi and Trotter, 2002 ; Trotter et al., 2002 ). The actual mortality rates are probably higher than the number of reported cases. A survey indicated that the lay public would be willing to undergo right hepatectomy as a liver donor, even with a marginal outcome in the recipient. In addition, the respondents were willing to accept a mortality rate among donors that was nearly 100 times the current rate (Trotter et al., 2002 ). On October 7, 2002, the National Institutes of Health launched the A2ALL (adult-to-adult living liver donor) registry, which enables data collection from 10 U.S. centers over 7 years to allow adequately powered studies to examine outcomes and determine the risk-benefit ratio to the donor and recipient.

All three of these techniques have associated complications, with split-liver grafts having the highest rates of associated complications and mortality. Because the integrity of the transected surface of the liver cannot be fully assessed until after reperfusion of the graft, these procedures all have an associated increased ( Moreno et al., 1991 ) blood loss in comparison to whole organ transplantation. In addition, bile duct leaks and seroma formations are not uncommon in the transected liver. Although this specific complication was initially associated with split-liver transplantations, alterations of the surgical techniques have resulted in bile leak complications similar to those seen with reduced-size liver transplantation. The incidence of hepatic artery and portal vein thrombosis is clearly reduced with the use of these techniques. Survival of grafts and of patients at 1 year is better after living-related liver transplantation (81%) ( Epstein, 1985 ) than with split-livers (67%) ( Broelsch et al., 1991 ); however, overall 5-year survival with all of these procedures is similar.

▪ ARTIFICIAL LIVER ASSIST DEVICES

Acute liver failure (ALF) is a disease with a high mortality with standard therapy at present being OLT. Liver transplantation, however, is hindered by the increasing shortage of organ donors even in the setting of an increased volume of living related and unrelated liver transplantation. ALF has a high mortality on the order of 50% to 80%, depending on the inciting event that has resulted in hepatocellular destruction ( Lee et al., 2001 ; Liu et al., 2001 ). For over five decades, liver assist therapies have been explored as alternative therapy for ALF. The bioartificial liver (BAL) therapy appears to be the most promising revelation as a solution to this problem to act as a bridge for ALF patients to obtain liver transplantation or to liver regeneration, as these systems showed significant survival improvement in experimental studies. The ultimate goal of these devices is to prevent the ultimate complication of ALF, which is hepatic encephalopathy, cerebral edema with uncal herniation, and ultimately death.

Nonbiologic Liver Support

The biology of ALF seems to be a result of a number of lower and middle molecular weight toxic substances that are no longer cleared by the dysfunctional hepatocytes or, conversely, the lack of production of hepatotrophic proteins and other molecules essential for cellular homeostasis. Many attempts have been made to develop nonbiologic liver support therapies based on detoxification of the patient's blood (Mito, 1986 ; Rahman and Hodgson, 1999 ; Stockmann et al., 2000 ; Davenport, 2001 ; Kjaergard et al., 2003 ). In the 1950s, hemodialysis was introduced in an attempt to remove toxins; however, no improved survival was appreciated ( Jones et al., 1959 ; Kiley et al., 1958 ; Knell and Dukes, 1976 ; Opolon et al., 1976 ; Matsubara et al., 1990 ). Hemofiltration showed limited outcome ( Bellomo and Ronco, 2000 ; Agarwal and Farber, 2002 ). With the introduction of hemoperfusion and plasma perfusion, a more aggressive approach was also undertaken for the removal of protein-bound substances (Schlechter et al., 1958 ; Mori et al., 2002 ). Various types of resins have also been used ( Rozenbaum et al., 1971 ; Juggi, 1973 ) and were particularly effective in the removal of lipophilic substances. Additionally, activated charcoal as an adsorbent of possible toxin has been used. However, the varied combination of filters, methodologies with charcoal and cation exchange resins, did not improve ultimate survival, although there were invariable reports of clinical improvement as well as survival ( Yarmush et al., 1992 ; Ash, 1994 ; Flendrig, 1998 ).

The most promising nonbiologic support therapies to date combine detoxification of water-soluble and protein-bound toxins in a dialysis system, such as the molecular adsorbents recirculating system (MARS) ( Mitzner et al., 2000 ; Schmidt et al., 2001 ; Stange et al., 2002 ; Steiner and Mitzner, 2002 ). Only MARS treatment to date has shown significantly improved survival in a controlled trial of a subgroup of patients with hepatorenal syndrome. MARS uses a system that integrates charcoal hemoperfusion in parallel with a system for removal of albumin-bound molecules perfused across an albumin exchange chamber. However, the imprecise removal of compounds by these systems and their lack of capacity to synthesize liver-specific proteins and other hepatotrophic factors probably account for their limited effect. Mortality rates in the control group were 100% at day 7 compared with 63% of the MARS-treated group in the aforementioned trial ( Mitzner et al., 2000 ) in ALF patients treated with MARS to date. As with biological support devices, however, a significant number of patients have also been transplanted while being treated, hence limiting the understanding of the true efficacy of this system. The ability to proceed with a true randomized double-blind controlled prospective study in this population of patients raises a number of ethical questions. Clearly there is an approved therapy for ALF, which is OLT. To withhold this treatment with the likelihood that a patient may die as part of the randomized study would be less than ethical, given the mortality rate of 80% in this patient population when left untreated by liver transplantation.

Biologic Liver Support

Biologic approaches for the treatment of ALF rely on the functionality of livers or hepatocytes from xenogeneic or human origin that can be exploited to support the patient's liver. These functions consist of detoxification, numerous metabolic functions, synthesis of proteins (e.g., coagulation cascade proteins and albumin), and various other molecules. Additionally, approximately 70% of the body stores of potassium is maintained in the liver. In 1956, it was demonstrated that fresh bovine liver homogenate could be used to metabolize salicylic and barbituric acids and ketone bodies and produce urea from ammonium chloride ( Sorrentino, 1956 ). The many different biologic approaches that followed thereafter engaged xenogenic cross-hemodialysis, in which the patient's blood was dialyzed against blood of a living animal ( Kimoto, 1959 ) or animal liver tissue preparations ( Mikami et al., 1959 ; Nose et al., 1963 ). Although these techniques could be beneficial to patients with liver failure, they were not considered to be suitable for clinical application because of the complexity of the procedure and the rapid loss of efficacy. Moreover, xenogeneic extracorporeal liver perfusion in humans temporarily had been shown to improve biochemical parameters and the patient's clinical neurologic condition ( Abouna et al., 1999 ; Horslen et al., 2000 ).

A major concern with all nonhuman biological liver assist devices is the potential for xenozoonoses. Xenozoonoses are pathogens that may be transmitted to humans from animal species, in this instance, swine. With porcine cells being the preferential substrate of choice, the concern here is for the introduction of porcine endogenous retrovirus (PERVs), which could prove deadly to humans. Controlled clinical trials indicating survival improvement have as yet not been reported ( Eiseman et al., 1965 ; Stockmann et al., 2000 ). Liver support, however, as mentioned earlier, can be provided by human cross-circulation ( Burnell et al., 1967 ), although the potential toxicities and adverse reactions in the human donor severely limited this approach. Also, significant moral and ethical questions have again been raised, hence forcing researchers to look at other venues and possibilities. Exchange transfusion, another seemingly logical and brilliant maneuver, was associated with reversal of hepatic coma ( Yamazaki et al., 1987 ; Kondrup et al., 1992 ; Clemmesen et al., 2001 ). This treatment in combination with hemodialysis improved survival from 18% to 50% (four of eight patients) in one uncontrolled, nonrandomized trial ( Brunner and Losgen, 1987 ). A major problem with exchange transfusion is the need for a large amount of plasma. Furthermore, this technique might at the same time remove essential hepatotrophic factors. Moreover, the administration of plasma to the patients nullifies any possibility of determining if there is improvement of hepatocellular function by the measurement through the routine measurement of the coagulation system; plasma exchange transfusion will ultimately correct the coagulation defects of ALF ( Brunner and Losgen, 1987 ).

Isolated liver cells have been used in a variety of configurations in the development of the BAL: suspended, substrate attached, and encapsulated in semipermeable membranes. Hepatocytes used for liver support can be divided into two categories: implantable systems and extracorporeal systems. Several case reports and case series concerning transplantation of human hepatocytes have shown beneficial effects in liver failure ( Strom and Fisher, 2003 ). In 1987, Matsumura and others reported the first application of a BAL support system in a patient. The principle of this BAL support system was against a suspension of functioning cryopreserved rabbit hepatocytes. Two years later, Margulis and others (1989) reported a controlled trial that included 126 patients. The BAL device that was used contained porcine hepatocytes in a polychlorovinyl capsule. This BAL treatment was relatively simple and cheap. There was no mention of specified pathogen-free status of the animals from which the hepatocytes were harvested for the two aforementioned systems. What is astonishing is that there have been no further published reports in the literature concerning patient treatment with the Matsamura or Margulis systems.

Use of xenogeneic hepatocytes for hepatocyte replacement and transplantation in humans has not yet been reported. The BAL systems are extracorporeal systems, temporarily connected to the circulation of the patient. BAL systems consist of an artificial component (i.e., the bioreactor and its equipment) and a biocomponent (i.e., hepatocytes, most often xenogenic). Although an increasing number of BAL devices have been produced or are currently under development, only 11 different BAL devices have thus far been exploited clinically. Significant prolongation of survival has been shown in animal studies with BAL systems, and therefore clinical application of a BAL has high expectations ( Flendrig et al., 1999 ; Suh et al., 1999 ; Berry and Phillips, 2000 ; Gerlach et al., 2001 ; Sosef et al., 2002 ).

Hybrid and Modular Assist Devices

Another possibility and consideration for a support device has been to bridge the artificial and bioartificial xenogenic devices given the varying degrees of reported success with the technologies independently. Hence, the Liver Support System (LSS) device ( Gerlach, 1996 ; Sauer et al., 2001 ; Mundt et al., 2002 ) was first developed in Berlin, Germany. This device consists of a specially designed bioreactor endeavored at improving cellular oxygenation and mass exchange. The system is fabricated by a multitude of interwoven hollow fiber membranes, creating a three-dimensional framework over which hepatocyte aggregates are distributed. The LSS is the only system that has been used in clinical studies with primary porcine hepatocytes as well as primary human hepatocytes derived from discarded donor livers. Porcine endogenous retrovirus (PERV) transmission was tested and found to be negative in these clinical trials ( Gerlach et al., 2002 ).

The modular extracorporeal liver support (MELS) system, seemingly the preeminent hybrid of MARS and BAL, combines different extracorporeal therapy units, tailored to suit the individual clinical needs of each individual patient ( Sauer et al., 2002 ). The MELS consists of the LSS system combined with a Detox Module based on single-pass albumin dialysis for removing albumin-bound toxins. The human hepatocytes used were harvested from cadaveric/deceased donors livers that were being discarded because of steatosis, cirrhosis, fibrosis, or mechanical injury. This system has been used in a limited number of patients to date and has shown no profound improvement in morbidity or mortality in the patients treated. No adverse events were observed. Albeit, in all cases, neurologic status improved, and slight improvement of coagulation was observed during the treatment period.

Biochemical Improvement Following Bioartificial Liver Treatment

Hitherto, biochemical improvement as a result of BAL treatment, as judged by elimination of ammonia and bilirubin, was reported in most clinical studies by the varied devices used in the research protocols. According to Mundt and others (2002) , the assessment of only biochemical variables before and after liver support treatment might fail to detect a beneficial effect, because of continuing deterioration of the patient. Ellis and others (1996) , Hughes and Williams (1995) , and Colletti and others (1994) emphasized that any additional function provided by the device is difficult to assess because changes in blood tests may not discriminate between synthetic and detoxification functions of the liver assist device and those of the native liver. Comparing plasma samples from the inlet and outlet of the device at the same time can also be used to assess efficacy of the BAL treatment. Except for the ELAD system, which was associated with an increase in ammonia and bilirubin levels, application of other systems, tested experimentally, was associated with more or less a biochemical improvement. Nonetheless, it is imperative to elucidate whether the noted clinical improvements are in fact due to the devices or simply a result of washout of molecules and substances being measured. The expectation should be, as with all systems that use large-volume plasma exchange for several hours, that the serum levels of molecules such as bilirubin and ammonia will be diminished as they diffuse down their concentration gradients.

Everything considered, the concept of BAL support has proved to be successful in experimental animal studies. In addition, clinical application of BAL devices has proved to be safe by the current methodology of practice. Clinical evaluation of BAL treatment is rather mired by the variation in the patient groups studied. Additionally, the fact that most patients undergo subsequent OLT prevents any clear understanding as to whether or not these systems significantly improve morbidity and mortality. However, neurologic and biochemical parameters appeared to improve after treatment with different BAL systems. To ultimately determine the effect of BAL treatment on survival, controlled, randomized trials in an appropriate animal model or controlled clinical trials in large patient groups will be required to yield statistically significant outcomes. A multicenter human clinical trial, however, raises several ethical and moral dilemmas as previously discussed, given that there is an approved effective treatment for the disease entity to be investigated, that is, liver transplantation. In parallel, BAL research should focus on the replacement of hepatocytes of animal origin by hepatocytes of human origin, either primary hepatocytes or immortalized cell lines, to overcome possible immunologic reactions and xenozoonosis

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ MULTIVISCERAL AND INTESTINAL TRANSPLANTATION

The technical feasibility of intestinal transplantation was first described in 1905 by Alexis Carrel. Given the early successes with kidney transplantation in identical twins during the early 1960s, Lillehei and others described experimental transplantation of the stomach, intestine, and pancreas (1967). Simultaneously, Starzl and Kaupp (1960) described transplantation of multiple abdominal viscera in dogs and, many years later, in humans ( Starzl et al., 1989 ). Until the late 1980s, there were no long-term survivors of small bowel transplantation beyond 6 months. With the introduction of cyclosporine and tacrolimus, as well as an improved understanding of graft rejection in pigs, successful long-term survival was possible ( Grant et al., 1990 ). This procedure has a high rate of morbidity and mortality. The major cause of graft failure is due to acute or chronic rejection (small bowel transplant [SBT] 79%; small bowel/liver transplant [SB/LT] 71%; multivisceral transplant [MVT] 56%). Infection, CMV enteritis, lymphoproliferative disease, and multisystem organ failure are major causes of death. The rate of GVHD after intestinal transplantation is 0% to 16% ( Pirenne et al., 1997 ; Abu-Elmagd et al., 1998 ; Reyes et al., 1998 ; Sudan et al., 2000 ). Patient and graft survival rates are lower than for solid organ transplantation, with approximately one half of the patients receiving intestinal transplants surviving 5 years.

Multivisceral transplantation may include SBT in isolation, in combination with liver transplantation (SB/LT), or in combination with multiple organs (MVT) (Starzl et al., 1991a, 1991b [575] [584]). An isolated SBT is typically recommended for patients on home parenteral nutrition (HPN) who have exhausted their venous access. Combined SBT/LT is recommended for patients with irreversible HPN cirrhosis or intestinal failure associated with a hypercoagulable state that can be corrected by a simultaneous liver transplant. MVT is for patients with locally aggressive tumors that necessitate evisceration of the abdominal organs (duodenal fistulas, locally aggressive tumors, multiorgan failure with a nonreconstructable gastrointestinal tract) or in the patient with benign conditions involving the liver, pancreas, or stomach ( Tzakis et al., 1989 ).

The Health Care Financing Administration's (HCFA) clinical indications for intestinal transplantation implemented in 2001 include impending liver failure due to HPN, thrombosis of major central venous channels, frequent line infection and sepsis, and frequent episodes of severe dehydration. Significant bone disease, metabolic disorders, failure to thrive, and significant limitations on social and personal activities are not considered indications. As most patients function well on HPN, the risks of intestinal transplantation are only warranted with failure of HPN therapy. The goal of intestinal transplantation is to eliminate the need for TPN and to reverse or prevent TPN-associated liver disease. The first year of waiting list candidates for intestinal transplantation with UNOS was 1993.

