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

PART FOUR – Associated Problems in Pediatric Anesthesia

Chapter 32 – Systemic Disorders in Infants and Children

Lynne Maxwell,Salvatore R. Goodwin,
Thomas J. Mancuso,
Victor C. Baum,
Aaron L. Zuckerberg,
Philip G. Morgan,
Etsuro K. Motoyama,
Peter J. Davis



Endocrine Disorders, 1032



Diabetes Mellitus, 1032



Diabetes Insipidus, 1035



Syndrome of Inappropriate Antidiuretic Hormone Secretion,1036



Adrenal Insufficiency, 1037



Thyroid Disorders, 1039



Pheochromocytoma, 1042



Respiratory Disorders, 1044



Upper Respiratory Tract Infection,1044



Reactive Airways Disease, 1046



Bronchopulmonary Dysplasia, 1051



Cystic Fibrosis, 1053



Cardiovascular Disorders, 1055



Anesthetic Management, 1055



The Child with a Murmur and Possible Heart Disease, 1057



Noncardiac Manifestations of Congenital Heart Disease,1058



Kawasaki Disease, 1058



Takayasu's Arteritis, 1059



Hematologic-Oncologic Disorders, 1060






Oncologic Issues, 1064



Coagulation and Hemostasis: Developmental Aspects, Disorders, and Perioperative Management, 1067



Overview of Hemostasis, 1067



Developmental Hemostasis, 1071



Inherited Coagulopathies, 1072



Acquired Coagulopathies, 1075



Intraoperative Coagulopathies,1077



Treatment of the Bleeding Patient, 1081



Safety of Transfusion and Factor Replacement, 1081



Treatment Triggers, 1081



Anticoagulant-Induced Coagulopathy, 1081



Agents Used to Control Bleeding, 1082



Complications of the Treatment of the Bleeding Patient,1084



Miscellaneous Problems, 1086



Acquired Immunodeficiency Syndrome,1086



Latex Allergy, 1088



Epidermolysis Bullosa, 1090



Down Syndrome, 1091



Genetic Muscle Disorders, 1092



Metabolic Diseases, 1099



Summary, 1100

Among patients presenting special problems for pediatric anesthesiologists are children whose underlying conditions complicate anesthetic management and may be associated with an increased risk of morbidity. The number of rare diseases that may be encountered in infants and children is great, although only a few are mentioned here. Chosen for discussion are the diseases seen with some frequency, those carrying an increased risk related to anesthetic management, and a few of unusual interest. Modifications to the understanding of mechanisms of coagulation are included along with consideration of coagulopathic states. Katz and Steward (1993) have provided a complete review of the anesthetic implications of uncommon pediatric diseases. A list of syndromes with possible anesthetic implications is included in Appendix D .



The endocrine problem most frequently dealt with in the perioperative period is the management of glucose homeostasis in children with diabetes mellitus. The prevalence of type 1 (insulin-dependent) diabetes in the United States has remained stable for the past 15 years at 1 in 500 school-aged children (CDC, 2003), whereas the incidence of type 2 diabetes is increasing, especially among American Indian, African American, and Hispanic children and adolescents. Diabetes mellitus is the result of an absolute or functional deficiency of insulin production by the pancreas. In type 1 diabetes, this deficiency is caused by an autoimmune pathophysiologic process. Insulin deficiency results in abnormalities of glucose transport and storage and in lipid and protein synthesis. These metabolic derangements result in vascular pathology over time, which leads to the end-stage complications of renal, cardiac, and eye disease, which rarely occur before adulthood. The anesthetic implications of type 1 diabetes in childhood differ from those seen in adults with the same disease, for whom the primary concern is about the type and severity of end-organ disease.

Children with insulin-dependent diabetes may be treated with different kinds of insulin on a daily basis to maintain tight glucose control, with the aid of frequent blood glucose monitoring. Since 1982, most newly approved insulin preparations have been produced using recombinant DNA technology with laboratory-cultivated bacteria or yeast. This process allows the bacteria or yeast cells to produce complete human insulin. Recombinant human insulin has mostly replaced animal-derived insulin, such as pork and beef insulin, in diabetes management ( Plotnick, 1998) . Insulin products called insulin analogs are produced so that the structure differs slightly from human insulin (by one or two amino acids) to change onset and peak of action. An example of an analog is human lispro (Humalog, NovoLog), an ultra-short-acting insulin, which is given only 15 minutes before a meal and whose peak and duration of action parallel the glucose rise resulting from carbohydrate ingestion.

Another new insulin is glargine (Lantus), which almost mimics an insulin pump, providing a 24-hour, continuous low background level of insulin. Table 32-1 lists some of the insulin preparations most commonly used in children. Some children may be managed with an external insulin pump, which provides a low background infusion of insulin and the ability to give small boluses before meals. Most diabetic children administer insulin at least three times and check blood sugar at least four times each day. Type 2 diabetes in children and adolescents may be controlled with diet and exercise, but they also may be taking metformin (Glucophage).

TABLE 32-1   -- Kinetics of commonly used insulins

Insulin Products


Onset (hr)

Peak (hr)

Effective Duration (hr)






Lispro (Humalog)



0.5 to 1.5

3 to 5



0.5 to 1.0

2 to 3

5 to 8



1 to 3

4 to 10

12 to 20

Glargine (Lantus)


2 to 4

No peak









0.5 to 1.0

2 to 5

4 to 6

IV, intravenous; SC, subcutaneous.




Insulin-dependent diabetic children are at risk for significant perioperative difficulties even when their preoperative glucose control is good because of the effects of surgical stress on glucose homeostasis. Brittle or noncompliant diabetic patients have additional problems, including an increased risk of perioperative hypoglycemia or hyperglycemia, osmotic diuresis with resultant hypovolemia, and altered mental status. The physician must document the child's current insulin regimen, degree of compliance, preoperative glucose control, and risk of hypoglycemia from preoperative fast. Much of this information can be obtained from the patient's endocrinologist or by examination of the child's blood glucose monitoring log. A recent growth history can indicate how well controlled the child's diabetes may be. Coordination and cooperation among the patient, parents, pediatrician, endocrinologist, and anesthesiologist are essential if the goal of optimal perioperative glucose homeostasis is to be achieved. The anesthesiologist must particularly heed the advice and counsel of the diabetic child's primary physician.

Insulin is an anabolic hormone that promotes glycogen and triglyceride storage and protein synthesis. It decreases glycogenolysis, gluconeogenesis, and lipolysis, with resultant ketogenesis and protein breakdown. It is present in small amounts even in the fasting state. Its complete absence at the time of surgery puts the patient in a state of starvation in which caloric intake is greatly restricted and substrate demands (e.g., for healing) are at their highest. The risk of a catabolic state is increased by the release of stress hormones, including catecholamines, cortisol, and glucagon. Perioperative insulin administration is essential for glucose control and to promote an anabolic state, which is most conducive to speedy healing and metabolic homeostasis.

Preoperative Evaluation

The preoperative evaluation should include measurements of the hematocrit, electrolyte levels, and glucose levels. A hemoglobin A1C level (i.e., glycosylated hemoglobin assay), although a useful index of long-term glucose control ( Nathan et al., 1984 ), is unlikely to affect the anesthetic plan and is not a necessary preoperative test. If glycohemoglobin results are available, one must realize that different laboratories have different ranges for hemoglobin A1C in normal subjects. The normal range may change from time to time even in the same laboratory. It is therefore important to know the laboratory's normal range to interpret results in diabetic patients. The normal range of hemoglobin A1C is 4.5% to 6.1% ( Siberry and Iannone, 2000 ).

Several systemic abnormalities may be present in the child with diabetes mellitus. Nineteen percent of diabetic children have a vital capacity two standard deviations below the predicted mean value, suggesting the presence of restrictive lung disease ( Buckingham et al., 1986 ). No apparent association exists between decreased vital capacity and duration of diabetes or presence of other diabetic complications. Abnormal lung elasticity ( Schuyler et al., 1976 ) and thickening of the alveolar basal laminae ( Vracko et al., 1980 ) have been reported in children with diabetes. Routine preoperative pulmonary function tests are not indicated in the asymptomatic diabetic child.

Decreased atlantooccipital joint mobility, resulting in difficult intubation, may be present in a subset of adolescents with a syndrome of diabetes mellitus, short stature, and tightness of small joints of the fingers, wrists, ankles, and elbows ( Salzarulo and Taylor, 1986 ). Abnormal cross-linking of collagen by nonenzymatic glycosylation is the postulated cause of this syndrome ( Chang et al., 1980 ).

Perioperative Management

Various regimens for managing insulin therapy perioperatively have been proposed, three of which are discussed here ( Table 32-2 ). Essential to optimal management, no matter which regimen is chosen, is the scheduling of elective surgery for the diabetic child as early as possible in the day (first case) to minimize the time the patient is fasting. Fasting interval should be the same as that recommended for nondiabetic patients: no solid food or milk for 8 hours, and clear liquids permissible until 2 hours before the scheduled time of surgery ( Schreiner et al., 1990 ). Children with diabetes should be encouraged to continue taking clear liquids until 2 hours before. If this is not possible, an intravenous infusion should be started (described later). As recommended in adult patients with type 1 diabetes, Glucophage should be stopped 48 hours before surgery, because of reports of lactic acidosis in patients who remain on the drug and are in a fasting state perioperatively.

TABLE 32-2   -- Protocols for perioperative insulin therapy


Morning of surgery procedure

Classic regimen

Start intravenous infusion of 5% dextrose in 0.45% saline or Ringer's lactate solution at 1500 mL/m2 per day.

Administer one half of usual morning insulin dose as regular insulin.

Check blood glucose before induction and during and after anesthesia.

Continuous insulin infusion

Start intravenous infusion of 5% dextrose in 0.45% saline or Ringer's lactate solution at 1500 mL/m2 per day.

Add 1 to 2 units of insulin per 100 mL of 5% dextrose.

Starting insulin dose is 0.02 units/kg per hour.

Check blood glucose before induction and during and after anesthesia.

Insulin- and glucose-free regimen (for operative procedures of short duration)

Withhold morning insulin dose.

If indicated for procedure, give glucose-free solution (e.g., Ringer's lactate) at maintenance rate.

Check blood glucose before induction and during and after anesthesia.

From Maxwell LG, Deshpande JK, Wetzel RC: Preoperative evaluation of children. Pediatr Clin North Am 41:93, 1994.




Although some investigators have recommended the withholding of preoperative sedation from diabetic patients to better monitor for signs of hypoglycemia, premedication is recommended in children. The use of agents such as benzodiazepines, opioids, or barbiturates does not alter glucose metabolism, and the failure to use such agents may elevate the blood sugar level due to anxiety, which causes a stress response with catecholamine release.

Classic Regimen

On the morning of surgery, one half of the usual dose of NPH insulin is administered subcutaneously after establishing an intravenous infusion of 5% glucose-containing solution at a rate of 100 mg/kg of glucose per hour (see Table 32-2 ). Plasma glucose concentrations should be maintained between 100 and 180 mg/dL. This target range is chosen because mild to moderate hyperglycemia (without ketosis) usually does not present a serious problem to the child, whereas hypoglycemia has devastating consequences. Hyperglycemia greater than 250 mg/dL should be avoided because of associated mental status changes, diuresis, and subsequent dehydration, which can occur because of the hyperosmolar state. Hyperglycemia has been associated with poorer outcomes in patients at risk for central nervous system (CNS) ischemia, including those undergoing cardiopulmonary bypass ( Lanier et al., 1987 ; Lanier, 1991 ). Postoperatively, supplemental subcutaneous doses of short-acting insulin can be given on a sliding scale to maintain the desired plasma glucose level. This regimen should be restricted to patients who are scheduled for short surgical procedures after which they are expected to resume eating promptly.