General Indications

In the pediatric population, chronic intestinal failure results from massive bowel resection (short bowel syndrome) or functional impairment of the bowel due to disturbances in motility or extensive parenchymal disorders ( Okada et al., 1994 ). Necrotizing enterocolitis, intestinal atresia (Todo et al., 1994a, 1994b [624] [625]), midgut volvulus, gastroschisis, microvillus inclusion disease, Hirschsprung disease, and intestine pseudoobstruction are the primary causes of isolated small intestinal failure. This is in marked contrast to the adult population, in which intestinal failure is caused primarily by Crohn's disease and thrombotic episodes involving the major splanchnic vessels. If the length of the small bowel is less than 60 to 70 cm, parenteral nutrition is required (normal length of a small bowel in the infant being 200 to 250 cm). For the patient to survive, HPN is essential. HPN has significant metabolic sequelae, the foremost being liver failure and bone disease ( Bowyer et al., 1985 ; Colomb et al., 1994 ;Sondheimer et al., 1998 ; Chan et al., 1999 ; Wasa et al., 1999 ; Cavicchi et al., 2000 ).

The hepatic dysfunction in the patient on long-term TPN includes, most commonly, hepatic steatosis and cholestasis, phospholipidosis, or cirrhosis, which is observed in 15% to 40% of patients after 3 years. Up to 100% of patients have biliary sludge or gallstones after 6 weeks. In the pediatric population this is a reversible form of liver dysfunction ( Grosfeld et al., 1986 ) if the bilirubin level is less than 30 mg/dL and the patient is returned to total enteral feeding. Patients are followed through the North American Home Parenteral and Enteral Nutrition Patient Registry supported by the Oley Foundation (formerly the OASIS registry, started in 1984) ( Howard et al., 1991 ). This registry reports survival for patients on long-term HPN to be 87% to 96% at 1 year and 70% to 90% at 3 years. The majority of deaths are related to progression of the underlying disease.

In 2001, the majority of the 111 intestinal transplants were performed in only four transplant centers in the United States, with short gut syndrome accounting for more than 60% of these cases. Sixty-one intestinal transplants were performed in pediatric patients. Children younger than 6 years were the recipients of almost half of all intestine transplants, with 74% of registrants on the waiting list 17 years old or younger, and half of these between the ages of 1 and 5 years. Patient and graft survival were 62% and 34%, respectively, at 3 years posttransplant in the 1- to 5-year age group ( UNOS/OPTN, 2005 ). There is no significant difference in outcomes between recipients of SB/LT versus those of isolated SB transplants. The International Transplant Registry and several large centers have shown that 77% to 93% of surviving recipients remain independent of parenteral nutrition beyond 6 to 12 months after transplantation ( Abu-Elmagd et al., 1998 ; Grant, 1999 ; Sudan et al., 2000 ).

The majority of multivisceral transplantations have been performed in adults. The efficacy of these procedures is still undetermined, as only a few procedures have been done worldwide. At the University of Pittsburgh the combined survival of all procedures is approximately 65% at 4 years ( Todo et al., 1995 ). Graft survival is 50% to 60%, with the best survival in patients receiving multivisceral or liver and intestinal grafts. Transplantation of the colon together with the rest of the viscera appears to diminish overall graft survival.

▪ PREOPERATIVE ASSESSMENT

The patient should be evaluated specifically for progressive liver disease and evidence of portal hypertension. Extrahepatic manifestation of the primary disease causing the patient's intestinal failure should be identified. Complications of TPN should be elucidated (infection, catheter occlusion, and hepatic disease). Comorbid conditions such as infection, renal disease, electrolyte abnormalities, and gastroparesis predisposing to regurgitation and aspiration should be considered. Appropriate evaluation of patency of the large vessels of the neck (subclavian and internal jugular veins) is essential because repeated central vein cannulation or long-term indwelling catheter use for the administration of HPN may lead to loss of vascular access due to venous thrombosis ( Grosfeld et al., 1986 ). Doppler ultrasonography is sometimes useful to access central venous access, although the gold standard is a venogram.

Knowledge of the patient's prior surgeries as well as the abdominal vascular anatomy is important, particularly in a patient scheduled for a multivisceral transplant, because these are the most technically complex surgical procedures. A discussion with the surgical team regarding the planned approach is essential, particularly because multiple blood vessels may be partially or fully cross-clamped during the operation. Because of the high rate of postoperative infectious complications, broad-spectrum antibiotics, antifungal drugs, and ganciclovir prophylaxis are routinely administered.

▪ SURGICAL TECHNIQUE: RECIPIENT OPERATION

The final decision to proceed with either a multivisceral or an intestinal transplant is ultimately made after a laparotomy and a meticulous inspection of the native vessels and abdominal organs. Thus, continuous communication between the donor and recipient teams is essential. In addition, procurement of both the donor iliac artery and vein (Starzl et al., 1991a, 1991b [575] [584]) as well as the thoracic aorta is essential for vascular reconstruction of the graft. The graft is usually preserved with cold University of Wisconsin (UW) solution. The length of time the organ is kept in the preservation solution should be minimized because intestinal mucosal damage occurs in UW solution due to increased lipid peroxidation ( Takeyoshi et al., 2001 ).

The operation begins with a midline incision, which is extended to either a unilateral or bilateral transverse subcostal incision. The choice of incision depends on the planned operation, with a bilateral incision used preferentially in the multivisceral transplant. The procedure continues as described by Todo and others ( Fig. 28-12 ); in the patient receiving an isolated intestinal transplantation, the superior mesenteric artery is anastomosed exclusively to the infrarenal aorta. Venous blood from the isolated small bowel graft is drained into the mesenteric venous system at one of three sites: the donor superior mesenteric vein (SMV) to the distal end of the recipient SMV, SMV to the hilar portion of the main portal vein, or donor SMV to the confluence of the SMV and splenic vein (Todo et al., 1994a, 1994b [624] [625]).

 
 

FIGURE 28-12  Varied forms of intestinal and multivisceral transplantations. A, Isolated intestinal transplantation. B, Combined liver-intestine. C, Full multivisceral with resection of the native retrohepatic vena cava with multivisceral transplantation. PV, portal vein; SMV, superior mesenteric vein; SMA, superior mesenteric artery; VC, vena cava; IVC, inferior vena cava.  (From Todo S, Tzaki AG, Abu-Elmagd K, et al.: Intestinal transplantation in composite visceral graft or alone. Ann Surg 216:223–234, 1992, with permission.)

 

 

 

In the recipient of liver-intestine or multivisceral graft, the use of venovenous bypass is usually impossible because of vascular thromboses of the major vessels seen with the long-term use of HPN. The liver is usually placed in a piggyback fashion, and occasionally a temporary portacaval shunt is used to decompress the abdominal viscera. Vascular anastomoses are performed as illustrated in Figure 28-13. The arterial and venous anastomoses are performed before reperfusion of the graft. Arterial anastomoses in this instance are usually with a Carrel patch (see Fig. 28-13 ), containing both the celiac and superior mesenteric artery for the combined intestinal and multivisceral graft to the infrarenal abdominal aorta. In some instances, an aortic conduit may be used to facilitate the anastomoses of the superior mesenteric artery (SMA) and celiac axis to the abdominal aorta. If a portacaval shunt is performed, it is subsequently converted to a portaportal anastomosis to facilitate perfusion of the liver with the splanchnic hepatotropic factors.

 
 

FIGURE 28-13  Multivisceral allograft with the utilization of the Carrel patch with the superior mesenteric artery and the celiac axis origins.  (From Todo S, Tzakis A, Abu-Elmagd K, et al.: Current status of intestinal transplantation. Adv Surg 27:295–316, 1994.)

 

 

 

After completion of the vascular anastomoses, the gastrointestinal continuity is reestablished by anastomosing the appropriate donor intestine to recipient bowel. In the multivisceral recipient, proximal intestinal reconstruction is accomplished by anastomosing the distal esophagus to the anterior wall of the donor stomach. A pyloroplasty is routinely preformed, followed by a gastrostomy, the first of three essential enterotomies, which helps to prevent delayed gastric emptying and decompress the intestine. A jejunostomy is performed for enteral feeding. The final enterotomy is achieved by exteriorization of the distal end of the donor intestine in a chimney fashion. The recipient ileum or colon is then anastomosed to the side of the graft distal to the stoma. Finally, a cholecystectomy follows, as well as biliary reconstruction by a choledochojejunostomy or Roux-en-Y procedure.

▪ ANESTHETIC MANAGEMENT

Small Bowel Transplantation

In the patient scheduled for isolated small bowel transplantation, the anesthetic management is similar to that for other major abdominal surgeries. The patient usually has a central venous catheter, although it is sometimes placed in an unconventional site if the subclavian and internal jugular veins are thrombosed (right atrial, transhepatic, or direct inferior vena caval catheters). These procedures are lengthy and lend themselves to significant third space losses and major fluid shifts. Two large-bore intravenous catheters above the diaphragm and a radial arterial catheter are recommended. CVP should also be monitored as a guide for fluid replacement. If central vein cannulation is impossible, it is best to proceed without its use; femoral vein cannulation may be used for volume replacement. All blood products should be CMV-negative and irradiated to minimize the risk of GVHD.

The choice of anesthetic agents depends on the patient's underlying disease and hemodynamic status. Nitrous oxide should be avoided because it may cause additional bowel distention. The choice of fluids remains controversial in patients undergoing bowel surgery. Not infrequently, significant bowel swelling and distention are noted after reperfusion of the graft. Frequently, diuresis is recommended as a means to treat this problem, although it is often ineffective. Moreover, the etiology of the intestinal edema is most likely related to the preservation of the organ. The use of colloids, preferentially albumin, is recommended in patients who have a low albumin level preoperatively.

Reperfusion of the isolated small bowel graft usually has minimal hemodynamic effects. The reperfusion syndrome seen with liver transplantation is absent in this instance as a result of the relatively low potassium load and the low volume of effluent extruded from the graft. Hemodynamic stability is the norm, and coagulopathy or metabolic derangements are unusual.

Multivisceral Transplantation

Anesthetic considerations for the patient scheduled for multivisceral transplantation are identical to those for the patient undergoing OLT. There are, however, unique and specific considerations with respect to planned vascular anastomoses ( Todo et al., 1995 ; Starzl, 1993 ) (see Fig. 28-13 ). The liver is usually placed in a piggyback fashion in this instance. A partial cross-clamping of the abdominal aorta should be anticipated for the placement of the arterial anastomosis using a Carrel patch (see Fig. 28-13 ).

The surgical procedure is divided into three stages, similar to those with solitary liver transplantation. Completion of the abdominal viscera exenteration during the preanhepatic stage is the period of greatest blood loss ( De Wolf, 1991) . Hemodynamic alterations during this period are related to complications of massive transfusion and manipulation of the abdominal viscera. Ionized hypocalcemia, hypomagnesemia, lactic acidosis, and progressive hypothermia should be anticipated. In addition, a progressive coagulopathy, as seen in the patients undergoing OLT, is expected. Thus monitoring of coagulation is essential. The anhepatic stage of the surgery is usually performed without the use of venovenous bypass. The liver is placed in a piggyback fashion, and vascular anastomosis of the intestine follows. A significant difference with respect to reperfusion of the multivisceral graft from that of the liver is that the arterial anastomoses must be performed before graft reperfusion. The graft is flushed with 50 mL/kg of saline solution before reperfusion to reduce the potassium load from the preservation solution.

Reperfusion of the multivisceral graft is similar to that of the hepatic graft. Hypotension and bradycardia are the usual observations secondary to the release of a large volume of hypothermic, hyperkalemic acidotic preservation solution into the right heart. These changes are usually short lived, with normalization of the hemodynamics within minutes after reperfusion. The incidence of the postreperfusion syndrome in this group of patients is not well defined.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ KIDNEY TRANSPLANTATION

The earliest kidney transplant in a child was performed by Michon and colleagues in Paris on Christmas Eve in 1952. A 16-year-old boy had just undergone nephrectomy for a right ruptured kidney after a fall. Unfortunately, it was discovered he had no left kidney. An ABO-compatible kidney from his mother was placed in the iliac region. Initially, the kidney excreted urine and had good renal function. However, on posttransplant day 21, abrupt anuria occurred, indicating rejection and the patient died. Two years later, Murray and colleagues performed the first successful kidney transplant between two identical twins. The first successful pediatric transplant was performed by Goodwin, Mims, and Kaufman at the University of Oregon in 1959 between pediatric identical twins, one of whom had glomerulonephritis. Eighteen years posttransplant, the kidney was still functioning with normal morphology by biopsy ( Papalois and Najarian, 2001 ).

Routine kidney transplantation in pediatric patients, however, awaited the development of effective immunosuppressive agents. Potent corticosteroids, calcineurin inhibitors such as cyclosporine or tacrolimus, monoclonal antibodies, antimetabolites like azathioprine, and the purine synthetase inhibitor MMF have all been used successfully in pediatric patients to prevent rejection ( Papalois and Najarian, 2001 ). Superior survival and improved long-term growth and development can be obtained with kidney transplantation compared with chronic hemo- or peritoneal dialysis. Newer immunosuppressive regimens relying less on high-dose corticosteroids have further improved the growth and development of children receiving a renal transplant. In addition, pediatric patients who receive a kidney transplant are much more likely to have a normal lifestyle compared with those requiring hemodialysis ( So et al., 1987 ; Beebe et al., 1991 ; Turenne et al., 1997 ; Benfield et al., 1999 ; Elshihabi et al., 2000 ; Healy et al., 2000 ; McDonald et al., 2000 ; Qvist et al., 2000 ; Papalois and Najarian, 2001 ; Qvist et al., 2002 ; Smith et al., 2002 ).

Approximately 300 pediatric patients undergo living related kidney transplantation a year in the United States and 150 to 200 receive a cadaveric transplant. Infants and small children (<15 kg) constitute between 10% and 15% of both cadaveric and living related transplants in the pediatric age group ( Elshihabi et al., 2000 ; McDonald et al., 2000 ).

Numerous studies have shown that the overall success rate for renal transplantation in children and teenagers is similar to that of adults ( Elshihabi et al., 2000 ; McDonald et al., 2000 ; Smith et al., 2002 ). The most recent 1- and 5-year patient survival rates in patients receiving living related kidney transplants were 97% and 94%, respectively. The graft survival rates over the same time periods were 91% and 78% ( McDonald et al., 2000 ). The patient survival rates for recipients of cadaveric organs are slightly lower: 96% at 1 year and 91% at 5 years. However, the graft survival rates at 1 (81%) and 5 years (64%) are much lower in recipients of cadaveric organs. Rejection is the main cause of graft loss ( Elshihabi et al., 2000 ).

In contrast, most reports show that the 1-year patient survival following transplantation is lower if the recipient is less than 2 years of age compared with older children following living-related transplantation (89%); graft survival is also less (≈85%). Both the mortality and graft loss are greater in cadaveric transplantation as well ( Elshihabi et al., 2000 ; McDonald et al., 2000 ). Vascular thrombosis is much more likely to be a cause of graft loss in infants than older children or adults. Although renal transplantation has been successful in very small children (<10 kg), clearly infants and small children constitute a high-risk group for kidney transplantation ( Beebe et al., 1991 ; Singh et al., 1997 ; Benfield et al., 1999 ; Elshihabi et al., 2000 ; Healy et al., 2000 ; McDonald et al., 2000 ; Neipp et al., 2002 ).

Unique Characteristics of Pediatric Recipients

Recipients of renal transplants differ from their adult counterparts in several ways. Obstructive nephropathy or hypoplastic kidneys are common causes for transplantation in the pediatric age group. Glomerulonephritis is less common, and, in contrast to adults, diabetes as a cause of renal failure in this age group is rare ( Benfield et al., 1999 ) ( Table 28-7 ). Consequently, many of the diseases that cause renal failure in children do not recur and successful transplantation could, in theory, be a permanent solution. Also, although most adults have received dialysis before transplantation, up to 35% of children who receive a transplant have never had dialysis before. Of the children who are on dialysis, one half are receiving peritoneal and one half hemodialysis ( Elshihabi et al., 2000 ; McDonald et al., 2000 ). Finally, kidney transplantation using infants or small children as donors has a lower success rate because of the small size of the donor vasculature. Therefore, children usually receive a transplant from someone who is an adult or large child, often much larger than the recipient. In recipients who are infants or small children, the kidney may be many times larger than they would normally have (Miller et al., 1983 ; Beebe et al., 1991 ; Healy et al., 2000 ).

TABLE 28-7   -- Causes of renal dysfunction in the 4898 children undergoing kidney transplantation from the 1997 North American Pediatrie Renal Transplant Cooperative Study

Diagnosis

n (N = 4898)

%

Obstructive uropathy

804

16.4

Aplastic/hypoplastic/dysplastic kidneys

783

16

Focal segmental glomerulosclerosis

582

11.9

Reflux nephropathy

274

5.6

Systemic immunologic disease

232

4.7

Chronic glomerulonephritis

206

4.2

Syndrome of agenesis of abdominal musculature

138

2.8

Congenital nephrotic syndrome

132

2.7

Polycystic kidney disease

131

2.7

Medullary cystic disease/juvenile nephrosclerosis

131

2.7

Familial nephritis

116

2.4

Pyelo/interstitial nephritis

112

2.3

Cystinosis

111

2.3

Membranoproliferative glomerulonephritis type 1

111

2.3

Renal infarct

87

1.8

Idiopathic crescentic glomerulonephritis

84

1.7

Membranoproliferative glomerulonephritis type 2

47

1

Oxalosis

33

0.7

Wilms tumor

30

0.6

Membranous nephropathy

27

0.6

Drash syndrome

27

0.6

Sickle cell nephropathy

9

0.2

Diabetic glomerulonephritis

5

1

Other

326

6.7

Unknown

235

4.8

From Benfield MR, McDonald R, Sullivan EK, et al.: The 1997 Annual Renal Transplantation in Children Report of the North American Pediatrie Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 3:152, 1999.

 

 

 

Infants less than 2 years of age are an important subset of pediatric patients because they are at higher risk for graft loss. Unlike older children or adults, rejection in infants is not the primary cause of failure of the transplanted kidney. The main reason for graft loss in the younger recipient is vascular thrombosis ( Beebe et al., 1991 ; Singh et al., 1997 ; Healy et al., 2000 ; Neipp et al., 2002 ).

Infants also have a higher incidence of delayed function of the renal allograft. This is important because infants and children with delayed graft function have an increased incidence of graft loss in the years following transplantation. Kidneys with delayed function are likely to have sustained permanent injury and are susceptible to failure following rejection or other insult. Providing adequate perfusion of a very large kidney relative to the recipient size to prevent vascular thrombosis and delayed graft function is one of the main challenges for the pediatric anesthesiologist caring for an infant or a small child undergoing renal transplantation ( Tejani et al., 1999 ).

▪ PATHOPHYSIOLOGY OF RENAL FAILURE

The effects of chronic renal failure on infants and children result from the kidney's role as a filter of metabolic waste products and fluid regulation and its active role in hormone production. As the glomerulofiltration rate becomes reduced, the kidney's ability to clear acids, urea, and potassium diminishes; overall poor nutrition is the result. Therefore, infants and children with renal failure have growth retardation and often have developmental delay. Chronic metabolic acidosis, hyperkalemia, and phosphatemia develop. The elevated phosphorus binds to the serum calcium and magnesium, resulting in hypocalcemia and magnesemia. Fractures in active children can occur as calcium is leached from the bones. Chronic uremia can result in central nervous system depression and congestive heart failure and can impair platelet function. Seizures and permanent neurologic damage may be a consequence of electrolyte imbalances and fluxes from renal insufficiency and dialysis therapy. Volume overload can result as the kidney's ability to clear sodium and free water diminishes ( Belani and Palahniuk, 1991 ).

Hormone function of the kidney is affected by renal failure as well. Erythropoietin production may be severely reduced and cause anemia. Renin production becomes elevated as the kidney senses diminished perfusion, resulting in hypertension. Similarly parathyroid hormone levels become elevated as the parathyroid gland responds to a reduced serum calcium level. These changes are present in infants and small children to various degrees despite adequate dialysis and the administration of exogenous erythropoietin and vitamin supplementation. The net effect is a child who is small and frail, hypertensive, and chronically acidotic ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

▪ PREOPERATIVE ASSESSMENT

All systems are affected by end-stage renal disease. Attention must be paid to the extent of renal failure and its effects on organ function and to the child's growth and development. Smaller tracheal tube sizes and intravascular catheters may be needed if the child has not been growing adequately. The cause of renal failure, if a systemic disorder such as oxalosis exists, also affects other organ function. Agenesis or dysplasia of the kidneys may be associated with other congenital disorders such as ventricular septal defects. The presence of cardiac failure or congestive heart disease should be determined. Although most children with renal failure have a hyperdynamic circulation from chronic anemia, some do develop cardiac insufficiency from concurrent congenital heart disease, uremia, or chronic volume overload. The parents should be asked about frequent episodes of dyspnea or asthma attacks. In addition to usual reactive airway disease in children, asthma attacks in children with renal insufficiency may suggest volume overload. The presence of wheezing, rales, dyspnea, an enlarged liver, and hypertension on physical examination suggests fluid overload that may require dialysis before surgery. A history of frequent fractures suggests the child may have brittle bones from hypocalcemia and be at risk for dental injury during anesthesia. Finally, the parents and/or patient should be asked if the child has symptoms of acid reflux or delayed gastric emptying because those conditions are quite common with renal insufficiency ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

When examining the airway, the anesthesiologist must pay particular attention to the teeth, which may be fragile from chronic hypocalcemia. Vascular access is also often difficult in these patients because of frequent hospitalizations and repeated blood drawing and catheterizations. The extremities should be examined to plan where to obtain vascular access and place an arterial catheter, if indicated ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Preoperative Dialysis

One of the things the anesthesiologist and surgeon need to ascertain before surgery is if the patient needs dialysis. The day of the last dialysis and type of dialysis, hemodialysis or peritoneal, should be determined. Some patients who have not previously dialyzed are chronically hyperkalemic. Potassium can be transfused from the donor kidney as it is reperfused, particularly if it has been filled with a high potassium preservative, such as the UW solution. It is therefore best to reduce the potassium to normal levels either via dialysis or ion exchange resins (Kayexalate) before transplantation in the chronically hyperkalemic patient ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

If the patient is hyperkalemic (potassium >6.0 mmol/L), acidotic, or volume overloaded, the surgery should be delayed and dialysis performed. Although peritoneal dialysis may be adequate for the daily treatment of patients and is commonly used in children, it may be inadequate to prepare children for surgery. Therefore, children often are converted from peritoneal to hemodialysis several weeks before transplantation to ensure adequate dialysis. The large-bore (2 mm ID) Hickman catheters are usually used for hemodialysis in infants and young children; they also provide excellent vascular access for the renal transplant procedure ( Beebe et al., 1991 ).

▪ SURGICAL TECHNIQUE

The surgical technique has been described in detail elsewhere ( Miller et al., 1983 ). In relatively larger children (>20 kg), the kidney is placed in the pelvis as in an adult renal transplant. A lower flank incision is used with a retroperitoneal approach. Systemic heparinization is usually not required because heparin can be applied directly by the surgeon through the arteriotomy and venotomy and the anastomoses are performed quickly. The renal artery is anastomosed to the common iliac or hypogastric artery. The renal vein is usually attached to the common iliac or external iliac vein. The ureter is then anastomosed to the bladder ( Fig. 28-14A ). In this approach, only one lower extremity is without circulation before reperfusion. Occasionally, hypotension results from revascularization of the kidney in the older child or teenager. In general, the hemodynamic changes are minimal.

 
 

FIGURE 28-14  Surgical placement of renal allograft in adults and older children (A) versus infants. (B) The vascular anastomosis with the use of an adult-size organ in the pediatric patient is to the aorta and vena cava.  (From Belani KG, Polahniuk RJ: Kidney transplantation. Internat Anesth Clin 29:17–29, 1991.)

 

 

 

In contrast when transplanting an adult kidney into an infant or small child (<20 kg), the kidney is sewn directly on to the aorta and vena cava ( Fig. 28-14B ). Usually the peritoneum is opened and both the aorta and inferior vena cava are cross-clamped. Because the major vessels are clamped, low-dose heparinization (50 to 100 mg/kg) is often used. The lower extremity is deprived of both arterial perfusion and venous drainage during the anastomoses. Because the kidney is much larger relative to the recipient than in the older child or adult, the hemodynamic changes in an infant on reperfusion can be profound ( Beebe et al., 1991 ).

Infants and small children usually require other concurrent operations in addition to the kidney transplant. For example, if the cause of renal failure is vesicoureteral reflux with recurrent urinary tract infections, bilateral nephrectomies are often performed simultaneously to prevent graft sepsis. Concurrent splenectomy, although no longer routine, are occasionally performed if the spleen is enlarged to allow room for the kidney. A large-bore Hickman dialysis catheter is also placed in infants before beginning the transplantation if not already present for intravenous access and CVP monitoring ( Beebe et al., 1991 ).

▪ ANESTHETIC MANAGEMENT

There are many anesthetic techniques that have been used successfully in the anesthetic management of renal transplantation in children. However, when planning the anesthetic, several items unique to renal transplantation must be kept in mind. (1) The patient suffers from chronic renal failure and may manifest many of its effects, including anemia, hyperkalemia, and hypervolemia. (2) The transplanted kidney may not function effectively initially. Therefore, muscle relaxants, such as pancuronium, and other drugs dependent primarily on the kidney for excretion should not be used. (3) Immunosuppressive drugs need to be administered. Allergic reactions and hypotension may occur with some of the agents. (4) The kidney has been ischemic before transplantation, which may increase its vulnerability to further injury. Potentially nephrotoxic agents such as enflurane should be avoided. (5) Adequacy of the intravascular volume status before and following reperfusion of the allograft must be ensured. (6) The anesthesiologist must be prepared to deal with hyperkalemia, hyperglycemia, hypocalcemia, and other electrolyte disorders that may arise over the course of the operation and perioperative period ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Induction and Maintenance of Anesthesia

In general, most children without an intravenous catheter in place receive preoperative sedation with either oral or rectal midazolam (0.5 mg/kg). Ketamine (3 mg/kg) and atropine (20 mcg/kg) may be added to rectal midazolam if a greater level of sedation is desired ( Beebe et al., 1992 ). If an intravenous catheter is in place, midazolam 0.1 to 0.2 mg/kg intravenously may be administered for sedation.

An inhaled induction of anesthesia with sevoflurane with or without nitrous oxide may be used in stable patients with normal gastric function who have been NPO for an adequate length of time. Halothane also has been used for both induction and maintenance of anesthesia in children undergoing renal transplantation. However, hypotension and myocardial depression are more common with inhaled inductions using halothane, and it is the agent most often associated with hepatotoxicity. Therefore, halothane rarely is used since the advent of newer inhaled agents ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Often an intravenous induction of anesthesia is used in children undergoing renal transplantation, particularly if there is a concern that the patient may be unstable and require vasopressors or other drugs. Also, transplant surgeons often order oral immunosuppressive agents preoperatively. Sometimes the children will only take the drugs with milk or juice. If the medications are necessary and the surgery cannot be delayed, an intravenous induction and aspiration precautions are required ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Intravenous thiopental or propofol may be used in healthy children. Ketamine (1 to 3 mg/kg) has proved useful as an induction agent in infants and children suspected to be hypovolemic from recent dialysis. Ketamine maintains the autonomic tone and blood pressure while the volume status is corrected. Maintenance of the blood pressure and a strong pulse with ketamine is also useful when attempting to place an arterial catheter ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Tracheal intubation and skeletal muscle relaxation are always provided by an agent not dependent on the kidney for excretion, such as cisatricurium. Intermediate-acting steroidal muscle relaxants such as vecuronium or rocuronium may also be used, but their action may be prolonged because of partial renal excretion. Succinylcholine is usually not administered except in emergencies because it can raise the serum potassium concentration by 0.5 to 0.7 mmol/L. This could be dangerous in patients who are already hyperkalemic. Also, drugs dependent on renal excretion, such as pancuronium, should not be used because prolonged neuromuscular blockade can result if the kidney does not function properly in the perioperative period ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Following the induction of general anesthesia and tracheal intubation, anesthesia is maintained with isoflurane or desflurane. Even if sevoflurane has been used for an inhaled induction of general anesthesia, it usually is not used for maintenance because of concerns about nephrotoxicity with sevoflurane from fluoride ion and/or compound A production. Although nephrotoxicity in normal kidneys from sevoflurane in humans has never been demonstrated, its effects on transplanted kidneys are unknown ( Artru, 1998 ). Either isoflurane or desflurane is therefore usually used for maintenance of anesthesia.

Nitrous oxide had been used frequently in the past and may still be used in older children. An air-oxygen mixture is usually used in infants to prevent bowel distention that may occur with nitrous oxide in an abdomen that will be quite full with an adult kidney. Opioids such as fentanyl are also administered in moderate doses to reduce the amount of inhaled agent required and to provide postoperative pain relief ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Monitoring

In addition to standard monitors (ECG, pulse oximetry, noninvasive blood pressure, end-tidal gas analysis, temperature), all children undergoing renal transplantation need their CVP monitored. This helps ensure that the children have had adequate volume administered before perfusion of the allograft as well as providing a means to administer immunosuppressive agents that can only be given centrally (thymoglobulin, OKT3, etc.). As noted earlier, in infants, the CVPs are often monitored through a large-bore Hickman catheter. This also serves as an excellent, high-flowing catheter to allow transfusion directly into the central circulation as well as a means to provide dialysis should the kidney initially fail ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Arterial catheters are also useful in infants and small children who require cross-clamping of the aorta. Reperfusion of the kidney in this situation can result in profound hypotension. The beat-to-beat data provided by an arterial catheter allow more rapid correction of hypotension and greater stability. Arterial blood gases obtainable from an arterial catheter are also often helpful. However, because the lower extremity is not perfused during anastomosis, the arterial catheter must be placed in an upper extremity ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Care During Perfusion of the Allograft

In older children who receive a kidney that is appropriately sized for their body weight, patient care during reperfusion is relatively straightforward. The hemoglobin level and electrolytes are checked following induction of general anesthesia. Older children usually do not require blood unless the hemoglobin level is less than 8 mg/dL. Similarly, children with renal failure often have a chronic metabolic acidosis; sodium bicarbonate is rarely required unless the pH is less than 7.25 despite mild hyperventilation. To ensure adequate hydration before reperfusion, normal saline or albumin is administered, provided the hematocrit is adequate until the CVP is 12 to 14 mm Hg. The systolic blood pressure is also allowed to rise to approximately 100 to 120 mm Hg before reperfusion to prevent hypotension when the clamps are released. Sodium mannitol (0.5 g/kg) and furosemide (1 mg/kg) are also administered to stimulate a diuresis. If the systolic blood pressure falls below 90 mm Hg, administration of a vasopressor such as ephedrine may be necessary. Rarely, dopamine may be administered by infusion for persistent hypotension ( Belani and Palahniuk, 1991 ).

Management of perfusion of an adult kidney in an infant is more challenging. Unlike in older children or adults, both the aorta and inferior vena cavae are cross-clamped. Also unlike in adults, low-dose systemic heparinization (50 U/kg) is required before clamping the vessels. Since blood pools in the unperfused lower extremities while the kidney is sutured into place, release of the cross clamps causes ischemic byproducts in both the kidney and lower extremities to enter the central circulation. The adult kidney itself can initially absorb up to 300 mL of blood. Vasodilatation from ischemia can cause a large fraction of the infant's cardiac output to shunt through the new kidney. Occasionally potassium from the preservative solution from the new kidney is transfused rapidly into the central circulation of the infant, resulting in cardiac arrhythmias, hypotension, and sometimes arrest. Surgeons try to prevent this by perfusing the kidney with normal saline to wash out the hyperkalemic preservative solution (UW solution) but are not always successful. Also, in all cases, the kidney has been kept cold to preserve the organ while ischemic. Revascularization can result in significant hypothermia. Hypothermia may subsequently depress cardiac function and interfere with cardiac contractility that is needed to increase the cardiac output to perfuse the new kidney. Hypothermia also interferes with platelet and coagulation function, thereby predisposing the infant or child to increased perioperative bleeding ( Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

In the past, infants receiving this operation had a high incidence of profound hypotension with perfusion of the allograft. This was often followed by vascular thrombosis or ATN. Subsequent experience in infants receiving an adult kidney has been much more successful ( Beebe et al., 1991 ; Healy et al., 2000 ; Humar et al., 2001 ).