Insulin Infusion

If a long procedure or a prolonged period of postoperative fasting is anticipated, the continuous intravenous infusion of glucose and insulin may provide the best control. On the morning of surgery, a glucose infusion is begun at a maintenance rate of 100 mg/kg per hour, with the insulin infusion of 0.02 to 0.05 U/kg per hour “piggy-backed” into the glucose infusion. The glucose infusion can be D5 or D10 in half-normal saline with 10 to 20 mEq/L of potassium chloride. These infusions should be begun 2 hours before surgery to minimize the fasting interval and decrease the risk of the development of a catabolic state. Insulin is absorbed by intravenous bags and tubing. When the insulin solution is prepared, the first portion of the solution should be run through the tubing and discarded to saturate the sites in the tubing that bind insulin ( Kaufman et al., 1996 ). Blood glucose levels should be checked hourly for the first few hours, and adjustments of +0.01 U/kg per hour in the insulin rate should be made to keep the blood sugar in the acceptable range of 80 to 180 mg/dL. The glucose and insulin should be infused through a dedicated intravenous cannula to enable it to be well regulated apart from non-glucose-containing crystalloid solutions administered to replace blood or fluid losses. Most investigators believe that lactated Ringer's solution should not be used for blood and fluid replacement, as lactate is a glycogenic precursor and may result in higher blood glucose levels. This continuous infusion regimen has been shown to yield better control of glucose concentrations than the regimen in which intermittent subcutaneous insulin is administered ( Kaufman et al., 1996 ). There is no role for the administration of intermittent large intravenous insulin doses. This can result in big swings in glucose concentration (high and low) and a greater chance of lipolysis and ketogenesis. Patients with insulin pumps should have them turned off in the perioperative period and replaced by the continuous infusion regimen, as most anesthesiologists are not familiar with the details of operation of such pumps. Fifty percent dextrose solution should be available for administration in case of the development of hypoglycemia; 0.1 g/kg of dextrose raises the blood glucose level by approximately 30 mg/dL.

Alternative Procedure

For extremely brief procedures after which prompt resumption of oral intake is expected, the third protocol involves the administration of no insulin or glucose before or during surgery. When oral intake is established postoperatively, 40% to 60% of the usual daily insulin dose is given ( Stevens and Roizen, 1987 ). Myringotomy with tube placement is an example of a procedure for which this regimen would be appropriate. The surgical procedure should be performed as the first case on the morning schedule to avoid prolonged fasting and excessive delay in insulin administration.

The most serious perioperative complication that can occur in the diabetic child is hypoglycemia. Common signs of low blood glucose levels include tachycardia, tearing, diaphoresis, and hypertension. In the anesthetized patient, these signs may be misinterpreted as caused by inadequate anesthesia. Because the clinical signs of hypoglycemia are masked by sedation or anesthesia, frequent measurement of the serum glucose level (every hour) is critical for the prevention of hypoglycemia, independent of the glucose-insulin regimen chosen. Glucose test strips (ChemStrip bG, Roche Diagnostics Corp., Indianapolis, IN), with or without the use of a reflectance photometer, provide quick, convenient, and reliable bedside blood sugar measurements to guide therapy. Blood glucose determinations performed with reflectance photometers (Accu-Chek, Roche Diagnostics Corp., Indianapolis, IN) provide results that are generally within 10% of clinical laboratory glucose determinations done on the same specimen ( Chen et al., 2003 ). Visual evaluation of blood glucose strips is less accurate ( Arslanian et al., 1994 ). Postoperative insulin administration is determined by the time the patient's oral or enteral feeding resumes and the postoperative blood glucose concentration. The endocrinologist and surgeon should be active partners in the choice of an appropriate insulin regimen because they will be responsible for monitoring glucose homeostasis after the patient leaves the recovery room. For day-surgery patients, contingency planning for insulin management and mechanism for follow-up and consultation should be clearly defined for members of the care team and family.

Regional or general anesthesia is appropriate for the child with diabetes mellitus. If tolerated with minimal sedation, regional anesthesia might be argued to offer the advantage of allowing for observation of the level of consciousness as a monitor of hypoglycemia. Practically speaking, most children require general anesthesia, even when regional techniques are employed. The ease and availability of point-of-care glucose determination from venous or fingerstick specimens obviate the need for monitoring cerebral function.

Occasionally, diabetics require surgery for trauma or infection while in a state of ketoacidosis. Diabetic ketoacidosis occurs when there is hyperglycemia (plasma glucose concentration > 300 mg/dL) with glucosuria, ketonemia (ketones strongly positive at greater than 1:2 dilution of serum), ketonuria, and acidemia (pH < 7.30 or serum bicarbonate < 15 mEq/L, or both). It is common for intraabdominal catastrophes with infection to precipitate ketoacidosis. Foster and McGarry (1983) have succinctly summarized the pathophysiology of diabetic ketoacidosis. The initiating event is usually cessation of insulin therapy or onset of stress that renders the usual dose of insulin inadequate. Glucagon, catecholamines, cortisol, and growth hormone levels rise. A catabolic state is produced as substrates are mobilized, resulting in hepatic production of glucose and ketone bodies, which causes hyperglycemia and ketoacidosis. Subclinical brain swelling nearly always occurs during diabetic ketoacidosis therapy, although most patients remain asymptomatic ( Krane et al., 1985 ). Fatalities from cerebral edema do occur, and some studies suggest that high rates of fluid administration early in treatment (>50 mL/kg in the first 4 hours) greatly increase the risk of herniation (Mahoney et al., 1999). Studies using 4 L/m2 for the first 24 hours followed by 1 to 1.5 times maintenance resulted in clearance of ketoacidosis equal to that in patients given more fluid, but there remained a low but persistent incidence of symptomatic cerebral edema (0.35% to 0.5%) ( Felner and White, 2001 ). Administration of isotonic fluid only and frequent monitoring of serum osmolality by direct measurement or calculation to ensure that elevated osmolality is reduced gradually are the best methods to prevent the development of this devastating complication. Insulin therapy should be tailored to decrease the blood glucose concentration at a rate no greater than 100 mg/dL per hour. To prevent a more rapid decrease in blood glucose concentration, 5% dextrose, and, if necessary, 10% dextrose should be added to the rehydration solution to slow the rate of fall, rather than decreasing the rate of insulin infusion ( Arslanian et al., 1994 ). Fortunately, the anesthesiologist is rarely called on to administer anesthesia during this severe metabolic derangement. If an anesthetic is required during diabetic ketoacidosis, preoperative attention should be directed toward the correction of hypovolemia and hypokalemia along with beginning an insulin infusion. Invasive hemodynamic monitoring may be indicated preoperatively to optimize the patient's fluid and electrolyte balance and to monitor the patient's hemodynamic status accurately. Surgery should not be delayed inordinately because correction of the metabolic derangements may be impossible before the underlying source of infection or organ dysfunction is corrected. For patients with signs of cerebral edema, intracranial pressure monitoring may be necessary.


Diabetes insipidus is a clinical syndrome of hypotonic polyuria in the face of elevated plasma osmolality that results from inadequate production of, or inadequate response to, antidiuretic hormone (ADH). Central diabetes insipidus results from inadequate production or release of ADH from the posterior pituitary gland. ADH is synonymous with arginine vasopressin. Nephrogenic diabetes insipidus is characterized by partial or complete renal tubular unresponsiveness to endogenous ADH or exogenously administered arginine vasopressin.

The causes of diabetes insipidus are outlined in Box 32-1 . This discussion will focus on central diabetes insipidus. Nephrogenic diabetes insipidus has been reviewed by Cramolini (1993) and Malhotra and Roizen (1987) . The clinical manifestations of diabetes insipidus are polyuria and polydipsia. The urine is hypotonic relative to the plasma. The urine osmolality is usually less than 200 mOsm/L, and urine specific gravity is less than 1.005 ( Weigle, 1987 ). When there has been inadequate access to water, severe dehydration and hypernatremia ensue because a large volume of dilute urine is continually produced.

BOX 32-1 

Causes of Diabetes Insipidus

Vasopressin Deficiency (Neurogenic Diabetes Insipidus)









Traumatic (accidental, surgical)



Neoplastic (craniopharyngioma, metastasis, lymphoma)



Granulomatous (sarcoid, histiocytosis)



Infectious (meningitis, encephalitis)



Vascular (Sheehan's syndrome, aneurysm)



Familial (autosomal dominant)

Excessive Water Intake (Primary Polydipsia)






Idiopathic (resetting of the osmostat)




Vasopressin Insensitivity (Nephrogenic Diabetes Insipidus)






Infectious (pyelonephritis)



Postobstructive (urethral, ureteral)



Vascular (sickle cell disease or trait)



Infiltrative (amyloid)



Cystic (polycystic disease)



Metabolic (hypokalemia, hypercalcemia)



Granulomatous (sarcoid)



Toxic (lithium, demeclocycline)



Solute overload (glucosuria, postobstructive)



Familial (X-linked recessive)

Adapted from Malhotra N, Roizen MF: Patients with abnormalities of vasopressin secretion and responsiveness. Anesthesiol Clin North Am 5:400, 1987.


Patients with preexisting diabetes insipidus may come for incidental surgery. These patients are usually taking maintenance doses of vasopressin, which for relatively short, uncomplicated, elective procedures, should be continued through the perioperative period. Desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]), a longer-acting (8 to 20 hours) vasopressin analog, has a decreased vasopressor effect relative to its antidiuretic effect ( Hays, 1990 ). DDAVP is usually given intranasally (2.5 to 10 mcg once or twice daily) to prevent diuresis ( Lee et al., 1976 ), but also may be given subcutaneously or intravenously (1 to 2 mcg twice daily). The most common situation encountered by the anesthesiologist, however, is the development of diabetes insipidus intraoperatively or postoperatively in patients having surgery for pituitary or hypothalamic tumors, most commonly craniopharyngiomas. Perioperative diabetes insipidus may present in one of four ways:



Transient polyuria probably is related to the onset and resolution of transient cerebral edema rather than to injury to the pituitary stalk. It usually resolves in 24 to 36 hours.



A triphasic pattern with an interlude of normal urine output reflects the release of stored vasopressin from the posterior lobe or median eminence of the pituitary. This is followed by resumption of polyuria when the stored supply of vasopressin is exhausted.



Mild polyuria reflects partial diabetes insipidus, which is exaggerated by local edema and corticosteroid administration.



Permanent diabetes insipidus is caused by destruction or removal of all cells capable of producing and storing vasopressin.

If any degree of diabetes insipidus is going to occur, the onset is most commonly within 18 hours after operation. A review of craniopharyngioma resection in children found a very high incidence of the development of diabetes insipidus (30 of 32 patients). Recommendations for therapy are reviewed by Lehrnbecher and others (1998) .

The goal of perioperative management of diabetes insipidus is to maintain normal fluid and electrolyte balance, urine output, and hemodynamic stability. Urine output may be prodigious (10 to 20 mL/kg per hour). Care must be taken to differentiate polyuria caused by diabetes insipidus (urine specific gravity < 1.005) from diuresis caused by mannitol administration or hyperglycemia (urine specific gravity usually > 1.015), or simple excessive administration of crystalloid (urine specific gravity > 1.005). Patients with partial ADH deficiency usually do not require supplemental aqueous vasopressin perioperatively because large quantities of ADH are produced in response to surgical stress ( Malhotra and Roizen, 1987 ). Serum osmolality should be measured frequently, however, and aqueous vasopressin should be given if the plasma osmolality exceeds 290 mOsm/L ( Malhotra and Roizen, 1987 ).

If central diabetes insipidus is present preoperatively and the planned surgery is prolonged, an infusion of aqueous vasopressin is begun preoperatively and continued intraoperatively. The recommendations for adults include a bolus of 100 mU of aqueous vasopressin followed by a continuous infusion of 100 to 200 mU/hour, accompanied by the intraoperative administration of isotonic fluids ( Malhotra and Roizen, 1987 ). For the pediatric population, an infusion is begun at 0.5 mU/kg per hour and increased until a urine osmolality twice that of plasma and a urine output of less than 2 mL/kg per hour are achieved. It is rarely necessary to use more than 10 mU/kg per hour ( Weigle, 1987 ). Side effects from vasopressin administration are minimal at doses used for antidiuresis; at larger doses, generalized vasoconstriction can occur and has resulted in tissue ischemia and myocardial infarction.