The main difference in the care of infants for reperfusion of the kidney received by an infant compared to an older child or adult is that the central venous pressure must be raised to a much higher level, at least 18 mm Hg, before reperfusion. Packed red blood cells and colloids (5% albumin and/or fresh frozen plasma if clotting parameters are diminished) all can be used to achieve this before reperfusion. The systemic blood pressure must also be at least 20% higher than the preoperative value for the infant to tolerate cross-clamp release. Often this is achieved with transfusion to elevate the CVP and lowering the anesthetic concentration to 0.5 MAC. However, some infants require an infusion of dopamine (3 to 5 mcg/kg per min). As in older children and adults, sodium mannitol 0.5 to 1.0 g/kg is administered before cross-clamp release, as well as Lasix (0.5 to 1 mg/kg) ( Beebe et al., 1991 ).

The amount of volume required to raise the CVP to 18 mm Hg is often impressive. Many times greater than 100% of the infant's calculated blood volume is administered before reperfusion of the kidney. Additional volume is often required after reperfusion to replace ongoing blood loss and/or support the blood pressure if still inadequate ( Beebe et al., 1991 ).

One must keep in mind that all blood products administered through the Hickman catheter during kidney transplantation in children require warming because transfusion of cold blood into the central circulation can result in myocardial depression as well as worsen hypothermia ( Beebe et al., 1991 ).

Forced air surface warming with a device such as the Bair Hugger is also helpful to prevent hypothermia in kidney transplantation in children. However the lower extremities should not be warmed until unclamping of renal vessels has been accomplished. Warming of the lower extremists using forced-air surface warming during aortic cross-clamping in animals resulted in hypotension, pulmonary hypertension, and myocardial depression. This was thought to result from greater production of ischemic byproducts in lower extremities warmed during aortic cross-clamping ( Beebe et al., 1993 ).

Immediately before cross-clamp release, atropine (20 mcg/kg) and calcium chloride (10 mg/kg) are administered. Atropine is administered because infants can occasionally develop vagally mediated profound bradycardia with the sudden loss of SVR. Calcium is important because potassium may immediately be transfused into the central circulation from the kidney if it has not been flushed of the high-potassium preservative solution (UW solution) before reperfusion. Often sodium bicarbonate is administered as well (1 mmol/kg) to neutralize the acid that develops in the ischemic lower extremities and new kidney. The dopamine infusion may need to be increased and other inotropes (e.g., epinephrine 1 mcg/kg as single aliquots) may be necessary immediately after reperfusion, but generally the pressure stabilizes at the initial, preoperative value ( Beebe et al., 1991 ) ( Fig. 28-15 ).

 
 

FIGURE 28-15  The systolic blood pressure (BP), heart rate (HR), and central venous pressure (CVP) during renal transplantation in infants.  (From Beebe DS, Belani KG, Mergens P, et al.: Anesthetic management of infants receiving an adult kidney transplant. Anesth Analg 73:725–730, 1991, with permission.)

 

 

 

In both infants and older children, the urine output is replaced milliliter per milliliter with one-half normal saline solution as soon as it can be measured. This solution is chosen because this is the concentration of sodium excreted by a kidney with some degree of ATN and/or having received large doses of diuretics. Replacement of all the urine output with intravenous fluid ensures a brisk diuresis, and it is continued for up to 2 days following surgery. Dextrose is not added to the replacement solution because, if large volumes are administered due to a brisk urine output, hyperglycemia often results (Belani and Palahniuk, 1991 ; Beebe et al., 1991 ).

Postoperative Care

Following closure of the wounds, virtually all older children can have skeletal muscle relaxants reversed and be extubated as soon as they are awake and strong. Pain relief is achieved by means of patient-controlled analgesia with morphine, fentanyl, or hydromorphone. Most older children are cared for in the transplantation unit or ward. Rarely is intensive care unit admission required, although most infants and small children require care in the pediatric intensive care unit overnight. Urine is replaced milliliter per milliliter with one-half normal saline for 2 days postoperatively. After this time, these children are allowed to begin oral intake and diuresis is no longer forced. Discharge to home varies with the patient's ability to tolerate oral feedings, but is usually within 1 week of surgery ( Belani and Palahniuk, 1991; Beebe et al., 1991 ).

Infants usually can be extubated in the operating room or recovery room as well despite the presence of a large adult kidney, which causes obvious abdominal distention. Chest radiographic evidence of pulmonary edema due to the large amounts of fluid administered to infants is present in at least 25% of patients in the recovery room. Despite this, less than 10% of infants require mechanical ventilation in the intensive care unit postoperatively. Fluid management is similar to older children, but the amount of urine output from the adult kidney can be profound (i.e., 80 mL/kg per hr). Electrolytes therefore must be closely monitored. Eventually over several days the kidney adjusts to the smaller size of the recipient and produces the proper amount of urine ( Beebe et al., 1991 ).

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ PANCREAS AND ISLET CELL TRANSPLANTATION

Diabetes mellitus (DM) has reached epidemic levels in the United States, given the increased incidence of obesity estimated at 62% in both the pediatric and adult populations. In 2004, there were a documented 13 million people living with DM and an estimated 5 million undiagnosed or untreated patients in the United States ( Diabetes Control and Compilation Trial Research Group, 1993 ). Worldwide, the disease incidence of DM is astronomical and is noted to be in the top five causes of morbidity and mortality in the industrialized world. This multisystem disease process results in end organ dysfunction in not only the kidneys, but in the neurological, ophthalmologic, cardiovascular, and vascular systems predominantly; it spares no organ system, including the hematologic, from its negative deleterious effects. This all occurs as a result of hyperglycemia, a consequence of the inability of the beta-islet cells of Langerhans of the pancreas to secrete insulin, or inaction at the insulin receptor. Remarkably, the aggregate mass of the islet cells of the adult pancreas weighs only 1 to 1.5 grams. With this seemingly simple genetic or acquired defect of this ostensibly tiny, yet important, mass of cells, DM results in complications with the consequences of blindness in 15%, renal failure and myocardial infarctions in approximately 20%, and strokes and amputations in an estimated 10% and 12%, respectively, of patients afflicted. Given these complications, the costs estimates in 2002 alone were approximately $132 billion spent in for medical care and lost productivity owing to DM ( Diabetes mellitus, 2004 ). With these estimates and noted disease complications, it is then simple to rationalize the need for alternative therapies, such as pancreas, islet cell, and kidney-pancreas transplantation, as potential treatments for patients with DM.

The first clinical pancreas transplantation was performed in 1966, with a simultaneous kidney transplant in a uremic, diabetic patient at the University of Minnesota by Kelly, Lillehei and others ( Lillehei et al., 1970 , Sutherland 1979) . Since that initial event, simultaneous kidney pancreas (SPK), pancreas after kidney transplant (PAK), pancreas transplant alone (PTA), and islet cell transplantation have taken a quantum leap ahead in the field of solid organ transplantation. Over 100 institutions in the United States and nearly the same number worldwide have performed these procedures in the latter part of the 20th century (Gruessner and Sutherland, 1997, 2003 [231] [230]). With the rapid growth of these procedures and their relative success since 1980, and with the introduction of newer immunosuppressive drugs as well as immunosuppressive regimens, the International Pancreas Transplant Registry was created in 1980. Simultaneously, there has been data tracking by UNOS, as mandated by this governmental agency since 1987. In the United States, the Center for Medical Services–Medicare deemed pancreas transplantation to be a reimbursable procedure. The longest survivor of a SPK transplant, in a procedure performed at the University Hospital in Zurich on April 10, 1981, is still alive and well as of 2005 with both organs functional. It has been more than 24 years since the procedure, performed when the patient was 30 years old. Initially, poor success and survival was noted in the 1980s; however, by the early 1990s, over 1000 pancreatic transplants were being performed annually, as the surgical procedure was refined and many of the inherent complications were resolved.

Pediatric patients, however, account for a very small percentage (less than 3%) of all pancreas transplant procedures, and are the smallest relative percentile group of any solid organ transplant. As of April 1, 2005, UNOS reported a total of 147 pancreas (PTA+PAK) and 23 simultaneous kidney pancreas transplants (SKP) performed since 1988 in the pediatric patient population; a total of 170 of the cumulative 27,682 pediatric solid organ transplants performed to date in the United States ( UNOS, 2005 ). Data compiled by the International Pancreas Transplant Registry (IPTR) at the University of Minnesota (tracked to June, 2003) indicate more than 19,600 pancreas transplants reported. The majority (14,300) were performed in the United States.

The total number of pediatric candidates on the waiting list as of April 2005 was 22 for pancreas and 3 for kidney pancreas. These data are in significant contradistinction to those of the adult population: on the UNOS waiting list, at the same time period, there were 1694 and 2455 candidates awaiting pancreas (PTA+PAK) or SKP transplant procedures, respectively. The reason for these disparate numbers is intuitively evident, given the fact that organ transplantation, in most cases, is reserved for patients with end organ damage and complications, a process that may take some 10 to 20 years to develop in the diabetic patient.

In the United States, from 1988 through 2002, 79% of these transplant patients underwent SPK. Approximately 14% of these patients per year underwent PAK, whereas only 6% underwent PTA (data from the IPTR, University of Minnesota). The one-year graft survival for SPK is approximately 86% to 91%, PTA is 83.8%, and PAK is 78.4%. The one-year patient survival data are the following: 95.9% for SKP, 99.2% for PTA, and 96.6% for PAK. These data are the best of any solid organ, transplant patient population, except the living-related kidney transplant patient population. Long-term insulin independence is achieved in 70% to 80% of pancreas transplant recipients ( Bland, 2003 ; Kahl, Bechstein and Redi, 2001) .

Islet cell transplantation, first performed in 1974, is still in its infancy, yet a successful procedure was accomplished with the first case. This procedure, similar in kind to bone marrow transplantation, is dependent on the total mass or number of transplanted islet cells. Most notably, islet allotransplantation had not been consistently successful until the early 1990s ( Gruessner and Sutherland, 2003 ), with the ability of patients to achieve sustained insulin independence. Moreover, success was achieved recently for a repetitive series of multiple consecutive recipients. The number of procedures performed worldwide to date has been reported to be over 450, with patient and graft survival at 75% and 65%, respectively. The majority of procedures have been performed in the United States; and in Europe, the majority of cases have been performed in Giessen, Germany, and Milan, Italy. Although it is possible that islet cell transplantation may become the dominant form of beta islet cell replacement in the near future, the need for SKP, PTA, and PAK will remain, since only 4% of patients with islet cell transplantation are currently insulin independent at one year. This unsettling result may indeed be related to the aforementioned low beta cell transplanted mass and has been demonstrated clinically at the University of Edmonton in Alberta and the University of Miami. At these institutions, strategies to improve beta cell mass have been undertaken by the use of more than one donor per patient. By these means, insulin independence has occurred after the second or third transplant. The acquisition of insulin independence is improved in islet allotransplantation after kidney transplantation (IAK), 45% at one year, and in simultaneous islet and kidney transplantation (SIK), 74% at one year with normalized glycosylated (glycated) hemoglobin. These data have been reported by the Giessen Group ( Meyer et al., 1998 ; International Transplant Registry [ITR] News Letters #8, 1999; #9, 2001).

▪ ISLET CELL TRANSPLANTATION

Islet cell transplantation has gained recognition as an acceptable potential cure for type 1 DM. The Diabetes Control and Complications Trial Group demonstrated the value of maintaining near normal blood glucose levels with intensive insulin therapy, for the prevention or delay of the devastating long-term complications related to diabetic neuropathy micro- and macroangiopathy ( Diabetes Control and Complications Trial Research Group, 1993 ; Manske et al., 1999 ; Sollinger et al., 1998 ; Gruessner and Sutherland, 2003 ). Pancreas transplantation can achieve long-term glucose metabolic control, in a state of complete insulin independence, as noted previously ( Diabetes mellitus, 2004 ). Unfortunately, pancreas transplantation is still associated with some morbidity and mortality ( Powers, 2001 ), hence, the endeavors undertaken to achieve beta cell transplantation. Islet cell transplantation presents the great advantages of a fast and easy procedure with virtually absent or minimal perioperative morbidity, but its success has yet to match those of pancreas transplantation.

Although restricted to the few institutions where the technique is available, the indications for allogeneic islet cell transplantation are currently the same as those for whole organ pancreas transplantation. The procedure is primarily offered to type-1 diabetic patients with end-stage renal failure and is performed as either a simultaneous islet-kidney (SIK) or an islet-after-kidney (IAK) procedure. Another potential indication for islet transplantation is after pancreatic graft failure, as re-transplantation is associated with an increased incidence of graft failure ( Federlin et al., 1999) . Patients with DM due to cystic fibrosis or hemochromatosis are also candidates for islet transplantation although exocrine pancreatic function is also required ( Hering and Ricordi, 1999 ). Transplantation of islets alone in patients with functioning kidneys, in order to prevent the development of diabetic complications, is not yet considered a reasonable option, because of the burden of lifelong immunosuppression and the significant associated risk of developing severe infections and malignancies.

The field of islet cell transplantation made revolutionary progress in the late 1980s by automated islet cell isolation with the use of a computerized centrifugation system and continuous enzymatic digestion of the pancreas for islet purification in discontinuous gradients ( Ricordi et al., 1988 ; Kahl et al., 2001 ). This increased the yield of the islet isolation procedure and allowed for the first time recovery of a critical mass of beta cells from a single donor sufficient for transplantation in a diabetic recipient ( Linetsky et al., 1997 ; Ricordi et al., 1992 ).

Islet cell infusion into the liver is the most common technique and site for this procedure. Other sites of implantation include the peritoneal cavity, epiploic flaps, and the spleen, but without the significant success seen with hepatic implantation. Numerous advantages are associated with the use of the liver: it is easily and readily accessible via the portal route and considered to be immunologically protective. Moreover, functioning islets have been demonstrated to survive there for several years after transplantation, which is similar to dendritic cells ( Ricordi et al., 1996 ).

Monitored anesthesia care (MAC) is all that is required, as with many invasive radiological procedures. Implantation of the islets is performed via a minimally invasive radiological procedure. The portal vein is cannulated by a transhepatic percutaneous approach with angiographic guidance. Alternatively, for SIK transplantation, an open procedure may be performed after completion of kidney transplantation via a midline incision. In this case, the portal system is usually accessed by catheterization of a mesenteric vein. The purified islet suspension is slowly infused with continuous monitoring of the intraportal hydrostatic pressure ( Oberholzer et al., 1999 ).

The morbidity and mortality associated with intraportal islet infusion are minimal. Among 215 recipients of an islet allograft reported to the International Islet Transplant Registry (ITR) from 1990 through 1996, one patient died as a direct consequence of the procedure because of an inadvertent hepatic arterial injury, resulting in a fatal hemorrhage (ITR News Letter #9, 2001). Four nonlethal complications have been reported: perforation of the gallbladder requiring laparoscopic cholecystectomy; tear of the splenic capsule requiring splenectomy; bacteremia due to infusion of a contaminated islet preparation; and portal vein thrombosis in a simultaneous liver-islet transplant procedure ( Hering et al., 1999) .

Through December 2000, greater than 450 islet allografts have been performed worldwide, including 306 since 1990, as a result of the breakthrough due to the automated method of islet isolation (ITR News Letter #9, 2000; Oberholzer, 1999) . Cumulative 1-year patient and graft survival of 96% and 35%, respectively, were obtained in 200 C-peptide negative, type-1 diabetic patients who underwent transplantation from 1990 through 1997. The persistence of graft function can be assessed by measurable levels of basal serum C-peptide, at a threshold of 0.5 ng/ml. The observation that 32% of recipients lose graft function within 1 month of transplantation (and 46% within 3 months) indicates that primary nonfunction might be a major cause of islet graft loss (ITR Newsletter #9, 2000; Meyer et al., 1998 ).

Although the evidence of measurable C-peptide in the serum indicates unequivocal survival of the islet graft, it does not necessarily imply that patients can achieve lasting survival without supplemental insulin. However, it must be emphasized that islet graft function in the absence of insulin independence is still associated with markedly improved metabolic control, glucose counter regulation, and hypoglycemia awareness ( Meyer et al., 1998 ).

Analysis of parameters reported to the ITR has allowed identification of four determinants of persisting graft function at 1 year and insulin independence for more than 7 days. The four criteria derived from these findings that form the basis for state-of-the-art islet allotransplantation are (1) transplantation of an islet mass (6000 islet equivalents [IEQ]/kg body weight; IEQ is the calculated number of islets if all had an ideal diameter of 150 μm); (2) cold ischemia time of the pancreas (< 8 h); (3) immunosuppression induction with antilymphocyte or antithymocyte globulins, or anti-IL-2R monoclonal antibodies, as opposed to OKT3 or none; and (4) liver as the site of islet graft implantation. A significantly beneficial effect is obtained especially when all four criteria are fulfilled (ITR News Letter #8, 1999).

Remarkable results have been obtained by the Giessen group with the implementation of new strategies aimed at promoting islet engraftment and transplant survival (ITR News Letter #8, 1999). The Giessen protocol included, in addition to fulfillment of the four aforementioned criteria, strategies based on observations made in experimental animal models, namely the use of endotoxin-free reagents, the use of antioxidant agents (nicotinamide), and the administration of IV insulin starting 2 to 3 days prior to transplant in order to diminish metabolic demand on the graft. With this protocol, insulin independence has been achieved in approximately 30% of transplanted patients ( Beebe et al., 1995 ).

As already highlighted, the majority of islets are lost early after transplantation. The early events leading to graft loss are collectively termed primary nonfunction and are not related to an immune phenomenon. Rather, they result from poor intrinsic quality of the islet preparation or from interaction of the islets with inflammatory elements of the hepatic microenvironment in which they are implanted. Direct islet damage provoked by cytokines and nitric oxide released by activated Kuppfer cells and sinusoidal endothelial cells, as a result of islet implantation, has been clearly demonstrated ( Kaufman et al., 1990 ). Islets are an essentially avascular graft, which renders them particularly prone to hypoxia, at least during the few days it takes before neovascularization ensues for the islets ( Bretzel et al., 1999).

A second set of problems arises from the high metabolic demand imposed on the islet graft, which results from several factors. A normal pancreas consists of approximately 1 million islets, a figure that is far from being matched with the threshold of 6000 IEQ/kg considered necessary for graft function. When one considers that a significant number of transplanted islets are lost to the noxious inflammatory environment, it is evident that the engrafted islet mass is by and large marginal for its insulin release workload. To make matters worse, islet transplantation currently necessitates conventional immunosuppression, based on the association of several drugs consisting of a calcineurin inhibitor (such as cyclosporin A or tacrolimus) and steroids. All three drugs have long been known to have a diabetogenic effect, which further increases the metabolic load on the islets ( Shapiro et al., 1998 ).

Islet grafts are also prone to destruction by recurrence of autoimmunity in addition to allorejection. There has been no clear indication so far that islets are more susceptible to allorejection than are whole pancreas transplants. The inflammatory insult to islets in a microenvironment of activated macrophages leads to a situation of increased availability of islet allopeptides and antigen-presenting cells, which may enhance alloantigen presentation to host T-cells and, thus, promote ensuing immune graft loss ( Halloran et al., 1997 ; Sutherland et al., 1989 ). Although immune rejection and recurrence of autoimmunity are exceedingly difficult to distinguish, there is strong evidence that the latter is a significant mechanism of islet graft loss despite adequate conventional immunosuppression ( Jaeger et al., 1997 ).

Renewed enthusiasm has arisen from the improved results of clinical islet transplantation. Marvelously, the advent of newer immunosuppressive agents has resulted in a reduction of the need for the administration of diabetogenic calcineurin inhibitors. Notably, due to the synergistic actions of rapamycin and cyclosporin, the dosage of both drugs can be lowered significantly with optimal immunosuppressive properties but minimal toxicity ( Hricik et al., 1998 ; Kahan et al., 1998) . Protocols using mycophenolate mofetil also allow early tapering and withdrawal of steroids in the immunosuppressive regimen ( Hricik et al., 1998) . Induction protocols including anti-IL-2 receptor monoclonal antibodies (basiliximab, daclizumab) are under evaluation ( Basadonna et al., 1998 ).

One major potential advantage of islet grafts over whole pancreas is the possibility of expanding the pool of transplant tissue. Several alternate sources are being explored, such as cell lines or in vitro expansion of cultured cells. However, porcine xenogeneic islets are likely to become an important alternate source of insulin-producing tissue. The rationale for choosing the pig as an islet donor for humans is manifold: (1) its supply is “unlimited” and it is easy to raise in a controlled fashion in a clean environment; (2) its size and weight match those of humans; and (3) the sequence of porcine insulin differs from the human sequence by only one amino acid and adequately substitutes for human insulin.

The difficulties observed in isolating and culturing adult porcine islets can be partially overcome by using fetal or neonatal piglets as islet donors. Mechanisms of islet xenorejection and immunosuppressive regimens are under investigation in several animal models; and ten type-1 diabetic patients have received fetal porcine islet xenografts infused in the portal bloodstream or under the kidney capsule in a Swedish pilot clinical trial ( Groth et al., 1994 ; Berney et al., 1999 ; Soon-Shiong et al., 1994 ). Although no patient became insulin-independent, evidence of porcine islet function for 200 to 400 days was obtained by the detection of porcine C-peptide in the urine of four of the recipients. These results, published in 1994 and obtained under a classic cyclosporin/azathioprine-based regimen, are an encouraging baseline, considering the advances in transplantation immunology and immunosuppression made in the past 10 years (Ricordi et al., 1996, 1997 [509] [507]). A major concern remains regarding the safety of xenotransplantation. The risk of xenozoonoses, notably porcine endogenous retroviruses (PERVs), is under acute scrutiny and is at the center of a debate that goes beyond purely scientific issues. In this regard, it is noteworthy that the ten Swedish recipients of porcine fetal islets screened negative for PERV in a study conducted by the Centers for Disease Control and Prevention in Atlanta 5 to 8 years after transplantation ( Heneine et al., 1998 ; Groth et al., 1994 ).

▪ PANCREAS AND KIDNEY-PANCREAS TRANSPLANTATIONS

Diabetes mellitus is a pathogenic process, which results in hyperglycemia. Typically, type 1 DM (insulin dependent diabetes mellitus [IDDM]) is usually the result of the synergistic effects of genetic, environmental, infectious, and immunologic factors leading to pancreatic beta cell destruction and the resultant absolute absence of insulin production or secretion ( Powers, 2001 ). Its incidence appears to be on the order of approximately 30,000 new onset cases per year in the United States, and it has been the predominant cause of DM in the pediatric population until the end of the past decade.

Type 2 DM (non-insulin dependent diabetes mellitus [NIDDM]) is most often associated with obesity and seen in the elderly population, albeit not exclusively, as it has been noted to be occurring with increasing frequency in the pediatric population, linked to the increased incidence of obesity. Furthermore, genetic differences exist between both IDDM and NIDDM as evidenced by twin studies ( Barnett et al., 1981) . In this classic publication, the concordance rate (both twins affected) of IDDM was 50% as contrasted with a concordance rate of greater than 90% for twins having NIDDM, demonstrating the importance of genetic factors playing a much larger role in this variant of the disease.

Approximately 5% to 10% of diagnosed cases of diabetes are type 1 diabetes mellitus ( Clinical Topic Tours, 2004 ; Powers, 2001 ). Acute complications include diabetic ketoacidosis, in addition to coronary artery disease, peripheral vascular disease, cerebrovascular disease, nephropathy, autonomic and peripheral neuropathy, and retinopathy ( Diabetes Control and Complications Trial Research Group, 1993 ; The Diabetes Control and Complications Trial Research Group, 2000 ; Laditka et al., 2001 ; Rabbat et al., 2003 ). The usual treatment of type 1 DM is the lifelong administration of exogenous insulin. Pancreas transplantation offers patients who have IDDM an endogenous source of insulin, hence its importance for this variant of DM particularly. Type 2 DM (NIDDM) is managed by exercise, weight loss, diet, oral hypoglycemic agents, or exogenous insulin administration ( Powers, 2001 ). It is distinctive by its noted insulin resistance without an absolute insulin deficiency. Acute complications include hyperosmolar non-ketotic coma, but ketoacidosis may also be a mode of presentation.

The primary objective of pancreas or beta-islet cell transplantation is to restore endogenous insulin secretion to a diabetic individual, by the provision of the missing normal beta cell function, in order to achieve euglycemia as well as glucagon response to hypoglycemia, allowing patients to be insulin-free, eat a regular diet, and ultimately prevent the multisystem organ complications previously noted. Occasionally, exocrine pancreatic function is also desired to restore both types of hormonal functions of the pancreas as a result of possibly total pancreatectomy or cystic fibrosis ( Powers, 2001 ; Kahl et al., 2001 ; Hakim, 2003 ; Kiberd and Larson, 2000 ; Paty et al., 2001 ; Coosemans and Pirenne, 2003 ). Carbohydrate, fat, and protein metabolism is expected to normalize after pancreas transplantation and may eventually stabilize and even prevent the development of microvascular disease ( Coosemans and Pirenne, 2003 ). An additional goal of all pancreas transplants is to improve the patients' quality of life ( Hakim, 2003 ; Kiberd and Larson, 2000 ; Kalathil et al., 2000 ). Although exogenous insulin administration with tight glucose control has been shown to delay and even prevent the progression and complications of DM (infections, diabetic retinopathy, nephropathy, and neuropathy), the mean serum glucose was only normalized to 155 + 30 mg/dL, and the primary adverse effect was a two- to threefold increase in the incidence of hypoglycemic episodes ( Diabetes Control and Complications Trial Research Group, 1993 ). Patients who are “brittle diabetics” are best treated with the beta-islet cell replacement therapy.

Unfortunately, progression of macrovascular disease has occurred despite successful kidney and pancreas transplantation. This might be a result of the vascular drainage of insulin from the transplanted graft, directly into the systemic circulation, bypassing the normal portoenteric circulation with drainage of insulin into the liver, its principal site of action ( Nankivell et al., 2000 ). The hyperinsulinemia has been postulated to be pathogenic in this regard.

For diabetic patients with imminent or established end-stage renal disease (ESRD) who have had, or plan to have, a renal transplant, the American Diabetes Association now recommends pancreas transplantation as an acceptable therapeutic alternative to exogenous insulin therapy ( American Diabetic Association, 2003) . Diabetic patients should be considered for pancreas transplantation (PTA) in the absence of indications for kidney transplantation in the setting of frequent, acute, and severe metabolic complications, incapacitating clinical and emotional problems with exogenous insulin therapy, and consistent failure of insulin-based management to prevent complications. In the majority of cases, pancreas transplantation is performed in the setting of type 1 DM with end stage renal disease. Patients for PTA or PAK procedures must have stable and adequate kidney function at the time of transplant, as both the operative procedure and the immunosuppressive agent may result in a further decline in the patient's renal function. As beta-islet cell transplantation is still in the developmental stage, and should be performed only in a controlled setting where facilities for this procedure are available, it should be reserved for patients who may not be appropriate surgical candidates for the previously mentioned procedures.

Absolute contraindications to transplantation of any type include active malignancy or infection; recently treated malignancy not meeting the minimum disease-free observation period as suggested by the Clinical Practice Guidelines of the American Society of Transplantation ( Diabetes Control and Complications Trial Research Group, 2000 ); psychiatric disease so severe or unstable that the stress of this surgery would likely result in marked decompensation; and patients unable or unwilling to take immunosuppressant medications regularly such that graft failure would be certain.

As with kidney transplantation, patients with pancreatic failure for any of the group of procedures for beta-islet cell replacement will require a thorough evaluation, given the constellation of complications of hyperglycemia in diabetic patients. These include ischemic heart disease, cardiomyopathy, renal failure, autonomic neuropathy and gastroparesis, hypertension, cerebrovascular, ophthalmologic, and macrovascular diseases. A meticulous review of the current list of medications and allergies must be undertaken. The patient selected to receive a cadaveric/deceased donor organ requires urgent attention, evaluation, and preparation for the procedure, as the procured organ has a limited life in the preservation solution, usually not to exceed 24 hours. Hence, the anesthetic evaluation, if not previously completed as part of the pretransplant evaluation, will require a de novo thorough evaluation in a timely manner.

The degree of renal dysfunction, if any, is of particular importance, as it will in essence dictate the particular type of procedure that the patient should receive; that is, SPK versus PTA, given the fact that SPK transplants account for 79% of pancreas transplants, and PAK transplants account for 14% of transplants. Most often this decision has been made as part of the preoperative evaluation in order to have the patient placed on the waiting list. Moreover, a determination of the patient's acid-base status, daily serum glucose, electrolyte concentrations, and time of last hemodialysis is of great importance. Anemia associated with ESRD, due to diminished production of erythropoietin and chronic bone marrow suppression, is often associated with an increased morbidity and a diminished graft success ( Koehntop, Beebe, and Belani, 2000 ).

The principal cause of perioperative mortality in adult pancreas recipients is coronary artery disease ( Bland, 2003 ). Hence, screening tests that are mandatory for the preoperative cardiovascular evaluation include coronary angiography in addition to the usual noninvasive studies, which often may include a dobutamine stress echocardiogram ( Rabbat et al., 2003 ; Boston et al., 2002). Moreover, depending on the findings, pretransplantation coronary revascularization reduces the risk of subsequent cardiac events ( Rabbat et al., 2003 ).

The pediatric patient for pancreas transplant, however, is usually devoid of cardiovascular and significant renal complications, as his or her disease process is usually not of as long a duration as in the adult patient. Nonetheless, it is imperative that all end organ damage be fully assessed and excluded from the history.

A history of gastroparesis needs to be addressed appropriately in the pediatric patient as this may warrant an IV rapid sequence induction as opposed to an inhalation induction. Aspiration prophylaxis with H2 receptor antagonists, metoclopramide, and possibly a nonparticulate antacid should be considered. Autonomic neuropathy, which results in gastroparesis, may predispose these patients to episodes of hypotension during the transplant or any anesthetic.

Airway evaluation is of special importance, but adult diabetics have an increased incidence of difficult intubations (Hogan, Rusy and Springman, 1988). This correlates with the longevity of the disease and may prove irrelevant in children.

Surgical Procedures

Several surgical techniques for pancreas transplantation have been described. However, the approach taken for a patient is dependent on the type of procedure chosen. Initially considered, is the recipient to receive an SKP or PTA? After the appropriate blood and tissue typing for human lymphocyte antigen (HLA) markers and ABO compatibility, the organ is prepared on the back table, and vascular grafts, if needed, are also anastomosed at this time, while the organ is maintained in cold preservation solution (a measure to minimize warm ischemic preservation injury).

Postinduction of general anesthesia and placement of the standard monitors including an arterial and a central venous catheter, a surgical midline incision is made in order to facilitate implantation of the pancreas graft as well as the kidney if necessary. The right colon is mobilized by incising the peritoneal reflection, allowing its positioning cephalad. The right iliac vessels are then dissected, and in patients undergoing bladder drainage (BD) technique, the right iliac vein is completely mobilized by ligating and dividing all posterior branches. Mobilizing the sigmoid colon and reflecting it medially then accomplishes exposure of the left iliac system. Ligating and dividing the posterior branches as on the right side then allows mobilization of the iliac vein. The graft is then implanted with the head of the pancreas and the duodenum directed toward the pelvis. In BD grafts, the site for the vascular anastomosis is usually the common iliac vein and the common iliac artery. The graft with duodenal “button” is then anastomosed to the bladder as noted in Figure 28-16 .

 
 

FIGURE 28-16  Solitary pancreas transplant (PTA) with the urinary bladder being utilized for exocrine drainage (bladder drainage [BD] technique). Note the native pancreas is in situ (see text).