DDAVP, rather than aqueous vasopressin, is the drug of choice for treatment of perioperative diabetes insipidus because of its potent antidiuretic effect with minimal pressor activity or other side effects. In the perioperative period, it may be given intravenously until intranasal administration can be started or resumed. The suggested intravenous dose is 0.5 to 4.0 mcg, with a single dose having a duration of action of 4 to 23 hours ( Harris, 1989 ; Lehrnbecher et al., 1998 ). The ease of intermittent dosing with DDAVP with low incidence of side effects must be balanced against the ability to titrate the continuous vasopressin infusion cited earlier. In either case, careful monitoring of fluid balance is essential.

The anesthesiologist rarely may encounter children who are receiving nightly nasal DDAVP for the treatment of enuresis. A review of its use reveals a negligible incidence of water intoxication (and no permanent effect on enuresis when treatment is stopped) ( van Kerrebroeck, 2002 ). Given the known duration of action, DDAVP given the night before outpatient surgery should not affect the urine output on the day of surgery.


Just as central diabetes insipidus is caused by ADH deficiency, syndrome of inappropriate ADH secretion (SIADH) is caused by an excess production of ADH, which is inappropriate with respect to the state of the intravascular volume. The most common causes of SIADH are listed in Box 32-2 . The hallmark of SIADH is hyponatremia in the face of high urine osmolality and sodium levels. A comparison of the urine and serum electrolyte status seen in diabetes insipidus and SIADH is presented in Table 32-3 . The treatment for mild cases of SIADH is fluid restriction (50% to 60% of maintenance fluid requirement) or insensible loss (400 mL/m2 per day, plus one half to three fourths of the urine output). If hyponatremia is severe enough to cause coma or seizures, treatment with hypertonic saline (3%) solution may be indicated, but caution should be employed because the administration of hypertonic saline may cause circulatory overload, because the intravascular volume is already increased. A too-rapid rise of osmolarity (>20 mOsm/kg or >10 mmol/L of sodium in 24 hours) carries a risk of central pontine myelinolysis, a condition that can result in death ( Laureno, 1983 ). This syndrome is thought to be caused by the sudden shrinkage of brain cells in response to rapidly increasing extracellular osmolality.

BOX 32-2 

Causes of Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Central Nervous System















Guillain-Barré syndrome

Neoplastic Process







Subarachnoid hemorrhage

Infectious Process












Infant botulism

Positive Pressure Ventilation









TABLE 32-3   -- Comparison of diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion

Laboratory Test

Results for Diabetes Insipidus

Results for SIADH

Urine specific gravity



Urine osmolality

50 to 200 mOsm/L

>200 mOsm/L

Serum osmolality

>280 mOsm/L

<280 mOsm/L

Serum sodium

High (usually >148 mEq/L)

Low (usually <132 mEq/L)

Urine sodium

<20 mmol/L

>20 mmol/L



Adrenal Insufficiency because of Primary Abnormalities of the Hypothalamic-Pituitary-Adrenal Axis

Adrenal insufficiency is an uncommon disease in childhood, but when it occurs, there are significant implications for the anesthesiologist. The causes of adrenal insufficiency are listed in Box 32-3 . Adrenal insufficiency may include glucocorticoid deficiency with or without mineralocorticoid deficiency. Isolated hypoaldosteronism is rare. The signs and symptoms of glucocorticoid and mineralocorticoid deficiency are presented in Box 32-4 . In the perioperative period, children with congenital adrenal insufficiency require glucocorticoid and mineralocorticoid replacement.

BOX 32-3 

Causes of Adrenal Insufficiency

Primary Adrenocortical Insufficiency



Congenital form

Enzyme Deficiency



Adrenal aplasia



Adrenocortical unresponsiveness to adrenocorticotropic hormone (ACTH)



Adrenoleukodystrophy or adrenomyeloneuropathy

Trauma or Septic Origin



Adrenal hemorrhage of newborn



Adrenal hemorrhage of acute infection



Chronic hypoadrenocorticism (Addison's disease)

Related to Deficient ACTH Secretion






Cessation of glucocorticoid therapy



Resection of unilateral cortisol-producing tumor



Infants born to steroid-treated mothers



Respiratory distress syndrome






Inanition, anorexia nervosa

Related to End-Organ Unresponsiveness






Cortisol resistance

BOX 32-4 

Signs and Symptoms of Adrenal Insufficiency

Glucocorticoid Deficiency



Fasting hypoglycemia



Increasing insulin sensitivity



Decreased gastric acidity



Gastrointestinal symptoms (nausea, vomiting)




Mineralocorticoid Deficiency



Muscle weakness



Weight loss






Nausea, vomiting, anorexia

Salt Craving






Electrolyte disturbance










Adrenal Androgen Deficiency



Decreased pubic and axillary hair



Decreased libido



Increased β-lipoprotein levels




Chronic deficits in adrenal function result in the classic findings of Addison's disease, including hyperpigmentation, weakness, and hyponatremia. The hyperpigmentation results from high levels of adrenocorticotropic hormone (ACTH) and unopposed melanophore-stimulating hormone caused by cortisol insufficiency. The additional presence of aldosterone insufficiency may produce hyponatremia, hyperkalemia, hypotension, and a small cardiac silhouette resulting from hypovolemia ( Keon and Templeton, 1993 ).

Perioperative Steroid Management

The preoperative recognition of adrenal insufficiency and appropriate preoperative therapy minimize the likelihood of significant perioperative complications. Ninety percent of patients with congenital adrenal hyperplasia with adrenal insufficiency have 21-hydroxylase deficiency ( Migeon and Donohoue, 1994 ). Virilization of the external genitalia occurs in female patients, and they frequently require surgical revision of their external genitalia. An abnormal genital pigmentation occurs in male patients, but this finding may be subtle. Infants with undiagnosed congenital adrenal hyperplasia may undergo exploratory laparotomy for acute abdomen because of nausea and vomiting. It is important to be attuned to the signs and symptoms in the history, physical, and laboratory evaluation that point to this diagnosis to prevent or treat shock, which may occur because of failure to administer steroid replacement.

Mineralocorticoid deficiency can be managed by administering saline solution and avoiding potassium in intravenous fluids. Mineralocorticoid secretion rates in children are similar to those in adults, and the replacement dose is independent of age and weight. Desoxycorticosterone acetate is administered intramuscularly in a dose of 1 mg/day. The intramuscular injection may be replaced by a single daily oral dose of 9-α-fluorocortisol acetate (Florinef, 0.05 to 0.10 mg) when it is clear that an oral medication can be tolerated and absorbed.

Glucocorticoid deficiency is treated with cortisol (hydrocortisone) replacement. The importance of cortisol replacement for patients with known adrenal insufficiency should not be underestimated, although vastly excessive doses are unwarranted. In the normal individual the adrenal gland secretes 12 ± 2 mg of cortisol per square meter of body surface area every 24 hours ( Kenny and Preeyasombat, 1966 ). The normal replacement dose prescribed for unstressed children is 25 mg/m2 per day; the dose is double the normal production because of factors of bioavailability and half-life ( Migeon and Donohoue, 1994 ). In response to stress (fever, acute illness, surgery, and anesthesia), the normal adrenal gland secretes 3 to 15 times this amount. Consequently, in the past, the recommendations for “stress” steroid coverage in the perioperative period ranged from 36 to 180 mg/m2 per day.

More important than just the dose of steroid to be given, consideration should be devoted to the type of glucocorticoid administered, its half-life, the route of administration, and the timing of doses. The equivalencies for different steroid preparations in terms of their relative glucocorticoid and mineralocorticoid effects are presented in Table 32-4 . The most frequently cited recommendation for perioperative steroid coverage is hydrocortisone hemisuccinate (Solu-Cortef), given intravenously as 2 mg/kg immediately preoperatively and every 6 hours on the day of surgery, with reductions in the postoperative period depending on the degree of stress. Some practitioners feel that the half-life of hydrocortisone is so short that a 6-hour dosing interval may leadto periods of inadequate “coverage.” These practitioners recommend a preinduction dose of 25 mg/m2 of hydrocortisone given intravenously, followed by a continuous infusion of 50 mg/m2 administered during the estimated period of anesthesia. Postoperatively, 50 mg/m2 by continuous infusion is administered over the remainder of the first 24 hours. The total dose for the first 24 hours is 125 mg/m2, or 10 times normal physiologic production ( Migeon and Donohoue, 1994 ). The first bolus dose must be administered before induction of anesthesia rather than waiting for an intravenous cannula to be placed after inhalational induction because of the stress associated with anesthetic induction itself. In the postoperative period, the steroid dose is tapered to a level commensurate with the residual stress. It is replaced with the child's usual oral preparation when he or she clearly can tolerate and absorb oral medication.

TABLE 32-4   -- Potency of commonly used steroid preparations

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

Adapted from Migeon C, Donohoue PA: Adrenal disorders. In Kappy MS, Blizzard RM, Migeon CJ, editors: The diagnosis and treatment of endocrine disorders in childhood and adolescence. Springfield, IL, 1994, Charles C Thomas.




Hypothalamic-Pituitary-Adrenal Axis Suppression Caused by Exogenous Steroid Therapy

In addition to the diseases discussed previously, suppression of the hypothalamic-pituitary-adrenal (HPA) axis can also occur after exogenous steroid usage, such as that administered for the treatment of inflammatory (e.g., Crohn's disease, asthma) or autoimmune (e.g., lupus, juvenile rheumatoid arthritis) disease. Fifty years ago, two patients were reported ( Fraser et al., 1952 ; Lewis et al., 1953 ) who developed irreversible shock perioperatively after glucocorticoid administration was stopped preoperatively. Both patients were found to have adrenal atrophy and hemorrhage at autopsy. These two cases led to suggestions for “stress” steroid coverage in the perioperative period. HPA suppression places the steroid-dependent child at increased risk for complications in the perioperative period because these patients may be unable to respond to stress with an appropriate increase in the adrenal secretion of glucocorticoid. Dosages of cortisol or its equivalent that exceed 15 mg/m2 per day for more than 2 to 4 weeks invariably produce HPA suppression. A study in children with relatively short-term exposure to prednisolone or dexamethasone (5 and 3 weeks, respectively) for treatment of acute lymphoblastic leukemia showed that recovery of normal adrenal function (in response to ACTH stimulation) had a very wide range, occurring between 2 weeks and 8 months ( Petersen et al., 2003 ).

Although high dosages, prolonged therapy, and short duration between discontinuance of therapy and the surgical procedure increase the likelihood of HPA suppression, no practical test is available that unequivocally identifies patients who will need intraoperative steroids. Metyrapone (Metopirone) depresses the production of cortisol by the adrenal glands and can be used to test the capacity of the pituitary gland to respond to decreased plasma cortisol concentrations by increasing ACTH secretion ( Haynes, 1990 ). This test, however, takes 3 days, is expensive, and has the risk of inducing adrenal insufficiency. Similarly, an ACTH stimulation test can be performed at great expense to test adrenal responsiveness. However, even if cost and time were not issues, a study has shown a poor correlation between tests indicating normal HPA function and dose or duration of glucocorticoid therapy or basal cortisol levels ( Schlaghecke et al., 1992 ). Clinically significant events rarely occur during the perioperative period in unsupplemented patients who were receiving steroid medications for diseases other than adrenal insufficiency. Nevertheless, the potential for symptomatic adrenal insufficiency, although rare, coupled with the low risk of steroid-induced complications for short-term administration, suggests that steroids should be given in uncertain cases. If steroid therapy has been discontinued within the previous year, Migeon and Donohoue (1994) make the following recommendations:



If the dose of the glucocorticoid administered was less than replacement levels, independent of the duration of administration, there will be no major HPA suppression and therefore no need for supplementation.



If the dose of glucocorticoid administered was greater than replacement levels, HPA suppression will occur. If treatment lasted less than 2 weeks, suppression is transient, with prompt recovery (<2 weeks). If treatment lasted more than 2 weeks, HPA suppression may persist for 1 week to 6 months, with 50% of patients recovering function within 6 weeks. This is the case even if the glucocorticoid was administered on an every-other-day basis.