 

 

Compared with BD pancreatic allografts, the vascular anastomoses of enteric drainage (ED) grafts are achieved using the more proximal iliac vasculature. Usually, the venous anastomosis is performed in the area of the distal inferior vena cava and the arterial anastomosis is to the proximal right common iliac artery. The organ is then anastomosed to a proximal portion of the jejunum as noted in Figure 28-17.

 
 

FIGURE 28-17  Pancreas and kidney transplants (PAK or SKP) with the donor pancreas vascularized to facilitate enteric exocrine drainage to a proximal portion of the jejunum (enteric drainage [ED] technique). The donor kidney is implanted in the left iliac fossa anastomosed to the femoral vessels and a ureteroneocystostomy is performed. (see text).

 

 

A crucial element at the time of graft reperfusion is the sequence of release of the vascular clamps slowly. Over the course of several minutes, the vascular clamps are removed in the following sequence: proximal venous clamp, distal arterial clamp, proximal arterial clamp, and distal venous clamp. After each clamp is removed, careful hemostasis of bleeding vessels on the surface of the pancreas and at each vascular anastomosis, if necessary, is accomplished before any further clamps are removed.

The surgical approach to pancreas engraftment is dependent on whether or not exocrine secretions will be managed by either enteric (ED) or bladder drainage (BD). From 1987 to 1995, over 90% of pancreas transplants were performed using bladder drainage, initially described by Salinger and others and later modified by Corry and others to include the aforementioned duodenal “button,” which acts as a reinforcement of the anastomosis of the graft to the bladder. This approach allows for serial measurements of urinary amylase, one method for monitoring graft rejection ( Bland, 2003 ; Cooseman and Pirenne, 2003 ; Bloom et al., 1997 ; Cattral et al., 2000 ). Pancreatic biopsies are relatively effortless and less risky as the organ is placed lower in the pelvis (see Fig. 28-16 ).

Chronic loss of pancreatic secretions into the bladder can result in associated complications of metabolic acidosis, a finding in the majority of patients with BD, and perhaps dehydration. Electrolyte abnormalities, which are the result of the loss of sodium bicarbonate-rich pancreatic secretions, are not infrequent. Moreover, local bladder irritation, hematuria, urethritis, bladder leak, neurogenic bladder, chemical cystitis, urethritis, allograft pancreatitis, duodenitis, bladder calculi, urethral erosions, prostatitis, urethral strictures, and infections are all inherent possible complications ( Kahl et al., 2001 ;Bloom et al., 1997 ; Cattral et al., 2000 ). In fact, the frequency of urological complications is high, (50% to 77% with this approach), but it rarely affects either patient mortality or graft loss.

The kidney, if implanted as during a SKP, is positioned in the left iliac fossa and an ureteroneocystostomy is performed. Vascular anastomoses are to the dissected left iliac vessels in the child over 20 kg (see Fig 28-17 ). However, in the infant less than 20 kg, the graft is implanted with anastomoses of the vasculature to the aorta and vena cava.

The enteric drainage technique has become the surgical technique of choice given the reputed constellation of complications ( Bland, 2003 ; Cooseman and Pirenne, 2003 ; Bloom et al., 1997 ; Cattral et al., 2000 ). Initially, enteric drainage was associated with a high morbidity rate because of peritoneal leakage and the need for frequent reoperations. In this procedure, the pancreatic duct is inserted into the small bowel using a “button” of duodenum or a roux-en-Y limb (see Fig. 28-17 ). Although Roux-en-Y was used predominantly for enteric drainage at most centers, its role has diminished. This is primarily a result of the reduced need for monitoring of graft rejection as immunosuppressive regimens have improved with a contemporaneous reduction in the frequency of rejection episodes. Currently over 55% to 77% of pancreas transplants are with enteric drainage as reported to UNOS for the period from 1999 to 2002.

Enteric drainage, by nature, avoids the complications associated with bladder drainage ( Coosemans and Pirenne, 2003 ; Bloom et al., 1997 ; Cattral et al., 2000 ). Vascular management of the pancreatic graft has also evolved. Venous graft effluent can be drained into either the systemic or portal circulation. Portal venous drainage was used in approximately 25% of pancreas transplants from 1996 to 2002 (Bland, 2003 ). Both portal and systemic drainage are associated with excellent glycemic control; however, fasting serum insulin levels are significantly lower in portal drainage without effect on graft survival rates at 1 year for SPK or PAK ( Bland, 2003 ; Cattral et al., 2000 ). PTA has a slightly higher graft survival rate with portal drainage ( Bland, 2003 ). A postulated advantage of portal venous drainage is the avoidance of hyperinsulinemia, which has been associated with advanced atherosclerosis and vasculopathy. Pancreas grafts have been associated with the highest surgical complication rate of all routinely transplanted solid organs. Causes for technical failure of the cadaveric/deceased donor primary pancreas transplants include vascular thrombosis, pancreatitis, anastomotic leak, bleeding, rejection, and infections ( Laftavi et al., 1998 ; Troppman et al., 1998; Humar et al., 2000; Sutherland et al., 2001 ; Michalek et al., 2002).

Vascular thrombosis is the most commonly cited cause of graft failure and previously was assumed to be associated with technical complications of the operation. After a thorough pathological evaluation of sequential cases of massive thrombosis, it is now evident that unrecognized hyperacute rejection is far more common than had been appreciated in this setting. Hence, organ rejection may in fact be the most common cause of graft loss and the culprit to blame. Significant risk factors for graft loss include older donor age, re-transplantation, re-laparotomy for infection, leakage, and bleeding (Troppman et al., 1998; Humar et al., 2000). The quality of a cadaveric/deceased donor graft can directly affect graft performance. As experience with pancreas transplant has increased, the incidence of re-laparotomy has decreased (Humar et al., 2000). Risk factors for recipient death include older recipients, re-transplantation, re-laparotomy for thrombosis, infection, leakage, and bleeding (Troppman et al., 1998).

Anesthetic Management

After appropriate positioning and placement of the standard monitors, anesthesia is induced, either with an intravenous technique or an inhalation technique with agents appropriate for the patient's baseline metabolic condition, followed by orotracheal intubation. In children, a central venous catheter and preferably a radial arterial catheter are inserted (as both iliac arteries may potentially be used for vascular anastomoses). Following the induction, the volatile anesthetic agent should be isoflurane or desflurane in patients with renal dysfunction, as they appear to be virtually devoid of nephrotoxicity and physiologically do not diminish renal arteriolar blood flow. Nitrous oxide is avoided as it increases the size of gas-containing spaces such as the bowel. A balanced anesthesia technique may also be used to maintain general anesthesia.

Morphine-6-glucuronide and normeperidine, the metabolites of morphine and meperidine, respectively, may accumulate in renal failure. The accumulation of normeperedine in this setting causes seizures. Hydromorphone may be used in preference to these agents, as it is less dependent on renal excretion. However, intraoperatively and immediately postoperatively, fentanyl is the opioid of choice; it has minimal associated hemodynamic alterations. The choice of muscle relaxant is dependent on the degree of renal impairment.

In patients with significant cardiovascular disease, direct arterial pressure monitoring and right heart monitoring with a pulmonary artery catheter should be considered as well as continuous transesophageal echocardiogram (TEE) as needed. These measures, however, are rarely necessary in the pediatric patient. Serum glucose levels must be carefully monitored at least hourly during general anesthesia, particularly after graft reperfusion, with maintenance of the serum glucose between 100 and 200 mg/dL ( Koehntop, Beebe and Belani, 2000 ), as hyperglycemia will trigger early islet cell dysfunction (Clark et al., 1982; Imamura et al., 1988). Maintaining serum glucose levels in an acceptable range is accomplished by continuous infusion of regular insulin at a rate of 0.1 U/kg/h, with concurrent dextrose infusion when serum glucose levels are 150 mg/dL. The addition of dextrose ensures uninterrupted intracellular fuel to avoid perioperative ketosis. Pancreatic beta cells may function as early as 5 minutes after reperfusion with the release of insulin (Troppman and Gruessner, 2004). Delayed graft function may be treated postoperatively with an insulin infusion titrated to keep blood glucose levels 150 mg/dL (Sealey, 1988). Somatostatin may also be administered to decrease exocrine pancreatic secretion ( Bloom et al., 1997 ).

Prior to allograft reperfusion with release of the vascular clamps, the hemodynamics are optimized to ensure adequate perfusion and prevent hypotension. Intravenous fluids, either crystalloid or colloid, are administered to achieve a central venous pressure in the range of 12 to 14 mm Hg and a systolic blood pressure of at least 140 mm Hg ( Koehntop, Beebe, and Belani, 2000 ). Alternatively, in patients with a pulmonary artery catheter, careful titration of volume versus filling pressures and cardiac output can be used to optimize intravascular fluid status before vascular unclamping. The end tidal concentration of the inhaled agents may need to be reduced, as reperfusion of both grafts may result in short-lived hypotension as a result of vasodilation, cytokine release, transient myocardial dysfunction, and metabolic acidosis. This may require the administration of fluids, vasopressor (preferably dopamine), intravenous bicarbonate or thamasol, and blood products when appropriate.

It is imperative to maintain adequate and even supranormal perfusion pressure and blood flow to the new allograft. This may help to prevent graft vessel thrombosis, the most common cause of technical pancreatic graft failure ( Bland, 2003 ). This complication more than likely is related to organ rejection. Most patients should preferably be extubated in the operating room at the end of surgery if the usual criteria are met. Serum glucose, hemoglobin, electrolytes, and troponin levels should be checked along with a baseline arterial blood gas for the determination of any residual acidosis immediately upon arrival in the intensive care unit or the recovery room. A patient with a bladder anastomosis often requires supplemental sodium bicarbonate to treat the metabolic acidosis caused by the loss of pancreatic secretions into the bladder ( Sudan, Sudan, and Stratta, 2000 ; Kahl, Bechstein, and Redi, 2001 ; Coosemans and Pirenne, 2003 ; Troppman and Gruessner, 2004). Postoperatively, patients receive 5% dextrose in 0.45% saline as maintenance fluid. Nasogastric and urine output losses are replaced in equivalent amounts with half (0.45%) normal saline.

Pancreas transplant recipients have a higher incidence of acute rejection and immunologic graft loss than any other solid organ recipients. There were four main protocols of initial maintenance immunosuppression from 1996 to 2002 for cadavericprimary pancreas transplants in the United States: azathioprine, cyclosporine, mycophenolate mofetil, and tacrolimus; one other additional agent is sirolimus ( Bland, 2003 ). There is great variation in immunosuppression induction therapy: namely, T-cell depleting polyclonal antibodies (Atgam, lymphocyte immune globulin) versus T-cell depleting monoclonal antibodies (OKT3) versus T-cell nondepleting antibodies (anti-CD25– directed daclizumab [Zenapax] and basiliximab [Simulect]) (Van der Pijl et al., 1996; Gruessner et al., 1997 ; Cattral et al., 2000 ; Kahl et al., 2001 ; Stegall et al., 2001; Knight et al., 2003). In the United States, the most common induction protocol uses an antibody induction in combination with tacrolimus, mycophenolate mofetil, and steroids ( Bland, 2003 ). Pancreas transplant recipients are at risk of developing infection for numerous reasons, including immunosuppression, contamination from the duodenal segment of the graft, and serum glucose irregularity because of DM (Troppman et al., 2004). Infection prophylaxis with broad spectrum antibiotics targeting staphylococci, gram-negative bacteria, anaerobes, and cytomegalovirus is routine in many centers ( Bloom et al., 1997 ; Humar et al., 2000; Coosemans and Pirenne, 2003 ). Prophylaxis against vascular thrombosis consists of either low-dose intravenous heparin (300–500 U/h) or subcutaneous administration of heparin followed by aspirin (Humar et al., 2000; Coosemans and Pirenne, 2003 ).

Pancreas transplantation is now an established procedure for the surgical treatment of diabetes mellitus. It is most commonly performed simultaneously during kidney transplantation. Islet cell transplantation will no doubt be the procedure of choice once it becomes a more routine procedure because of the minimal surgery involved and particularly so, as the scientific obstacles to transform this procedure into one which is customary seem to have been overcome. The perioperative care of patients for pancreas transplantation involves understanding of the pathophysiology of DM and renal failure and the goals of the procedure.

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▪ BONE MARROW TRANSPLANTATION

Bone marrow transplantation was first performed in an infant in 1968, when a 2-year-old boy received bone marrow from his sister to treat Wiskott-Aldrich syndrome. Since that time, bone marrow transplantation is increasingly used to treat a variety of hematologic, metabolic, genetic, and oncologic disorders in pediatric patients. Although the death rate from graft failure, infection, and GVHD is still high (approximately 40%), the success rate has improved over time with advances in immunosuppression, chemotherapy, antibiotics, and supportive care ( Beebe et al., 1995 ). The number of children receiving bone marrow transplantation for various disorders is increasing approximately 10% per year ( Goldman and Horowitz, 2002 ).

Patients can receive bone marrow from a relative or unrelated donor (allogenic transplants) or syngeneic donor (identical twins) or can receive their own marrow back following a course of chemotherapy (Stein et al., 1990 ; Beebe et al., 1995 ). The cord blood of newborn donors has become popular as a marrow source for both pediatric patients and adults. There is minimal risk of viral exposure with cord blood, and the donor is not placed at risk. The primary benefit to cord blood transplantation, however, is for reasons probably related to the immaturity of the newborn stem cell; the incidence of GVHD is markedly lower than standard bone marrow or peripheral stem cell transplants ( Cohena and Nagler, 2003 ).

Prior to receiving a bone marrow transplant, children require bone marrow ablation with chemotherapy and occasionally total body irradiation. The processed donor marrow or stem cells from peripheral or cord blood are administered intravascularly, where they circulate and settle into the patient's bone marrow beds. Occasionally engraftment will fail to occur. Even if engraftment is successful, complications are frequent and include (1) infection, (2) GVHD, (3) toxicity from chemotherapy or radiation therapy, or (4) veno-occlusive disease of the liver ( Gentet and Bernard, 1988 ; Stein et al., 1990 ; McDowall, 1993 ; Beebe et al., 1995 ; Schure and Holzman, 2000 ; Wah et al., 2003 ).

Infection is one of the main causes of morbidity and mortality in bone marrow transplant recipients. Ablation of the bone marrow renders a patient neutropenic for as long as several weeks before full engraftment occurs. T- and B-cell function may also be depressed for several months following bone marrow transplantation and cause recipients to be susceptible to viral and fungal infections ( Stein et al., 1990 ; Beebe et al., 1995 ).

GVHD occurs when the T-lymphocytes derived from the donor's bone marrow react against the host. Acute GVHD occurs between 2 and 10 weeks posttransplantation and may manifest itself as skin rash, watery or bloody diarrhea, or hepatic involvement with hyperbilirubinemia. Chronic GVHD develops 3 to 15 months after bone marrow transplantation. It occurs most commonly in patients who have previously had acute GVHD. Chronic GVHD may present with scleroderma, oral mucositis, interstitial pneumonitis, and polymyositis ( Stein et al., 1990 ; Beebe et al., 1995 ; Schure and Holzman, 2000 ;Wah et al., 2003 ).

Total body irradiation may cause pneumonitis, restrictive cardiomyopathy, pulmonary fibrosis, and oral mucositis. Chemotherapeutic agents such as doxorubicin can result in cardiomyopathy or other toxicities. In addition, veno-occlusive disease of the liver may develop following intensive chemotherapy and radiation therapy. This complication, which is most often fatal, occurs approximately 2 weeks posttransplantation when the small hepatic venules become fibrotic and develop pericentral hepatocyte necrosis and congestion ( Gentet and Bernard, 1988) .

Before receiving a bone marrow transplant, pediatric patients often require anesthesia for indwelling central venous catheterization, bone marrow biopsies, and total body irradiation. Following transplantation, children often require anesthesia for (1) biopsies to evaluate the status of the bone marrow transplant and determine if GVHD has developed and (2) treatment of the surgical complications that may follow this procedure. Most patients undergoing bone marrow transplantation tolerate anesthesia for these procedures without difficulty. However, complications can occur, particularly in those recipients less than 2 years of age, and anesthesiologists must keep in mind the unique medical problems associated with children undergoing bone marrow transplantation ( Stein et al., 1990 ; Beebe et al., 1995 ).