HPA suppression also can result from modes of steroid administration other than oral, including topical, nasal spray, and inhalers. Although adrenal suppression is rarely symptomatic with these modes of administration, some drugs, especially fluticasone propionate (Flovent), in high doses have been associated with growth failure and adrenal suppression ( Duplantier et al., 1998 ). With surgical stress, patients with adrenal suppression may become symptomatic, as has been reported for other kinds of stress. The patients reported by Drake and others (2002) all had been taking fluticasone and presented with hypoglycemia at times of stress from intercurrent illness. Anesthesiologists should have a high index of suspicion of adrenal suppression if an asthmatic child on inhaled steroids develops hypotension or hypoglycemia in the perioperative period.

For children who have been on prolonged courses of high-dose steroids (e.g., for asthma, treatment of ALL), the glucocorticoid regimen should follow that described earlier for patients with adrenal insufficiency. The dose given should be commensurate with the normal physiologic corticosteroid production in response to stress (as described), and does not need to be a multiple of the pharmacologic dose being administered for the underlying medical illness.

The dose administered should also be proportional to the perceived degree of surgical stress. For brief procedures, such as upper endoscopy, a single preoperative dose of steroids is suggested (50 mg/m2 of hydrocortisone); for more complicated cases, such as appendectomy or major intraabdominal operations, 100 mg/m2 is administered as a continuous infusion or divided into four doses per day. This dose is usually continued for 1 to 3 days after more complex surgical procedures ( Krasner, 1999 ). The dose is tapered postoperatively and replaced with the patient's usual oral steroid preparation and dose when he or she is able to tolerate oral medications. The dose these patients frequently take for the underlying disease often exceeds even maximum “stress” doses described for congenitally adrenal insufficient patients, and treatment required for the underlying disease may limit further tapering of the steroid dose. A small study of adults comparing “stress steroids” with saline showed no adverse effects in patients who continued their usual steroid dose for their underlying disease ( Glowniak and Loriaux, 1997 ).



Hypothyroidism occurs because of abnormally low production of thyroid hormone. It may be caused by primary thyroid dysfunction or result from pituitary failure with decreased production of thyroid-stimulating hormone (TSH). Normal values for routinely performed thyroid function tests are presented in Table 32-5 . The interpretation of these test results with regard to diagnosis is presented in Table 32-6 .

TABLE 32-5   -- Thyroid function tests



Normal Values

T4 RIA (μg/dL)

1 to 3 days

11.0 to 21.5


1 to 4 weeks

8.2 to 16.6


1 to 12 months

7.2 to 15.6


1 to 5 years

7.3 to 15.0


6 to 10 years

6.4 to 13.3


11 to 15 years

5.6 to 11.7


16 to 20 years

4.2 to 11.8

T3 resin RU


25% to 35%[*]

T index


1.25 to 4.20[†]

Free T4 (ng/dL)

1 to 10 days

0.6 to 2.0


>10 days

0.7 to 1.7

T3 RIA (ng/dL)

1 to 3 days

100 to 380


1 to 4 weeks

99 to 310


1 to 12 months

102 to 264


1 to 5 years

105 to 269


6 to 10 years

94 to 241


11 to 15 years

83 to 213


16 to 20 years

80 to 210


1 to 3 days

<2.5 to 13.3


1 to 4 weeks

0.6 to 10.0


1 month to 15 years

0.6 to 6.3


16 to 20 years

0.2 to 7.6

TBG (mg/dL)

1 to 3 days


1 to 4 weeks

0.5 to 4.5


1 to 12 months

1.6 to 3.6


1 to 5 years

1.3 to 2.8


6 to 20 years

1.4 to 2.6

Reverse T3[‡] (mg/dL)


90 to 250



10 to 50

Adapted from Johnson KB, editor: The Harriet Lane handbook. St Louis, 1993, Mosby–Year Book.

RIA, radioimmunoassay; RU, reuptake; T3, triiodothyronine; T4, thyroxine; TBG, thyroid-binding globulin; TSH, thyroid-stimulating hormone.



Measures thyroid hormone binding, not T3.

T4 RIA × T3 RU.

Reverse T3.


TABLE 32-6   -- Interpretation of thyroid function tests




T index

Free T4


Primary hypothyroidism






Secondary hypothyroidism





L, N, or H

TBG deficiency














Primary thyroid dysfunction may be congenital or acquired. Congenital hypothyroidism usually appears in infancy. Classic features in the infant include large fontanelles, wide sutures, large tongue, umbilical hernia, and decreased deep tendon reflexes. In the older child, manifestations include slow heart rate, narrow pulse pressure, growth failure, hypothermia, and cold intolerance. Severe hypothyroidism is rare but may be associated with coma, cardiovascular collapse, hyponatremia, hypothermia, and respiratory failure. Keon and Templeton (1993) reviewed the anesthetic management of patients with hypothyroidism and stressed the importance of correcting hypothyroidism gradually over a 2-week period. Sudden death has been reported in children with myxedematous heart disease 2 to 3 weeks into therapy ( LaFranchi, 1979 ). It is suggested that these children receive one fourth of the maintenance dose of thyroid hormone (6 to 8 mcg/kg per day for an infant) ( Siberry and Iannone, 2000 ), with gradual incremental increases over a period of 2 to 4 weeks until a maintenance dose is reached. Patients who are adequately replaced will have normal thyroid hormone and TSH levels. Patients with incompletely restored thyroid hormone levels may require hemodynamic monitoring and support to maintain hemodynamic stability. Patients with severe hypothyroidism may have associated adrenal insufficiency and, if so, should receive stress steroid coverage as outlined earlier.

The anesthetic care of the symptomatic patient with hypothyroidism can be problematic and requires caution when any depressant medications are given. Prolonged effects may result from decreased drug metabolism. Table 32-7 outlines important considerations in the management of hypothyroidism as described by Keon and Templeton (1993) . Invasive monitoring may be indicated when significant blood loss or fluid shifts occur. Care should be taken to minimize heat loss intraoperatively. Postoperative care should include monitoring of oxygen saturation, blood pressure, heart rate, and respiratory rate; postoperative ventilation may be necessary in the patient with delayed emergence from anesthesia.

TABLE 32-7   -- Anesthetic implications of hypothyroidism

Anesthetic Considerations



Possible lower minimum alveolar concentration (MAC) value, prolonged recovery from opioid anesthesia.


Decreased cardiac output, heart rate, and stroke volume; increased peripheral vascular resistance and decreased intravascular volume; myocardial depression resulting from impaired cellular metabolism or myxedematous infiltration; baroreceptor dysfunction


Abnormal response to hypercapnia and hypoxia


Hypothermia resulting from reduced basal metabolic rate and reduced ability to increase core temperature


Increased incidence of adrenal insufficiency; consideration for stress steroid coverage


Syndrome of inappropriate secretion of antidiuretic hormone; hypoglycemia with prolonged fasting


Delayed gastric emptying; consideration for full-stomach precautions




Hyperthyroidism is a syndrome produced by excess levels of circulating thyroid hormone. The most common causes are congenital hyperthyroidism and Graves—disease (i.e., toxic goiter). Less commonly, acute suppurative thyroiditis, hyperfunctioningthyroid carcinoma, thyrotoxicosis factitia (i.e., exogenous administration of thyroid hormone), and toxic uninodular goiter (i.e., Plummer's disease) may produce this syndrome. The McCune-Albright syndrome (i.e., precocious puberty with polyostotic fibrous dysplasia) is also frequently associated with hyperthyroidism ( Jones, 1988 ).

Congenital Hyperthyroidism

Congenital hyperthyroidism is a transient phenomenon seen in newborns that results from the transplacental transfer of thyroid-stimulating antibody from mothers who commonly have a history of Graves—disease. Most of these infants have a goiter and typically appear anxious and restless or irritable. Signs of hypermetabolism, including tachycardia, tachypnea, and elevated temperature, may be present. In the severely affected infant, symptoms may progress to weight loss, severe hypertension, and high output cardiac failure with hepatomegaly ( Smith et al., 2001 ). Appropriate medical therapy (propylthiouracil) should be instituted early. Because maternal immunoglobulins have a short half-life in the infants, the hyperthyroid state resolves in a few weeks to a few months, and it sometimes may be followed by a period of hypothyroidism ( Higuchi et al., 2001 ).


Diffuse toxic goiter (Graves—disease) is the most common cause of hyperthyroidism in children. Its peak incidence occurs during adolescence, and it is five times more common in girls than in boys. The clinical course is generally gradual, with symptoms developing over a period of 6 to 12 months. Early signs include motor hyperactivity, emotional disturbances, and nervousness. Affected children are progressively more irritable and restless, and may have increased sweating, increased appetite, palpitations, and tremors of their fingers. Most children have obvious exophthalmos and an enlarged palpable thyroid. The cardiopulmonary symptoms of hyperthyroidism include systolic hypertension, tachycardia, palpitations, dyspnea, and cardiac enlargement, which may progress to frank cardiac decompensation. On rare occasions, atrial fibrillation or mitral regurgitation may also be present.

Thyroid Storm

An acute onset of hyperthermia, severe tachycardia, and restlessness comprises the syndrome of acute uncompensated thyrotoxicosis, or “thyroid storm.” Without appropriate and timely therapy, the patient's condition may deteriorate to delirium, coma, and death. Therapy includes treatment of hyperthermia by cooling; maintenance of intravascular volume with balanced salt solutions; and β-adrenergic blockers, such as propranolol, titrated to ameliorate the cardiovascular response. Specific thyroid suppression therapy with propylthiouracil should be instituted. The clinical presentation of thyroid storm may occur intraoperatively, and this hypermetabolic state may be mistaken for malignant hyperthermia ( Peters et al., 1981 ). It is well known that perioperative surgical stress can trigger the development of thyroid storm in a patient with previously unrecognized thyrotoxicosis ( Stevens, 1983 ). For this reason, patients with signs and symptoms that may indicate the presence of hyperthyroidism should be carefully evaluated. Patients should be rendered euthyroid before any elective surgery, even if it is minor. The use of dantrolene mitigated the clinical signs in a patient who turned out to have thyroid storm (Bennett and Wainwright, 1989 ).

Laboratory Evaluation

Serum levels of thyroxine (T4) and triiodothyronine (T3) are usually elevated in hyperthyroidism. TSH secretion is suppressed and may be unmeasurable. T3 toxicosis (elevated T3 level with normal amounts of T4) is more common in adult patients and rarely seen in children. For borderline cases, thyrotropin-releasing hormone (TRH) stimulation tests may be needed. Many patients with Graves—disease of recent onset may have elevated levels of thyroid-stimulating immunoglobulin. Radionuclide scans can also be helpful in making a diagnosis. If a large goiter is present, neck radiographs, computed tomography (CT), or magnetic resonance imaging may be used to evaluate the degree of tracheal compression and deviation.


The management of hyperthyroidism is aimed at controlling the cardiovascular effects. β-Adrenergic receptor blockade, usually with propranolol (1 to 2 mg/kg per day), is titrated to effect. Antithyroid medications include propylthiouracil and methimazole, both of which inhibit the incorporation of inorganic iodide into organic compounds. Propylthiouracil inhibits the conversion of T4 to T3. Although early studies suggested that these agents might inhibit the formation of thyroid antibodies, later studies that included careful histopathologic analysis have shown this to be false ( Paschke et al., 1995 ). Saturated solutions of potassium iodide may be administered orally (one drop every 8 hours) to suppress thyroid hormone secretion. The clinical response to therapy is evident in 1 to 3 weeks, and the patient may require up to 3 months for adequate control to be achieved. Patients must have appropriate, regular surveillance to ensure that the T3 and T4 levels are in the normal range and TSH concentrations are normal. Clinically, the patient demonstrates a euthyroid state by return of the heart rate, blood pressure, and reflexes to normal.

Radioactive iodine is frequently used to treat hyperthyroidism in adults. Such therapy is avoided in children, however, because of side effects such as thyroid cancer, genetic damage to germ cells, and a higher incidence of hypothyroidism than occurs with pharmacologic therapy.

Anesthetic Management

Preoperatively, patients should be pharmacologically euthyroid. Any residual cardiovascular signs and symptoms should be well controlled through the use of a β-adrenergic receptor blocker. Esmolol is an excellent choice for intraoperative use. A large goiter may produce tracheal deviation or compression, and the possibility of airway compromise should be evaluated preoperatively with radiographic studies. Any commonly used sedative may be given for premedication. Atropine and other anticholinergics should be avoided or used with extreme caution because they decrease sweating and may interfere with thermoregulation. Medications, including antithyroid drugs and β-adrenergic blockers, should be administered through the morning of surgery.

Intraoperative Management of Patients for Thyroidectomy

In children with large goiters who have a compromised airway, anesthesia should be managed with caution, as in any other child with upper airway obstruction. A sedated fiberoptic intubation may be chosen or an inhalational induction performed with maintenance of spontaneous ventilation until the airway is secured. If a large goiter has caused prolonged tracheal compression, there may be a segment of tracheomalacia, and an armored endotracheal tube may be indicated.

For patients without issues of tracheal compression, anesthesia may be induced with thiopental or propofol. If the patient remains hyperthyroid, ketamine should be avoided, however, because of its effect on catecholamine release. Mask inductions may be prolonged in these patients because of an increased cardiac output, resulting in a slower rise in the alveolar concentration of the anesthetic if the ventilation is kept constant. Minute ventilation may be reduced if significant airway obstruction resulting from goiter or tracheomalacia is present. Care should be taken to lubricate, pad, and appropriately protect the eyes, especially if they are protuberant because of Graves—disease.

With respect to choice of drugs, muscle relaxants with few cardiovascular side effects, such as cis-atracurium, vecuronium, or rocuronium, provide a potential benefit by minimizing the occurrence of tachycardia. Similarly, for the maintenance of general anesthesia, anesthetics that have sympathomimetic effects should be avoided. If the child is in a hypermetabolic state, drug biotransformation may be accelerated; therefore, agents such as halothane, which has toxic metabolic products, are potentially more hazardous. Another reason to avoid halothane is its sensitization of the myocardium to catecholamines. If the patient is in a hypermetabolic state, controlled ventilation should be employed during the surgical procedure to minimize the development of hypercapnia, which can contribute to further sympathetic stimulation.

Anesthetic management at the conclusion of surgery may include deep extubation with direct or fiberoptic laryngoscopy performed to evaluate the presence or absence of vocal cord paralysis, which may result from surgical trauma to the recurrent laryngeal nerve (traction or section). Care should be taken after extubation to observe for signs of airway obstruction due to residual tracheomalacia. The decision to evaluate the airway prospectively at the time of extubation should be made jointly by the anesthesiologist and surgeon and is based on the likelihood of residual tracheal obstruction caused by tracheomalacia or of vocal cord paralysis because the surgeon thinks surgical trauma likely.

Postoperative Care

Children who have undergone thyroidectomy require close observation in the postoperative period ( Fewins et al., 2003 ). They may develop postextubation croup or upper airway obstruction as a result of paralysis of the vocal cords, tetany, residual tracheomalacia, or tracheal compression resulting from a hematoma. Patients with postextubation croup may respond to supportive measures, including humidified supplemental oxygen, nebulized racemic epinephrine, and possibly continuous positive airway pressure (or BIPAP). Occasionally, these patients require brief reintubation before they can be successfully extubated. Unilateral vocal cord paralysis may go unnoticed or be associated with only mild stridor. Bilateral vocal cord paralysis, on the other hand, may manifest as severe stridor and upper airway obstruction. The child with bilateral vocal cord paralysis requires reintubation for airway support. A muscle relaxant such as rocuronium should be used to facilitate reintubation to avoid damage to the abducted cords. If the paralysis is prolonged, the child may subsequently require tracheostomy. Compression of the trachea by a hematoma may occur immediately after the operation or over the course of several hours. The child requires reintubation and surgical evacuation of the hematoma to relieve tracheal compression. Opening the wound in the recovery room may be necessary and lifesaving. After the extrinsic obstruction has been relieved and the incision closed again (if necessary), the child may be safely extubated.

Inadvertent resection of the parathyroid glands during thyroidectomy may result in acute hypoparathyroidism after surgery. Clinical signs of hypocalcemia may become manifest within the first postoperative day or take as long as 72 hours to develop. A low serum ionized calcium level and a low concentration of parathyroid hormone are diagnostic. Clinical hypocalcemia, including tetany, is treated with intravenous calcium therapy. Surgical manipulation of the trachea and neck tissues can also lead to subcutaneous emphysema and the more serious possibility of pneumomediastinum or pneumothorax. Postoperative evaluation should include radiologic examination of the chest if respiratory distress occurs.


Pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells that most commonly arises in the adrenal medulla ( DiGeorge, 1987 ). It may be found anywhere along the abdominal sympathetic chain, however, particularly near the aorta at the inferior mesenteric artery or the aortic bifurcation. Other sites include the neck, the mediastinum, and the walls of the bladder or ureters. Pheochromocytoma is a rare neoplasm in the pediatric population. Less than 5% of the reported cases occur in children. The tumors may occur bilaterally or in multiple sites. It can be inherited as an autosomal dominant trait (most frequently in association with von Hippel-Lindau syndrome) or as part of a multiple endocrine neoplasia syndrome (MEN type II or III) ( Table 32-8 ).

TABLE 32-8   -- Multiple endocrine neoplasia syndromes

MEN Syndrome

Affected Organs

Disorder Features

Werner's syndrome (MEN type I, familial)

Parathyroid gland; pancreas; pituitary gland

Hypercalcemia; hypoglycemia; peptic ulcer

Sipple's syndrome (MEN type II, autosomal dominant)

Thyroid and parathyroid glands; adrenal medulla

Medullary carcinoma; hypercalcemia; pheochromocytoma

MEN type III

Nervous system; thyroid gland; adrenal medulla

Multiple neuromas; medullary carcinoma; pheochromocytoma

MEN, multiple endocrine neoplasia.




The abnormally high plasma levels of epinephrine and norepinephrine produce a clinical syndrome with signs and symptoms related directly to the level of each hormone present in the patient. Hypertension is common and frequently leads to hypertensive encephalopathy and seizures. In particular, paroxysmal hypertension is most suggestive of pheochromocytoma. The patient may also complain of associated headaches and palpitation, pallor, sweating, and vomiting. In severe cases, patients developchest pain that radiates to the arms, pulmonary edema, and cardiac decompensation. The catecholamine-induced hypermetabolism also can cause patients to have a voracious appetite but still lose weight and become cachectic. Polyuria, polydipsia, and abdominal pain may occur and be confused with diabetes mellitus.


It is extremely important to establish the diagnosis of pheochromocytoma before induction of anesthesia and start of surgery. The significant cardiovascular effects of excess catecholamines can pose difficulties for the anesthesiologist and endanger the patient during the perioperative period if an appropriate diagnosis is not made preoperatively. These tumors can produce paroxysms of hypertension and other symptoms. Between paroxysms, the patient may be totally asymptomatic, making diagnosis extremely difficult. The demonstration of increased levels of catecholamines is the most specific diagnostic test. Although pheochromocytomas can produce norepinephrine and epinephrine, the predominant catecholamine produced in children is norepinephrine, which leads to chronic hypertension. Urine catecholamine concentrations are directly proportional to circulating levels, and determination of 24-hour urinary excretion of the primary catecholamines and their metabolites (i.e., 3-methoxy-4-hydroxy vanillyl-mandelic acid [VMA] and metanephrine) used to be the primary means of establishing the diagnosis. The plasma-free metanephrine determination has better sensitivity (100%) and specificity (94%). Because normal values differ with age, it is important to use age-specific norms when interpreting results (Weise et al., 2002).

The differential diagnosis includes renal vascular disease, hyperthyroidism, Cushing's syndrome, coarctation of the aorta, adrenal cortical tumors, and essential hypertension. Cerebral disorders, diabetes mellitus, and diabetes insipidus may produce similar symptoms. Neoplasms of neural origin (e.g., neuroblastoma, ganglioneuroma) may also secrete catecholamines.

Before any contemplated anesthesia and surgery, the patient must undergo a complete evaluation to localize the tumor. Urinary catecholamine levels should be measured and a CT scan performed to localize the tumor. Differential venous catheterization may be needed to obtain blood from various sites for catecholamine levels. A radionuclide (I 131 meta-iodobenzylguanidine [MIBG]) scan may also help to localize the tumor. Sedation or anesthesia may be required to perform these studies in infants and children. Before sedation for these diagnostic studies, hemodynamic abnormalities must be normalized. Drugs that induce catecholamine secretion or histamine release should be avoided. General anesthesia for the diagnostic procedures must be conducted with the same extreme caution one would exercise for resection of the tumor itself.

Preoperative Preparation and Evaluation

Preoperative evaluation should include the measurement of serum electrolytes, determination of renal function, and a glucose tolerance test or test for fasting blood glucose level. Excessive serum epinephrine levels may be associated with hyperglycemia and hypokalemia. An electrocardiogram and echocardiogram are important to evaluate cardiac rhythm, size, and function. Some patients with pheochromocytoma have a catecholamine-induced cardiomyopathy with decreased left ventricular contractility. The patient should be evaluated for associated endocrinopathies that may be present as part of MEN II or III.

Symptomatic treatment includes the administration of phenoxybenzamine over a period of several days to weeks before surgery. Phenoxybenzamine is a long-acting, orally administered α-adrenergic blocking agent that attenuates the effects of catecholamines on the peripheral circulation by blocking excessive vasoconstriction ( Hoffman and Lefkowitz, 1990 ). There are no established starting doses of phenoxybenzamine for pediatric patients, although 0.2 mg/kg once daily is suggested (adult starting dose is 10 mg). The dose is then increased gradually until a clinical effect is obtained, that is, the patient's hematocrit decreases (because of vasodilation and increased blood volume), and the patient develops orthostatic changes in vital signs. Long-standing vasoconstriction produced by chronically high catecholamine levels causes decreased intravascular volume. Although the use of phenoxybenzamine will restore vascular capacity to normal, increased oral fluid intake should accompany administration of phenoxybenzamine to avoid severe orthostatic changes. In some children, β-adrenergic blocking drugs such as propranolol may be needed to control heart rate and blood pressure. However, β-blocking agents should never be used without concurrent α-blockade therapy because of the deleterious effects of unopposed α-agonism, which may result in cardiac failure due to increased afterload. Labetalol may have a role in the management of pheochromocytoma ( Blom et al., 1987 ), because it has α- and β-adrenergic blocking properties. It can be useful in minimizing the cardiovascular effects of excess catecholamines during the perioperative period, but it is not as potent an α-blocker as phenoxybenzamine for preoperative treatment.

In addition to the pharmacologic preparation, children with pheochromocytoma benefit from preoperative sedation to reduce the release of catecholamines caused by anxiety. Oral or intravenous midazolam alone or in combination with an opioid provides a good level of sedation.

Anesthetic Induction

Induction of anesthesia is accomplished with intravenous anesthetics. Ketamine is specifically contraindicated because it induces catecholamine release. Halothane should be avoided because it may sensitize the myocardium to catecholamines and produce dysrhythmias. Mask induction with sevoflurane is well tolerated if hemodynamic parameters are well controlled, and intravenous cannula placement can be deferred until after induction. Intubation may proceed in the usual fashion, facilitated by a hemodynamically neutral nondepolarizing muscle relaxant such as vecuronium. Pancuronium, which causes muscarinic blockade and tachycardia, should be avoided. Despite the fact that atracurium causes histamine release and vasodilation, it has been used safely in adult patients with pheochromocytoma ( Prys-Roberts, 2000 ). Before intubation, intravenous lidocaine (1 mg/kg) or fentanyl (2 to 5 mcg/kg), or both, are effective in minimizing the hemodynamic response to intubation.