▪ PREOPERATIVE ASSESSMENT

Prior to administering anesthesia, bone marrow recipients must be examined both for potential difficulties from the patient's underlying disease as well the complications arising from the bone marrow transplant. For example, tracheal intubation and airway care are often difficult in patients with the metabolic disorder Hurler syndrome, which is treated with bone marrow transplantation ( Belani et al., 1993 ).

The airway on all children receiving a bone marrow transplant must be examined for the presence of mucositis. Mucositis develops in bone marrow transplant recipients when they are neutropenic before the time the marrow becomes functional. Neutropenia leads to the development of oral infections and mucositis. Mucositis has been a cause of difficult intubation in pediatric bone marrow recipients. Mucositis also may increase the incidence of postextubation laryngeal edema in the postoperative period ( Beebe et al., 1995 ).

Thrombocytopenia is also common in children before the time engraftment occurs and may require platelet transfusions during surgery. Other coagulopathies may also be present, particularly in the presence of hepatic dysfunction ( Stein et al., 1990 ; Beebe et al., 1995 ).

Infection and/or GVHD may result in pneumonitis. Chronic GVHD can cause permanent restrictive pulmonary dysfunction. Preoperative examination of the pulmonary system is therefore important in these children and can help anesthesiologists plan for potential intraoperative complications and postoperative ventilation strategies ( Stein et al., 1990 ; Beebe et al., 1995 ; Schure and Holzman, 2000 ; Wah et al., 2003 ). Although chemotherapy may result in cardiac dysfunction, practically, this rarely is a concern in the pediatric transplant recipients ( Stein et al., 1990 ; Beebe et al., 1995 ).

Finally, radiation and/or chemotherapy and GVHD can result in nausea and vomiting. Tracheal intubation and airway protection may therefore be required ( Stein et al., 1990 ; Beebe et al., 1995 ).

▪ ANESTHETIC MANAGEMENT

There are a variety of anesthetic techniques that can safely be used to anesthetize a child undergoing bone marrow transplantation. No drug, agent, or technique is absolutely contraindicated ( Stein et al., 1990 ; Beebe et al., 1995 ). Some anesthesiologists have raised concern about the use of nitrous oxide in bone marrow recipients because of its known suppression of the enzyme methionine synthetase, which is required for nucleotide synthesis. However, a randomized study of cellular function and bone marrow engraftment of bone marrow recipients exposed to nitrous oxide anesthesia failed to show any deleterious effects of the agent ( Lederhaas et al., 1995 ).

The concern that is unique to bone marrow recipients is the high incidence and potential morbidity from mucositis that occurs when patients are neutropenic. Pediatric anesthesiologists must assume that patients are at risk for developing mucositis at some time during their treatment. Techniques should be chosen, when possible, that minimize potential for mucosal damage in the oropharynx. For example, intravenous propofol has proved useful for sedation for total body irradiation using spontaneous ventilation without airway instrumentation. Propofol also has a rapid recovery profile and antiemetic effects. Propofol may therefore allow earlier feeding and better nutrition in infants undergoing radiation therapy than other intravenous agents such as ketamine or thiopental ( Beebe et al., 1995 ).

The laryngeal mask has also been recommended to provide a more secure airway in infants and small children undergoing total body irradiation. However, damage to the posterior pharyngeal wall has been reported in an infant undergoing total body irradiation ( Marjot, 1991 ). It can prove useful for children with Hurler syndrome or other causes of a difficult airway undergoing total body irradiation or other procedures requiring anesthesia ( Haynes and Morton, 1993 ).

Patients who have already developed mucositis and require anesthesia present a challenge to the pediatric anesthesiologist. Most of these children require tracheal intubation to prevent aspiration of infected mucus. The preoperative airway examination may be difficult due to pain. For the same reason, awake intubation may be impossible as well. Movement and struggling during the procedure may cause bleeding and edema and obscure the laryngeal inlet. A rapid sequence induction usually provides the best conditions for an atraumatic tracheal intubation as well as minimizing the time aspiration of infected secretions may occur. However, in patients with mucositis who develop stridor or other signs of airway obstruction, an inhaled induction of general anesthesia with sevoflurane and oxygen similar to that used with a child with acute supraglottitis may be required. In all cases, the pediatric anesthesiologist must be prepared with adequate suction and several tracheal tube sizes if the laryngeal inlet is narrowed due to edema ( Beebe et al., 1995 ).

Care must be taken with extubation as well. Most patients with mucositis can be extubated when fully awake. Often these patients develop croup in the postoperative period, and may require treatment with dexamethasone (0.5 to 1 mg/kg) and one or more courses of racemic epinephrine treatment. However, patients with mucositis and severe edema of the laryngeal inlet may require prolonged intubation until the edema resolves ( Beebe et al., 1995 ).

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE

PTLD is one of the most life-threatening complications of immunosuppressive therapy in this era of organ transplantation even with the use of newer immunosuppressive agents as well as regimens for induction and maintenance. It is seen after both solid organ and bone marrow transplantation. Patients receiving bone marrow, liver, or kidney transplants have an estimated incidence of 1% to 3%, whereas recipients of heart and heart-lung transplantation have an incidence of 5% to 13%. EBV is confirmed in over 50% of pediatric and 85% of adult patients. The time to presentation of this disease ranges from 1 to 150 months after transplantation.

The most common sites of involvement are the lymph nodes and gastrointestinal tract, with homograft involvement dependent on the organ transplanted. The heart is usually spared from involvement with heart transplantation. However, with heart-lung transplantation, the lungs are the most frequently involved sites ( Sklarin, 1991) . Similarly, the liver is a frequent site of involvement in recipients of bone marrow transplantation.

Because lymphoproliferative disease requires the active infection of the B cell with the virus, it seems that pediatric patients have a higher likelihood for the development of lymphoproliferative disease, the rationale being that pediatric patients have not been exposed to the virus and thus have no antibodies for the prevention of infection. Cyclosporin A–induced suppression of the suppressor T-lymphocyte is responsible for continued uncontrolled polyclonal proliferation of the transformed B-lymphocyte, infected with the episomal EBV DNA. Tumors generated in response to the virus are varied. Non-Hodgkin's lymphomas are the rule with lymphomas.

Treatment of PTLD is by several modalities with reduction of the immunosuppressive agent being the most efficacious. This allows for the improvement of immunosurveillance; however, the reestablishment of the host defense may exacerbate organ rejection. Approximately two thirds of patients will be responsive to this maneuver in EBV-related PTLD. Alternatively, cytokines and immune globulin have been used to enhance the immune response. Fischer-Froehlich and others (2002) reported the use of anti-B-cell antibodies in controlling B-cell lymphomas. α-Interferon in conjugation with gamma globulin has also proved to be efficacious. Surgical resection of tumors has also improved survival in selected cases, with survival reported at 74% relative to the 31% overall survival after the presentation of PTLD ( Stieber, 1991) . Acyclovir inhibits EBV replication. Prophylaxis with this agent may prove to be beneficial because the drug does not prevent proliferation of EBV-infected cells already transformed.

Immunosuppression under tacrolimus apparently does not appear to confer protection from the development of PTLD. The time to development of the disease with its use appears to be similar to CyA; however, enough experience has not yet been gained with the use of this agent.

PTLD holds no special consideration for the anesthesiologist in the immediate preoperative period of the graft transplantation. Because these patients often return to the hospital for additional procedures posttransplantation, several points are noteworthy. Tonsillar hypertrophy is a frequent presentation of this disease in the pediatric patient and often requires bilateral tonsillectomy for diagnosis of the disease as well as management of upper airway obstruction. Occasionally these patients may have been treated with chemotherapeutic agents, which possibly resulted in additional organ dysfunction.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ INFECTIOUS DISEASES

The risk of infection in the transplant patient is directly influenced by two factors: the patient's environmental exposure and the patient's immunosuppressive regimen. The spectrum of causative agents varies with viral infections, with CMV being the most deleterious ( Ho, 1991 ; Patel et al., 1996 ). Antirejection therapy is the most important contributor to the development of infection, with CyA at the top of the list of implicated agents. A clear example of this is the incidence of CMV infection, which has increased from 15% in the pre-CyA era to over 50% today ( Rubin and Tolkoff-Rubin, 1991 ). Evolving evidence also demonstrates that immunosuppressive regimens with identical antirejection effects can have a different spectrum of infection.

The spectrum of presentation of CMV infection is bimodal and has two sources. The virus may be reactivated from a latent phase, or there may be active infection. Although prior infection confers acquired immunity, this may also be the source of latent infection in the immunosuppressed patient. The donor organ has been shown to act as a source of latent infection. The effects of CMV infection may be quite devastating, and damage to the grafted organ is frequently encountered. Obliterative bronchiolitis, chronic coronary atherosclerosis, and vanishing bile duct syndrome are often attributed to CMV infection of the lungs, heart, and liver, respectively.

Other viral infections with significant consequence to the host are hepatitis B and C virus and HIV infection. There is a significant reinfection rate of the hepatic graft in patients known to be ε-antigen positive before transplantation. This has raised the question as to whether this group of patients should have transplants. Hepatitis B is devastating to all graft recipients; a higher-than-normal rate of overwhelming hepatic failure is the rule. Hepatitis C is also a significant problem, with approximately 10% of solid organ recipients acquiring the virus. Data now suggest that up to 50% of organ recipients from donors who are antibody positive progress to develop active infection.

Fungal infections remain a major concern in organ transplantation (Castaldo et al., 1991a, 1991b [100] [101]). Divided into two categories, these infections may be either invasive and opportunistic or represent geographically restricted systemic mycosis. Amphotericin, the mainstay of therapy for systemic infections, has now been joined by fluconazole. Fluconazole is far less toxic than amphotericin and represents a significant advance in antifungal therapy.

Bacterial infections have a devastating consequence, cover a wide spectrum, and include atypical agents such as Nocardia asteroides and Mycobacterium. Prophylactic therapy for several infections has gained wide acceptance. For example, low-dose trimethoprim-sulfamethoxazole has been quite efficacious in the prevention of Pneumocystis carinii infection in all organ transplants, as well as in the prevention of urosepsis in the renal transplant patient.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ GRAFT-VERSUS-HOST DISEASE AND CHIMERISM

GVHD is a major complication of bone marrow transplantation. It occurs in 30% to 40% of patients and is fatal in a third of the patients afflicted ( Pienne, 1991) . The disease is caused by an immunologic attack of the donor cytotoxic T-lymphocytes on the target organs and tissues of the recipient, frequently sites involving the skin, liver, and gastrointestinal tract. Therapy and prevention for this disease are immunosuppression of the response mediated by the cytotoxic T cells. Since CyA selectively suppresses this response, it has become the therapy of choice. Drug therapy is usually required for 6 to 12 months. T-lymphocyte depletion before transplantation is now being explored as an alternate therapy; however, potential problems include graft rejection and leukemic relapse. An additional approach to the prevention of GVHD is the use of monoclonal antibodies to paralyze the recipient immune system.

In the past decade, with the noted subgroup of patients who no longer required immunosuppression, along with clinical understanding of GVHD, genesis of the idea of chimerism began to take hold. It became evident that solid organ transplant recipients were transformed into chimeras, to varying degrees irrespective of the organ transplanted. A chimera is defined as the acquisition by the recipient of the donor leukocytes and lymphoid and dendritic cells, which spread through vascular routes to the host's lymphoid tissue from the transplanted organ. Conversely the engrafted organ will acquire the recipient's immune system and a population of the recipient's leukocytes. This is clearly demonstrated in liver transplantation in which the entire macrophage system, including the Kupffer cells of the graft, is replaced by that of the host ( Starzl et al., 1992 ), which was the first actual biochemical realization of a chimera ( Fig. 28-18 ).

 
 

FIGURE 28-18  Result of traffic of the donor and recipient lymphoreticular cell traffic after successful liver transplantation (white, recipient cells; black, donor cells).  (From Starzl TE, Demetris A, Murase N, et al.: Cell migration, chimerism, and graft acceptance. Lancet339:1579–1582, 1992a.)

 

 

 

The early thoughts and dismissal of leukocyte chimerism-associated mechanisms were diversionary, in view of the early recognition that implanted organ allografts promptly become mixtures of donor and recipient cells (i.e., organ chimerism). The evidence was first presented in 1968 by karyotyping studies of livers that had been transplanted to female recipients from male cadaveric/deceased donors (Kashiwagi et al., 1969 ). Whereas the rest of the allograft remained male, the bone marrow-derived passenger leukocytes including Kupffer cells were largely replaced with recipient female cells within 100 days of transplantation. These alterations were incorrectly assumed to be a unique feature of the transplanted liver until it was demonstrated in 1991 that most of the lymphoid tissues of the engrafted rat (Murase et al., 1991 ) and human intestine ( Iwaki et al., 1991 ) were replaced by recipient cells of the same lineages. An epiphany occurred when comparable findings were confirmed in successfully transplanted human kidney, pancreatic ( Starzl, Demetris, et al., 1993 ; Randhawa et al., 1993 ), and thoracic organ allografts ( Randhawa et al., 1993 ), and thus it became unambiguously clear that all engrafted organs were chimeric structures.

In reality the first evidence, although circumstantial, of chimerism was first noted in the early era of organ transplantation (1962-1963 at the University of Colorado) when recipients who were noted to be PPD (purified protein derivative [tuberculin]) negative were transplanted with organs from donors who were PPD positive. In this series of patients, 77% of the recipients eventually converted to become PPD positive. Yet at the same time these recipients did not develop active tuberculosis. What accounted for this phenomenon? Some postulated that there must be adoptive transfer of donor cellular immunity by leukocytes in the renal graft vasculature and hilar lymphoid tissue ( Kirkpatrick and Wilson, 1964) . However, this postulate was almost unanimously discounted because neither the large quantity of passenger leukocytes nor the fact that these cells migrated was appreciated at the time.

Additional insight and understanding of chimerism were revealed within the past decade by a series of patients who had received solid organ transplantation but could be weaned successfully from the need for daily immunosuppression. In fact, a number of patients are now on chronically reduced levels and intervals for dosing of immunosuppressants or simply none at all as graft tolerance has occurred due to the evident microchimerism.

This two-way cell traffic seen in all forms of organ transplantation appears to be essential in the development of tolerance. In fact, the distinct differences in the amount of lymphoid cell transplanted from the donor along with the graft may confer the likelihood of that organ being rejected, as well as the likelihood for the development of GVHD, as seen with the small bowel transplant donor with its large reservoir of lymphoid tissue. The initial concerns for GVHD in multivisceral and intestinal transplantation, due to the large lymphoid tissue load in the mesenteric organs, have not been shown to be ones of significance. In fact, the increased incidence of GVHD seen in these particular types of solid organ transplantation may be related to the transplantation of lymphoid depleted organs. Indeed, the first two successful kidney (and the first successful transplantations of any species on the planet) was accomplished by sublethal total lymphoid irradiation of the recipients. The epochal events were performed in January and June 1959, first by Joseph Murray and colleagues in Boston ( Merrill et al., 1960 ; Murray et al., 1964 ) and then by a Paris team led by Hamburger (1959) . There had been no leukocyte infusions given to the recipients and the organs were donated by fraternal (not identical) twins and functioned for 20 and 26 years without maintenance immunosuppression. These results were and still remain astonishing and marked the cornerstone event yet unknowingly as the first insight into the mechanism of chimerism ( Starzl, 1992) . That the two-way cell traffic was essential in the prevention of GVHD in all solid organ transplantation was evident by the early 1990s ( Murase, 1995) .

Given these observations, it would seem evident that transplantation of the donor's bone marrow simultaneously with the graft may play a role in the induction of immunotolerance and the prevention of graft rejection. Infusion of donor-derived cells can improve organ allograft survival in animal models (Fontes et al., 1994, 1996 [191] [192]). Under certain conditions, it can even induce tolerance (i.e., unlimited organ survival without any maintenance immunosuppressive therapy) ( Starzl et al., 2004) . Among the numerous experimental protocols leading to tolerance of solid organs in animal models, how can we find our bearings in human transplantation? Numerous problems have yet to be solved: the type and amount of donor-derived cells (including stromal cells) to be used, the timing for infusion of donor cells in keeping with organ transplantation, the route of infusion (should it be intravenous, into the portal vein?), and the conditioning regimen. The first clinical trials would appear to indicate that tolerance induction in humans using donor-derived cells is a relatively safe solution that is both promising and realistic. A number of clinical experiments have demonstrated that this simultaneous transplantation has in fact conferred variable immunotolerance on the engrafted organ in all types of solid organ transplantation ( Shapiro et al., 1996 ).

The need became evident for minimal immunosuppression in transplantation, as overimmunosuppression clearly led to the prevention of the establishment of the chimera or microchimerism. Central to this clinical trial is the harvesting of the recipient's bone marrow for storage to be later used for bone marrow rescue in the event that there is the development of GVHD. Albeit the current data appear to be muddy, as the methodologies of induction of immunosuppression have changed as well as the agents being used for maintenance of therapy. The realization of the need to alter the prior practice has now lengthened the time frame of the clinical trials given this change.

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▪ XENOTRANSPLANTATION

As already outlined, the significant advances achieved in the field of organ transplantation, in the past three decades particularly, have led to an increased demand for organs, creating a wide gap between organ availability and supply. While the number of transplants performed worldwide is limited by this dramatic donor shortage, alternative sources need to be explored where a wider availability of organs would allow an expansion rather than a contraction of the indication for transplantation and at the same time a relaxation of the patient selection criteria. Hence, the renewed interest in xenotransplantation, which has been observed in the last decade ( Evans et al., 1992 ; Cooper et al., 1997 ).

Before the concept of xenotransplantation advances to a clinical reality, at least three practical challenges must be overcome. The first consists of the immunologic barriers as will be noted. The second issue is related to the potential risk of the introduction of novel and earth-shattering infectious organisms into the human recipient (and possibly into the human population at large) via the xenotransplant, often referred to as xenozoonoses. Last, xenotransplantation raises issues and concerns in several different fields, most notably theological and anthropological, with psychological, ethical, and legal considerations ( Caplan, 1985 ; Reemtsma, 1985 ). This commentary mainly focuses on the immunologic issues of xenotransplantation as well as on the risk of exposing the general public to novel infectious agents, xenozoonoses.

The pig, although considered to be the most suitable animal source of organs for humans, has significant obstacles associated with this endeavor as there are three main rejection mechanisms preventing the clinical application of a pig-to-human xenotransplantation procedure: hyperacute rejection (HAR), acute humoral xenograft rejection (AHXR), and cellular xenograft rejection (CXR). These immunologic barriers are significantly more difficult to overcome in a pig-to-human xenotransplant compared with a primate-to-human xenotransplant (e.g., baboon-to-human). In 1964, Reemtsma and others described six human recipients of chimpanzee kidneys, the longest survivor of whom died of causes unrelated to rejection 9 months after xenotransplantation ( Reemtsma et al., 1964 ; Reemtsma, 1991 ).

The first cardiac xenotransplantation, performed by Hardy and others in 1964, also represented the first attempt at cardiac transplantation in humans, predating Barnard's report by nearly 4 years. Since 1964, when Hardy and others at the University of Mississippi performed the world's first heart xenotransplant using a chimpanzee as a donor, there have been eight documented attempts at clinical heart xenotransplantation. Five of these donors were nonhuman primates (two baboons, three chimpanzees), and three were domesticated farm animals (one sheep, two pigs) ( Hardy et al., 1964 ; Cooley et al., 1968 ; Marion, 1969 ; Shapiro, 1969 ; Barnard et al., 1977 ). However, by the time the first human neonatal cardiac xenotransplantation was performed by Bailey in 1984 (the so-called “Baby Fae” case), there had been only limited experimental experience with prolonged graft survival in the newborn xenotransplant recipient. Baby Fae was a newborn infant with HLHS and became the longest survivor (Cooper et al., 2000 ) ( Table 28-8 ). This recipient heart of an ABO-blood group mismatched baboon functioned for 20 days ( Bailey et al., 1986 ). Studies presented by Bailey and others shortly before the Baby Fae case described a mean survival time of 72 days in newborn lamb-to-goat xenotransplants, with one survivor living to 165 days ( Bailey et al., 1985a ,b). Czaplicki and others in 1992 described a case in which they attempted the xenotransplantation of a pig heart into a human recipient with Marfan's syndrome.

TABLE 28-8   -- World experience in clinical heart xenotransplantation

Rights were not granted to include this content in electronic media. Please refer to the printed book.

Modified from Tanlgichi S, Cooper DKC: Clinical xenotransplantation—past, present and future. Ann R Coll Surg Engl 79:13–19, 1977. (Copyright © The Royal College of Surgeons in England. Reproduced with permission.)

 

 

 

In 1992, Makowka and colleagues (unpublished) in Los Angeles transplanted a pig liver into a 26-year-old woman dying of acute liver failure from autoimmune hepatitis and fulminant hepatic failure. Subsequently, also in the early 1990s, two baboon-to-human liver xenotransplantations were performed in Pittsburgh ( Marino et al., 1994 ). These experiences demonstrated that a human might live with a baboon liver. However, while in the past nonhuman primates have been preferred as a source of organs for humans, the transplant community and regulatory agencies (U.S. Food and Drug Administration) in the countries dealing with this issue currently are more auspiciously looking to pigs. This is because nonhuman primates potentially carry an increased risk of infection transmission and also because of a variety of other ethical and practical concerns (e.g., organ size and species on the endangered lists). The reality is that in the two cases of baboon-to-human liver xenotransplantation mentioned, it was possible to demonstrate only a single case of a baboon pathogen (a CMV), which was apparently transferred to a patient, and for all other primate xenotransplantation, there have been no reports of other zoonoses. Notwithstanding, this event did not result in a disease process ( Michaels and Simmons, 1994 ), and the death of both patients was unrelated to any sort of xenozoonoses. In both recipients, evidence was found of an adequately functioning liver mass, sufficient to sustain life. On the other hand, even though proved feasible, the use of baboons is complicated mainly by limited availability, inadequate size of organs for adult human beings, and high costs as well as the political and ethical issues raised.

Another nonhuman primate, the chimpanzee, is most likely the perfect donor for human transplantation, biologically speaking, primarily due to the very small genetic differences between this species and humans, or rather the enormous amount of genetic homology shared by the two; approximately 98% of the DNA of both species appears to be identical. Hence the patient, a woman as reported above in 1964, lived for 9 months ( Reemtsma et al., 1964 ) without dialysis with a functioning chimpanzee kidney and died free of rejection, possibly due to this shared genetic homology. The endangered status of the chimpanzee, however, prevents their widespread use for clinical purposes. In the United States, only 25 to 50 chimpanzees may be used annually for biomedical research, and it is estimated that only 70 chimpanzees per year would be available worldwide as potential organ donors. Therefore, their use (as well as the use of other great apes such as the gorilla) would further jeopardize these species and would raise insurmountable ethical concerns without solving or greatly impacting the organ shortage problem.

In the past decade, the use of genetic engineering has resulted in a marked improvement of the survival time of a pig organ transplanted in a nonhuman primate model ( Cozzi et al., 1995) . Nevertheless, substantial immunologic barriers still exist, and strategies to prevent HAR and AHXR in a pig-to-primate need to be developed further. Although the use of genetic engineering has resulted in significant improvement in survival time for a pig organ in a nonhuman primate (close to 3 months), these survival times do not yet approach that of human organ allotransplantation. The ultimate goal here is obviously to obtain immunologic tolerance of the graft by the recipient organism and hence enhanced graft and patient survival.

The barrier to successful xenotransplantation of vascularized porcine organs into humans is antibody and complement-mediated HAR, mostly as a result of naturally occurring anti-Gal(1,3) Gal antibodies. This carbohydrate epitope, which is not found in humans or Old World monkeys, may be induced by gut bacteria, which possess a related Gal(1,3)Gal structure ( Galili et al., 1988 ). The strategies to deal with these include transgenic approaches designed to reduce the antibody titer and to express either membrane-bound or soluble complement regulators, most notably, CD46, CD55, and CD-59. These approaches may be combined with attempts to modify the donor animals by the inactivation of their galactosyl transferase genes so as to diminish the synthesis of Gal(1,3)Gal, although this is still experimental in the pig. Such a strategy will probably also require nuclear transfer technology for the production of pigs with “knockout genes” or composite transgenic technology with multiple gene transfer ( Lambrigits et al., 1998 ; Sandrin and Mckenzie, 1999 ). In this regard preliminary evidence of these approaches shows that it appears to attenuate experimental hyperacute rejection.

Successful xenotransplantation may also require the induction of T-cell tolerance with the use of deliberate mixed hemopoietic chimerism using donor and recipient bone marrow; an approach that has been used successfully in baboons to transiently suppress anti-Gal responses in marrow transplant ( Ohdan et al., 1999 ). Human-to-baboon bone marrow transplantation has already been performed, after conditioning the donor marrow with nonlethal irradiation. It remains to be seen if incomplete or even full chimerism will change the image of animal organs sufficiently to make them immunologically be viewed as “allografts” by humans.

Newer approaches are of necessity complex if we are to entirely eliminate the offending epitope principally involved in xenografting. Cloning of pigs with inactivated Gal glycosyltransferase systems by a combination of available technology (notably cloning of animals from somatic cells) and modification of candidate genes in such clones by homologous recombination may provide an alternative to stem cell approaches ( Wilmut et al., 1997 ; McGrath et al., 2000 ).

There are also a number of other concerns limiting the wide application of xenotransplantation in a clinical setting. The most important of these is the infectious disease risks posed by xenozoonoses as outlined previously. The critical question is whether in our attempts to save individual human life through a xenotransplantation, are we putting the population at large at an increased risk from novel infectious disease. On one side of this debate there are those who believe that any chance of introducing new infectious organisms into the human population is far too great a risk to pay for the introduction of this technology and that, as a consequence, xenotransplantation should not be performed at all (Butler, 1998, 1999 [87] [86]). On the opposite side, however, others are convinced that there should not be any further delay in using this technology for life-saving procedures such as transplanting an animal liver or heart as a “bridge” solution in the treatment of a fulminant hepatitis or acute cardiomyopathy with HLHS, respectively, while awaiting a suitable human organ.

The true risk to humans of swine-related viral infection is unclear, but given views concerning the cross-species genesis of AIDS, variant Creutzfeldt-Jakob disease (commonly known as the prion implicated mad cow disease), chicken Hong Kong HSNI influenza virus, and the current Southeast Asian pandemic of Nipah virus (probably reservoired in fruit bats but transmitted to humans by swine contact and responsible for a number of recent fatal deaths in Malaysia and Singapore), a general social concern seems justified ( Hahn et al., 2000 ). Moreover, xenotransplantation could change the dynamics of infection by the breaching of the physical barrier towards cross-species infection (through surgical implantation), by attendant immunosuppression, and by human proteins, which normally modulate HAR serving as viral receptors and protecting against complement-directed antiviral attack ( Weiss, 1998 ).

The porcine endogenous retroviruses (PERVs) are viewed as carrying the most significant risk of xenozoonoses in clinical xenotransplantation, where it has been reported that PERVs are capable of infecting human cells in vitro ( Patience et al., 1997 ). The importance of the PERV agent is its capacity for vertical transmission, where the genome is incorporated into the genome of the host. Such a replication-competent virus has a potential for infecting totally unrelated species. These PERVs were originally detected being released from porcine renal cell cultures and are retroviruses that share homology with murine leukemia viruses ( Armstrong et al., 1971 ). Since the types of pigs used for xenotransplantation contain at least 50+ PERVs incorporated into their genome, until these are cloned and sequenced, it will be difficult to determine how replication competent they are and consequently what is their infectious potential ( Rogel-Gilliard et al., 1999 ). It is so far evident that in a large cohort of patients either receiving xenografts or undergoing extracorporeal perfusion of their blood through pig organs that none have shown evidence of PERV infection, either by seroconversion of PERV antibodies (using serologic assays or polymerase chain reaction viral genomic primers) or by the presence of PERV DNA detectable in peripheral blood monocytes ( Paradis et al., 1999 ). This, however, has been associated with the presence of porcine mitochondrial and centromeric DNA sequences in some patients often detectable for many years following extracorporeal therapies, which suggests that these viruses have little true contagious potential. These results need to be viewed with caution because it is possible that PERVs themselves may result in immune dysfunction ( Tackle et al., 2000 ). The hope of breeding PERV-free animals seems to be a realistic prospect for the not-too-distant future ( Stoye, 1997 ).

If, on the one hand, the obstacles discouraging the practice of xenotransplantation are well known to both clinicians and scientists (HAR, AHXR, and xenozoonoses), there are also undeniably strong arguments in support of xenotransplantation, which go beyond the mere problem of organ shortage. Xenotransplantation may offer many other clinical opportunities exceeding the simple idea of treating patients with end-stage organ diseases. In theory, a pig-to-human hepatic xenograft might be less susceptible to re-infection with HCV or of recurrence of an autoimmune disorder where xenotransplantation could be used to cure such diseases more effectively than allotransplantation.

It would be essentially unethical in fact to proceed with xenotransplantation research without putting in place strict principles, which limit these new risks as much as possible. In this context given all the clinical implications, the issue of xenotransplantation needs to be discussed in the social arena, in order to research the widest agreement on such a delicate matter involving philosophical, cultural, religious, and scientific themes ( Daar, 1997 ; Fishman et al., 1998 ). Such a debate will effectively parallel the recent debate, which has been carried out on the legislative and parliamentary floors in many countries concerning stem cell and human embryonic cloning research ( Toledo-Pereyra, 2003) . The outcomes of such legislation will affect not only the direction of approved research activity (a restriction hitherto little experienced by researchers) but also the make-up of high-quality personnel involved ( Crawford, 2002 ). The wrong decisions here will simply drive researchers to other countries or to other fields of endeavor or underground, as has happened in the past. Individual and collective informed consent for xenotransplantation will require public dialogue ( Barker and Polcrak, 2001 ), a process that has so far been somewhat waiting on the runaway train of legislation.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

▪ SUMMARY

Since the 1970s, solid organ transplantation has gained notoriety and acceptability as a viable form of medical therapy for many forms of end-stage organ disease in the pediatric patient as well as early therapy for congenital anomalies and varied inherited genetic diseases otherwise without a cure. Scientific advances in the development of better immunosuppression protocols have allowed enhanced survival of children from otherwise deadly diseases. The challenge for the future will be the development of more specific immunomodulation, better understanding of chimerism, and application of xenotransplantation where appropriate. Clearly, at this juncture, our understanding of the immunologic milieu has allowed us to offer cellular transplantation as a cure for genetic disease, as with bone marrow transplantation for the treatment of sickle cell disease ( Vichinsky, 2002 ). In addition, the application of an artificial cardiac and liver assist device will become invaluable in reducing the mortality of patients with fulminant hepatic failure and in the treatment of congenital cardiovascular anomalies.

Challenges for the anesthesiologist will remain having a greater impact on the perioperative care in this group of patients given the long duration of the procedures as well as the need for the transfusion of blood products, all of which alter the immunology of the recipient; these procedures often lend themselves to significant blood loss. Will the anesthesiologist be able to affect this immunologic environ by better optimization of hemostasis? If so, will this eventually affect the episodes of early organ rejection and infectious complications? With all of the knowledge gained, we are now left with significant ethical dilemmas as we now begin to push the limits of living related and unrelated organ transplantation. The proposal by UNOS to allow living related and unrelated donors who are not perfectly matched to their particular cohort recipient to trade organs to appropriately matched unknown recipients has created a new conundrum within the area of transplantation. The prospect of xenografts has yet to be realized, but this along with the potential of stem cell research for the treatment of several diseases cannot be ignored.

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Motoyama & Davis: Smith's Anesthesia for Infants and Children, 7th ed.

Copyright © 2005 Mosby, An Imprint of Elsevier

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