Intraoperative Management

After induction of anesthesia, an intraarterial catheter is placed to monitor the blood pressure continuously. Before induction, a reliable automated blood pressure device can provide frequent, accurate blood pressure measurements. A central venous catheter provides direct and reliable access for the assessment of intravascular volume and for infusions of fluids and emergency medications.

Anesthesia may be maintained with isoflurane or sevoflurane, air, and oxygen. Both anesthetic agents have been used without exacerbation of hypertension, despite the fact that they do not blunt the production of norepinephrine in response to surgical stimulation ( Suzukawa, et al., 1983) . Desflurane should be avoided because of its tendency to cause tachycardia and hypertension. The addition of moderately large doses of fentanyl (10 mcg/kg) or remifentanil (0.3 to1 mcg/kg per minute) will minimize the stress response and provide stable hemodynamics. If remifentanil is chosen, it is important to give a longer-acting opioid before the end of surgery to avoid hypertension due to pain on awakening. Adjunctive use of epidural anesthesia (i.e., local anesthetic with or without a small dose of fentanyl) is an excellent method of reducing the stress response and catecholamine release caused by usual surgical stimulation. None of these anesthetic strategies, however, blocks catecholamine release resulting from direct surgical manipulation of tumor tissue.

Blood pressure control during the induction and maintenance of anesthesia is best accomplished by an infusion of sodium nitroprusside or phentolamine. In addition to using propranolol preoperatively, esmolol has been effective as a continuous infusion titrated to the level of surgical stimulation ( Nicholas et al., 1988 ). Infusions of only short-acting vasodilators are recommended for control of hypertension before tumor resection, because with removal of the tumor, vasodilation due to persistent α-blockade and loss of excess catecholamines may lead to precipitous hypotension. Because phenoxybenzamine has a long half-life, some physicians recommend discontinuing it 24 hours before surgery to decrease the likelihood that persistent vasodilation due to α-blockade will cause severe hypotension after the tumor is removed because of withdrawal of the catecholamines of tumor origin ( Prys-Roberts, 2000 ). Hypotension is best treated with discontinuation of vasodilator infusions, titration of anesthetic agents, and administration of crystalloid or colloid and blood products if indicated by the magnitude of blood loss. If these measures are ineffective, vasopressors may be necessary, but the patient may be relatively resistant to α-agonists due to persistent α-blockade. If this occurs, judicious use of small doses of more potent, direct-acting vasoconstrictors (e.g., norepinephrine, epinephrine) may be necessary.

During surgery, arterial blood gases, serum glucose, urine output, and body temperature should be closely monitored. Hyperglycemia may occur in response to high catecholamine levels. Hypoglycemia may occur when the tumor is removed and catecholamine levels decrease. Because of the potential for dysrhythmias, the electrocardiogram should also be continuously monitored.

At the end of surgery, the muscle paralysis is reversed. Extubation can be accomplished when the patient meets all normal extubation criteria. Despite the recent increase in laparoscopic adrenalectomies for pheochromocytoma in adults, an open approach continues to be the norm in children. No alteration in hemodynamic parameters has been seen with the laparoscopic approach in adults; there have been no adverse effects on hemodynamics from insufflation of carbon dioxide. If laparoscopic surgery is proposed, anesthetic management is as outlined previously.

Postoperative Care

Postoperatively, the patient should be observed in an intensive care unit, with continuous monitoring of the arterial blood pressure and electrocardiogram. Hypertension usually resolves within 24 to 48 hours after surgery. If symptoms persist beyond this period, further investigation for residual pheochromocytoma is warranted. Good postoperative analgesia is provided with epidural infusion or intravenous patient (parent or nurse) controlled analgesia.

Copyright © 2008 Elsevier Inc. All rights reserved. -

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

Copyright © 2005 Mosby, An Imprint of Elsevier



Viral upper respiratory tract infections (URIs) are mild processes that do not preclude school attendance and other routine activities. However, URIs hold much greater significance for anesthesiologists. For many anesthesiologists, it is standard practice to avoid general anesthesia for elective surgery in children with a URI because of the respiratory complications during and after anesthesia reported in multiple small case series ( McGill et al., 1979 ; Cohen and Cameron, 1991 ; Konarzewski et al., 1992 ; Williams et al., 1992 ). Unfortunately, the vexing problem of runny noses in children is accentuated by the difficulty of differentiating URI from other causes of runny nose, such as allergic rhinitis, which does not increase the risk of complications.

Pathophysiology of Upper Tract Respiratory Infection

Many investigators suggest that complications, including bronchospasm ( Olsson, 1987 ), intraoperative hypoxemia with an increased alveolar-arterial oxygen gradient ( McGill et al., 1979 ), and postoperative hypoxemia ( DeSoto et al., 1988 ), occur more frequently in children who undergo anesthesia while they have a URI. The proclivity for these complications may be related to peripheral airway abnormalities, which have been demonstrated experimentally in adult humans ( Johanson et al., 1969 ; Fridy et al., 1974 ) and animals ( Dueck et al., 1991 ) infected with viral respiratory pathogens. These abnormalities include decreased diffusing capacity and increased closing volume, factors that can predispose patients to intrapulmonary shunting and hypoxemia, especially when combined with the effect of general anesthesia on lung volumes (decreased functional residual capacity) ( Murat et al., 1985 ) (see Chapter 2 , Respiratory Physiology). These studies were done in adults who had infections involving their entire respiratory tracts, rather than isolated URIs. These results may support separation of treatment of patients with truly isolated upper airway infections from those with any symptoms of more global airway or pulmonary parenchymal involvement. Although the mechanisms by which viral respiratory infections lead to alterations in airway function are unclear, these experimental studies support the clinical impression that increased risk of perioperative hypoxemia occurs in patients with a recent viral respiratory infection. Empey and others (1976) demonstrated in adult patients that acute viral respiratory tract infection (influenza) produced marked bronchial reactivity to experimental bronchoconstrictor challenge that may last for 6 weeks. Mechanisms by which viral infections lead to increased airway reactivity include the release of immunologic and inflammatory mediators such as leukotrienes, bradykinin, and histamine, which cause bronchoconstriction. Vagal-mediated mechanisms may be involved because viral infections have been associated with changes in muscarinic receptors on airway smooth muscle (Fryer et al., 1990). Tissue concentrations of important enzymes such as neutral endopeptidase, which break down the neuropeptides that cause bronchoconstriction, are also decreased in viral infections ( Jacoby et al., 1988 ; Dusser et al., 1989 ). These patients and animals, however, cannot be said to have only URIs because the airways below the larynx are clearly affected as well. Patients whose infections are truly uncomplicated URI or those with noninfectious causes of runny nose should be differentiated from those who have evidence of lower respiratory involvement.

Perioperative Risk

Many case reports in the literature document respiratory complications in the perioperative period in children with URIs, including bronchospasm, stridor caused by subglottic edema, hypoxia, and atelectasis ( McGill et al., 1979 ; Konarzewski et al., 1992 ; Williams et al., 1992 ). Three prospective studies have shown that patients with an active or recent URI had a 2- to 10-fold higher risk of bronchospasm or laryngospasm ( Olsson and Hallen, 1984 ; Olsson, 1987 ; Cohen and Cameron, 1991 ). The incidence was higher among younger children, especially those younger than 2 years, and in those whose tracheas were intubated ( Cohen and Cameron, 1991 ). Tait and others (1987b, 2001) [494] [496] have contributed retrospective studies of much larger numbers of patients. These studies show that there may actually be a higher risk of respiratory complications in asymptomatic children with history of a URI within the 2 to 4 weeks preceding surgery than in those with an acute URI. Tait and others (2000, 2001) [496] [498] found that the factors increasing the risk of adverse events were intubation, history of prematurity or reactive airways disease (RAD), parental smoking, airway surgery, copious secretions, and nasal congestion. Despite this increased risk of adverse events, complications usually were easily treated and were not associated with any significant prolonged morbidity ( Rolf and Cote, 1992 ; Tait et al., 2000, 2001 [498] [496]). However, some patients in one study developed atelectasis severe enough to require bronchoscopy and prolonged postoperative mechanical ventilation. Although most of these studies evaluated children having relatively minor elective surgery, Malviya and others (2003) reported that children with URI symptoms at the time of cardiac surgery also had increased risks for respiratory and other complications, including nonrespiratory infection. Despite these findings, patients—hospital stays were not prolonged, and the incidence of long-term sequelae was not increased.

One study found that children with URIs who undergo mask halothane-nitrous oxide-oxygen anesthesia for myringotomy surgery had reduced severity and duration of the URI symptoms in the postoperative period ( Tait and Knight, 1987a ). However, this reduction in symptoms may have resulted from the drainage and removal of infectious foci rather than from the beneficial effects of general anesthetics. Other investigators have reported no significant respiratory complications when children with URI were anesthetized ( Hinkle, 1989 ; Jacoby and Hirschman, 1991) . It is extraordinarily difficult to integrate the contradictory conclusions of these various series of patients to develop a logical algorithm for dealing with the child with a URI.

Anesthetic Decision-Making

It is apparent that no consensus has been reached in the literature or in the general anesthesia community with regard to the wisdom and safety of anesthetizing children with active or recent URI. The bulk of the literature, clinical and experimental, suggests that recent viral infection increases the perioperative risk for respiratory complications, albeit mild and treatable, when the surgical and anesthetic plans require intubation. In children with underlying RAD, the risk for pulmonary complications immediately after an acute URI is much greater than in the normal patient population, making intraoperative bronchospasm much more likely. The threshold for postponing surgery in the asthmatic child with a recent URI who requires intubation is much lower. These risks must be weighed against the physiologic, psychologic, and financial implications of delaying surgery.

The most conservative approach to the child with a URI or recent URI is to postpone elective procedures for 1 to 2 weeks for uncomplicated rhinorrhea, congestion, and nonproductive cough and for 4 to 6 weeks for patients with lower airway involvement (e.g., wheezing, productive cough). However, this may be an overly cautious and somewhat unrealistic recommendation. Normal children have an average of three to eight colds per year, and children whose mothers smoke, who live in crowded conditions, and who attend day care centers have a 61% incidence of URIs over a 2-week period ( Fig. 32-1 ) (Fleming et al., 1987 ). It may be nearly impossible to find a period when the child does not have a URI or is not recovering from one. The needs of the family must be considered. Often, parents have traveled significant distances, have taken time off from work, and have made alternative child care arrangements for their other children. Because the available data do not clearly indicate a single best approach to these patients, each anesthesiologist should develop a consistent approach appropriate to the individual practice.


FIGURE 32-1  Probability of upper respiratory tract infection according to age, crowding, maternal smoking, and day care status.  (From Fleming DW, Cochi SL, Hightower AW, et al.: Childhood upper respiratory tract infections: To what degree is incidence affected by day-care attendance? Pediatrics 79:55, 1987.)




The following is a summary of an approach to the child with symptoms of a URI. First, many children undergo operations directed at ameliorating their chronic upper respiratory tract symptoms. In cases such as myringotomy with tube placement, tonsillectomy, adenoidectomy, and cleft palate repair, the procedures are not automatically canceled or postponed unless the child's signs and symptoms are clearly “different from baseline” or clearly involve more than the upper respiratory tract. Children who undergo the procedures just listed have a high incidence of upper respiratory tract symptoms and may always have manifestations consistent with URI. Most parents will honestly state whether their child is more congested than usual.

Elective surgeries other than those cited previously are postponed if any of the following are present: “croupy” cough; rectal temperature greater than 38°C associated with any URI sign or symptom; malaise or decreased appetite; any evidence or recent history of lower respiratory tract involvement such as rales, wheezes, productive cough, or abnormal chest radiograph ( Box 32-5 ). Laboratory and radiographic tests are usually not helpful in the decision-making process, although some investigators recommend obtaining a chest radiograph and a white blood cell count to evaluate the child with a URI. The white blood cell count is neither sensitive nor specific in identifying URI, and chest radiography associated with a normal auscultative examination is unlikely to identify abnormalities ( Brill et al., 1973 ). The presence of rales or wheezes should lead to a postponement of elective surgery, regardless of the findings on the chest radiograph. A suggested algorithm for making decisions about proceeding with surgery is presented in Figure 32-2 .

BOX 32-5 

Signs and Symptoms of Upper Respiratory Tract Infections



Mild sore or scratchy throat*



Mild malaise









Nasal congestion or stuffiness



Nonproductive cough



Fever greater than 101°F (38°C)




*To diagnose an upper respiratory tract infection, two of any of the signs or symptoms are required. If 1 and 2, 3 and 4, or 5 and 6 are combined, one additional sign or symptom is required.

Adapted from Tait AR, Knight PR: The effects of general anesthesia on upper respiratory tract infections in children. Anesthesiology 67:930, 1987a.


FIGURE 32-2  Algorithm for clinical decision-making for patients with upper respiratory tract infection.  (From Martin LD: Anesthetic implications of an upper respiratory tract infection in children. Pediatr Clin North Am 41:121, 1994.)




Anesthetic Management

Several major principles of anesthetic management can be suggested in dealing with children with an acute or recent URI ( Tait and Malviya, 2005 ). These are especially important in anesthetizing children when surgery is urgent and cannot be delayed. In elective situations, it is best to avoid intubation if possible (if the surgical procedure allows), instead using regional anesthesia or general anesthesia by mask or laryngeal mask airway (LMA). A randomized, prospective study demonstrated a much lower incidence of bronchospasm in children with URI managed with LMA rather than ETT (0% versus 12.2%) (Tait et al., 1998 ). The incidence of all respiratory complications was reduced by 50% for the LMA group (19% versus 35%). LMA may be an excellent alternative for airway management for patients with URI if the planned surgical procedure and NPO status are compatible with its use. If intubation is indicated, it should be accomplished when the patient is at a deep plane ofanesthesia using an endotracheal tube at least one size (0.5 cm) smaller than age would determine. Any intravenous induction agent is acceptable, with the most important guiding principle being that enough should be given to achieve a deep level of anesthesia. An alternative is mask induction of inhalation anesthesia with sevoflurane, nitrous oxide, and oxygen. If the procedure is expected to be prolonged, heated humidification should be used, because use of dry gas may lead to inspissation of secretions. Adjunctive agents such as intravenous lidocaine (1 mg/kg) or opioid, or both, decrease airway reflexes ( Hirshman, 1983 ). The preoperative use of anticholinergic agents (i.e., atropine and glycopyrrolate) theoretically may block muscarinic receptors, thereby interrupting the airway reflex arc ( Jacoby and Hirshman, 1991 ). Their properties as antisialagogues may be helpful. These agents have not been shown to be beneficial in prospective studies. The use of glucocorticoids experimentally has decreased viral associated tachykinin-induced airway edema formation ( Piedimonte et al., 1990 ), although glucocorticoids are not routinely prescribed in this clinical situation, in contrast to their use in the patient with RAD. If intubation is necessary, tracheal suction of URI-associated secretions after intubation and before extubation may decrease the chance of atelectasis and mucus plugging, although this has not been studied.

Management of children with URI requires a logical approach. When this issue arises in the preoperative period, the patient, parents, surgeon, and anesthesiologist must participate in an informed fashion in the decision-making process. However, “in the final analysis, the name of the game is clinical judgment and a degree of good fortune” ( Berry, 1990 ).


Reactive Airway Disease (RAD), or asthma, is the most common chronic disease of childhood in industrialized countries. It has received wide public attention in recent years because of increases in morbidity and mortality. Asthma is the major cause of restricted activity, absence from school, and hospital admission in children, and it is responsible for significant health care costs in the United States (Newacheck and Halfon, 2000 ). The prevalence of asthma among children is greater than among adults, and it has increased by an average of 4.3% each year between 1980 and 1996 ( Akinbami and Schoendorf, 2002 ). Beginning in 1997, the survey questions used to determine the prevalence of asthma were changed, which resulted in a slightly lower prevalence than in previous years, but the increasing trend has remained constant ( Measuring childhood asthma, 2000 ).

Etiologic Factors and Pathophysiology

Asthma is a chronic inflammatory disorder of airways in which many cell types play a role, including mast cells and eosinophils. These cells release mediators of inflammation that, in susceptible individuals, cause symptoms associated with variable airway obstruction and airway hyperreactivity, which is partially or completely reversible spontaneously or with appropriate treatment. Understanding the important role of inflammation in the immunopathogenesis of asthma in recent years has changed the focus to a newer therapeutic approach using antiinflammatory agents. Among the immune regulatory pathways involved in the pathogenesis of asthma, two cytokines, interleukin-4 and interferon-γ, appear to be important in controlling IgE production. In asthmatic individuals, mast cells and eosinophils are attracted to airways and release cytokines and lipid mediators that cause inflammation ( Goldstein et al., 1994 ). The interplay of allergen/irritant, mast cells, eosinophils and their mediators, and the end effects on pulmonary vessels and airways is depicted in Figure 32-3 . Airway obstruction in asthma results from a combination of several factors, including airway smooth muscle spasm, airway mucosal edema, hypersecretion, and mucus plugging of small bronchi and bronchioles ( Djukanovic et al., 1990 ). These changes result in airway obstruction, increased work of breathing, uneven distribution of ventilation, and, in severe disease, air trapping, hyperinflation, and ventilation-perfusion imbalance, which leads to hypoxemia, diaphragmatic fatigue, hypercapnia, and respiratory failure.


FIGURE 32-3  Pathophysiology of asthma.



There is a strong association between asthma and allergy. Up to 90% of children with frequent wheezing respond positively to bronchoconstrictor challenge, especially when associated with atopy ( Clough et al., 1991 ). There is an increased prevalence of asthma among first-degree relatives of asthmatic subjects; over two thirds of children with asthma appear to have a familial predisposition ( Clifford et al., 1989 ). Various environmental factors precipitate airway hyperreactivity and trigger asthma.

The onset of asthmatic symptoms is often associated with viral lower respiratory tract infection, particularly respiratory syncytial virus (RSV) infection in infants and children ( Rooney and Williams, 1971). Severe viral bronchiolitis in infancy is significantly associated with the subsequent development of airway hyperreactivity and asthma, although familial factors cannot be ruled out ( Rooney and Williams, 1971 ; Gurwitz et al., 1981 ). The development of IgE antibody to the RSV may play an important role in inducing an allergic response to the virus ( Welliver et al., 1989 ). Children who experience respiratory failure and mechanical ventilation during infancy and early childhood, such as those with bronchopulmonary dysplasia (BPD), neonatal repair of congenital diaphragmatic hernia, or severe viral bronchiolitis, develop and sustain airway hyperreactivity even without a family history of asthma ( Mallory et al., 1989 ; Nakayama et al., 1991 ). Prematurity alone may be associated with a higher incidence of asthma in preadolescent children ( von Mutius et al., 1993 ). The primary site of airway obstruction and hyperreactivity in children with a history of neonatal respiratory failure appears to be in relatively small airways. This is in contrast to relatively large central airway obstruction and hyperreactivity in those with typical allergic (i.e., IgE antibody-mediated) asthma ( Mallory et al., 1991).

In children with RAD, parental smoking (passive smoking) increases the incidence of severity of symptoms and exacerbates airway hyperreactivity ( Soussan et al., 2003 ). Intrauterine exposure to maternal smoking also increases the incidence of airway hyperresponsiveness in infants ( Singh et al., 2003 ). Infants with gastroesophageal reflux and chronic esophagitis often develop airway hyperresponsiveness with or without chronic aspiration and resultant tracheobronchial inflammation ( Sheikh et al., 1999 ). Causative factors responsible for the development of airway hyperreactivity and asthma are listed inFigure 32-4 .


FIGURE 32-4  Contributing factors to the development of reactive airways disease. ARF, acute renal failure; LRI, lower respiratory tract infection; RSV, respiratory syncytial virus.



Precipitating Factors for Reactive Airways Disease

Viral lower respiratory infections, particularly those due to RSV and influenza, sensitize airways and provoke airway hyperreactivity even in nonasthmatic, nonallergic individuals for as long as 6 weeks (Empey et al., 1976 ). Exposure to dry, cold air can precipitate tracheobronchial constriction in asthmatic subjects, presumably in response to reduced tracheal temperature caused by evaporative heat loss (Gilbert et al., 1988 ). The same mechanism appears to be responsible for exercise-induced bronchospasm and precipitation of asthma with excitement, anxiety, and hyperventilation ( McFadden and Gilbert, 1994 ).

The period before and during the induction of anesthesia is uniquely suited to trigger bronchospasm in susceptible individuals because of the patient's emotional stress, fear, and excitement. There is resultant hyperventilation with mouth breathing of dry anesthetic gas mixtures, airway irritation by volatile anesthetics, and mechanical stimulation of the pharyngeal and laryngeal mucosa by laryngoscopy and endotracheal tube ( Box 32-6 ).

BOX 32-6 

Precipitating Factors for Bronchospasm



Lower respiratory tract infection (adenovirus, respiratory syncytial virus)



Irritants (cigarette smoke, inhaled anesthetics)



Allergens (inhaled)



Emotional stress; fear and excitement



Exercise, hyperventilation



Cold or dry gas (anesthetic gases without humidification)



Manipulation or mechanical stimulation of pharynx and larynx



Gastroesophageal reflux

Pharmacologic Agents for Asthma

The pharmacologic management of asthma consists of bronchodilators and antiinflammatory drugs and includes six different classes of drugs: β-adrenergic agonists, leukotriene inhibitors, methylxanthines, anticholinergics, cromolyn (or nedocromil), and corticosteroids. Initial treatment for asthma most commonly consists of inhaled corticosteroids and β-adrenergic agonists, with inhaled corticosteroids often being the first line drugs. Other first, line alternatives are cromolyn (or nedocromil) or, increasingly, leukotriene receptor antagonists (zafirlukast, montelukast) and leukotriene synthesis (5-lipoxygenase) inhibitors (zileuton). Montelukast (Singulair) has been used widely in children. Drugs in common use in children are listed in Table 32-9 . Theophylline has reentered the treatment algorithm if patients have exacerbations despite inhaled corticosteroids and β-adrenergic agonists. Oral corticosteroids in brief high-dose pulses are reserved for patients with moderate to severe asthma unresponsive to combinations of the other drugs ( Stempel, 2003 ).

TABLE 32-9   -- Drugs for asthma




Antiinflammatory Drugs

Inhaled Corticosteroids

Beclomethasone dipropionate (Vanceril)

MDI, 42 mcg/puff

2 to 4 puffs bid

Budesonide (Pulmicort)

DPI, 200 mcg/inhalation

1 to 2 inhalations bid

Flunisolide (AeroBid)

MDI, 250 mcg/puff

2 puffs bid

Fluticasone propionate (Flovent)

MDI, 44, 110, or 220 mcg/puff

1 to 2 puffs bid (max, 440 mcg/day)

(Flovent Rotadisk)

DPI, 50 mcg/inhalation

1 inhalation bid

Triamcinolone acetonide

MDI, 100 mcg/puff; DPI, 50 mcg/inhalation

2 to 4 puffs or inhalations bid

Oral Corticosteroids

Prednisone or prednisolone (Prelone, Pediapred)

Oral tablets, 1, 2.5, 5, 10, or 20 mg

Acute: 1 mg/kg qd or bid × 5 to 14d


Oral liquid, 1 mg/mL

Chronic: 0.25 to 2 mg/kg qod



Preoperative: 1 mg/kg/day × 3 days



Max 60 mg/day

Leukotriene Modifiers

Montelukast (Singulair)

Oral granules/chewable tablets, 4 or 5 mg

12 mo to 5 yr: 4 mg qd



6 to 14 yr: 5 mg qd

Zafirlukast (Accolate)

Tablets, 20 mg

10 mg bid

Cromolyn (Intal)

Spinhaler (DPI), 20 mg/capsule

1 capsule tid

Nedocromil (Tilade)

MDI, 1.75 mg/puff

2 to 4 puffs bid


β2-Agonists (inhaled or enteral)

MDI, 90 mcg/puff

2 puffs q 4 to 6 hr prn

Albuterol (Proventil, Ventolin)

Rotacaps (DPI), 200 mcg/capsule



Nebulized solution, 0.83 mg/mL; 0.63 or 1 to 2 inhalations prn



1.25 mg/3 mL; 5 mg/mL

0.1 to 0.15 mg/kg prn

Levalbuterol (Xopenex)

Nebulized solution, 0.31 or 0.63 mg/mL

0.31 to 0.63 mg prn

Pirbuterol (Maxair)

MDI, 200 mcg/puff

2 puffs prn

Terbutaline (Bricanyl, Turbuhaler)

DPI, 50 mcg/inhalation

1 puff q 4 to 6 hr prn

Metaproterenol (Alupent)

MDI, 200 mcg/puff

1 puff prn

Salmeterol (Serevent)

MDI, 21 mcg/puff

1 to 2 puffs bid



Oral solution, 90mg/5 mL

10 mg/kg/day


Tablet (immediate release), 100 mg

Max 16 mg/kg/day (>1 yr)


Capsule (sustained release), 125, 200, or 300 mg

Max 5 mg/kg/day + 0.2 (age in weeks) (<1 yr)


Ipratropium bromide (Atrovent)

MDI, 20 mcg/puff

1 to 2 puffs qid (3 to 14 yr)



2 puffs qid (>14 yr)

Adapted from Drugs for asthma. Treat Guidel Med Lett 1:7, 2002.

DPI, dry powder inhaler; MDI, metered-dose inhaler.





β2-Adrenergic Agonists

β2-Adrenergic agonists initiate their action on the receptor sites of airway smooth muscle cells and increase adenylate cyclase activity, which produces cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) and results in smooth muscle relaxation and bronchodilation.

β2-agonists are the most potent bronchodilators available and are the drugs of choice for the treatment of acute exacerbation in mild asthmatics, for maintenance therapy in more severe RAD, and for the prevention of exercise-induced bronchoconstriction. The recommended doses of commonly used β2-agonists are listed in Table 32-9 .


Methylxanthines (e.g., theophylline) produce bronchodilation by inhibiting adenosine-induced bronchoconstriction in asthmatic patients rather than, as was formerly thought, competitively inhibiting phosphodiesterase, which metabolizes cAMP ( Holgate et al., 1984 ). Although theophylline was the mainstay of pediatric asthma therapy in the 1970s and 1980s, it is no longer used for therapy in acute exacerbations of RAD ( Rooklin, 1989 ). Theophylline still has a role in decreasing the severity of persistent bronchospasm, especially that which occurs at night. Theophylline has a narrow therapeutic index with greatest efficacy at serum levels of from 5 to 15 mcg/mL. Levels greater than 20 mcg/mL are associated with symptoms of toxicity, such as nausea, irritability, learning difficulties in children, and headache ( Creer and Gustafson, 1989 ). Vomiting, tachyarrhythmias, and seizures can occur at higher levels. The great variability of drug metabolism and the necessity for monitoring of blood levels is one reason the use of theophylline has declined ( Drugs for asthma, 2002 ).


Ipratropium bromide is an atropine derivative and is available as a metered-dose inhaler and as a nebulizable solution. Ipratropium has a slower onset of action than β2-agonists, but the duration of action is longer (up to 8 hours). Side effects are uncommon.

Cromolyn Sodium and Nedocromil Sodium

Cromolyn sodium does not have a bronchodilator effect and, therefore, is exclusively a prophylactic agent and has no bearing on anesthetic practice. It attenuates bronchoconstriction caused by allergen, exercise, and bronchial challenge ( Stempel, 2003 ). Nedocromil sodium has similar chemical and biologic properties to cromolyn, which became available in the early 1990s ( Van Bever and Stevens, 1992). Cromolyn and nedocromil are thought to act on pulmonary mast cells and stabilize cell membranes. They reduce IgE antibody-induced release of inflammatory mediators, including histamine and leukotrienes, from activated mast cells ( Douglas, 1985 ). Maintenance therapy with cromolyn or nedocromil is recommended in children with moderate to severe asthma.

Leukotriene-Modifying Drugs

Leukotriene-receptor antagonists and leukotriene synthesis inhibitors are a class of drugs recently developed for the prevention and treatment of bronchial asthma. The formation of leukotrienes through the 5-lipoxygenase pathway depends on lipoxygenation of arachidonic acid, a major constituent of cell membrane phospholipids, detached by phospholipase A2 activity. Leukotrienes (LTs) are potent bronchial smooth muscle constrictors; on the molecular basis, LTC4 and LTD4 are approximately 1000 times more potent than histamine ( Undem and Lichtenstein, 2001 ). Bronchial smooth muscle constriction by leukotrienes is considered a major cause of asthmatic symptoms. Leukotriene-receptor antagonists (e.g., zafirlukast, montelukast) are selective high-affinity LT1 receptor antagonists ( Jones et al., 1995 ). Leukotriene synthesis inhibitors, such as zileuton, inhibit the formation of LTC4, LTD4, and LTB4, a potent chemotactic autocoid, and other eicosanoids that depend on LTA4 synthesis ( Undem and Lichtenstein, 2001 ). Montelukast has been reported to be effective as maintenance therapy in children with moderate to severe asthma with or without concomitant steroid therapy with minimal side effects ( Knorr et al., 2001 ; Phipatanakul et al., 2003 ).


Inhaled corticosteroids have become popular for the treatment of asthma because of their potent antiinflammatory effect on the airways with limited systemic effects compared with oral steroids. Regular use of an inhaled corticosteroid allows effective control of symptoms and improvement in lung function, reduces airway inflammation, and results in a gradual reduction in airway hyperreactivity ( Konig, 1988 ; Juniper et al., 1991 ). Recommended doses of inhaled corticosteroids generally have minimal effects on the HPA axis ( Barnes and Pedersen, 1993 ); however, high doses, especially of fluticasone (Flovent), have resulted in reduction of cortisol levels and symptomatic adrenal insufficiency in children ( Drake et al., 2002 ; Eid et al., 2002 ). Oral or parenteral corticosteroids are most effective for acute exacerbations of asthma unresponsive to maximal bronchodilator therapy ( Chapman et al., 1991 ).

Preanesthetic Considerations

The goal of the preoperative assessment of children with asthma is to ensure that each patient receives optimal treatment before reaching the operating room. The patient's history, physical examination, and laboratory tests are all helpful to determine if the patient's condition is adequately managed. Children with RAD rarely require preoperative pulmonary function testing, but they are commonly monitored by pulmonology or allergy and immunology services with frequent assessment of pulmonary function testing (i.e., spirometry with flow-volume curves). Some families use the peak expiratory flow rate (PEFR) for home assessment. If this is so, the family should be queried to ensure that PEFR is maximized.

Careful history taking is the single most important element of the preoperative evaluation of asthmatic children. The profile of a typical acute episode, precipitating factors, and time of the most recent episode of asthma should be obtained. Previous and current drug therapy, dosage, effectiveness, and side effects, if any, should also be documented. Specific points of importance in the history include the following:



Determine if the child has had episodes of bronchospasm and bronchodilator treatment in the previous 4 to 6 weeks. Ideally, elective surgery should be postponed for at least 4 to 6 weeks after an episode of symptomatic asthma because airway hyperreactivity may be worsened after acute exacerbations, and pulmonary gas exchange may still be impaired because of bronchoconstriction, mucosal edema, and mucus plugs.



Determine if there is a recent history of a URI or if the symptoms of URI still exist. A URI in children with RAD is frequently associated with the exacerbation of bronchospasm and requires a more conservative approach than in nonasthmatic children. Optimally the child with a history of RAD should be free of URI symptoms for 4 to 6 weeks before an elective procedure, unless the URI symptoms recur so frequently that an asymptomatic period is difficult to attain. If the child has had a lower respiratory infection, such as influenza, within the past 6 weeks, the postponement of scheduled surgery should be seriously considered because airway hyperreactivity would be exaggerated as long as 6 weeks even in nonasthmatic patients.



Ascertain the child's steroid requirements over the past year and the possible need for perioperative stress-dose steroid coverage (see preceding discussion). Children who often have bronchospasm that is poorly controlled with maximal therapy and require frequent courses of oral steroids may benefit from a short preoperative course of prednisone (1 mg/kg/day to a maximum of 60 mg once daily for 3 days, including the day of surgery), especially if endotracheal intubation is planned.

Physical examination should be focused on careful auscultation of the chest for clinical evidence of bronchoconstriction: expiratory wheezing; use of the accessory muscles of respiration; and a prolonged expiratory phase. During severe episodes of bronchospasm, air movement may become so limited that wheezing may be barely audible. Patients with a history of BPD and asthma are most likely to have lower airway obstruction and small airway hyperreactivity; wheezing and rhonchi may not be present.

Anesthetic Management

The anesthesiologist must get to know the asthmatic child and his or her parents and gain their confidence to minimize the child's anxiety before anesthesia induction. The child should be well sedated to avoid struggle and hyperventilation, which can provoke “exercise-induced” asthma. Midazolam, which may be administered transmucosally (oral, nasal, rectal) in infants and young children and orally or intravenously (if intravenous access present) in older children, works well for sedation. A β2-adrenergic agonist may be given prophylactically using a metered-dose inhaler or nebulizer before induction (see Table 32-9 ). Otherwise, the drug can be given after the induction of anesthesia through the endotracheal tube using the metered-dose inhaler and an aerosol chamber inserted in between the ET tube adapter and the anesthesia circuit.

The preanesthetic level of oxygen saturation should be obtained with a pulse oximeter while the child is breathing room air to determine the baseline oxygen saturation and to look for any preexisting hypoxemia. This information is exceptionally valuable for the postoperative assessment of lung function and gas exchange.

The anesthetic approach is similar to that for children with a URI. After applying standard monitors (a minimum of a pulse oximeter and precordial stethoscope if the child resists), the inhalation induction should be smooth and progress swiftly with sevoflurane and nitrous oxide (see Chapter 9 , Pediatric Anesthesia Equipment and Monitoring). For infants and young children, heated humidification should be used; the dry gas mixture from the anesthesia machine is a perfect environment for provocation of bronchospasm in an asthmatic child as a result of irritation and reduced tracheal temperature from evaporative heat loss of the tracheal mucosa ( McFadden and Gilbert, 1994 ).

For intravenous induction, propofol may be a better agent of choice than thiopental because it suppresses airway reflexes compared with barbiturates ( Brown et al., 1992 ), although thiopental, despite risk of histamine release, is not necessarily contraindicated in patients with asthma ( Gal, 1994 ). Propofol may also produce bronchodilation in patients with other types of airway disease ( Conti et al., 1993 ). Regardless of the drug chosen, it is important to give sufficiently large intravenous doses to blunt the response and to start adding sevoflurane before the peak effect of the intravenous agent is lost.

Whenever possible, endotracheal intubation should be avoided in asthmatic patients because the endotracheal tube stimulates large airway irritant receptors and can trigger bronchospasm ( Hirshman, 1983). When no contraindications exist, a laryngeal mask airway is a good choice for patients with RAD, as its use avoids the laryngeal and tracheal stimulation of intubation ( Groudine et al., 1995 ). It may also be prudent to avoid anesthetic agents that might release histamine (e.g., atracurium, morphine), although there is little clinical evidence that such drugs actually cause intraoperative bronchospasm.

An anesthetic technique using a volatile anesthetic may be preferable to a balanced technique (i.e., nitrous oxide, opioid, and a muscle relaxant) for asthmatic patients because of the salutary bronchodilating properties of volatile agents. Regional anesthesia can be combined with inhalation anesthesia with sevoflurane, halothane, or isoflurane.

Intraoperative Wheezing

The differential diagnosis of intraoperative wheezing includes “light anesthesia,” kinked endotracheal tube, mainstem bronchial intubation, increased airway secretions, airway foreign body, pulmonary edema, embolus, and aspiration. In the child with RAD, wheezing can result from exacerbation of airway hyperreactivity and requires immediate attention. The treatment of intraoperative bronchospasm is detailed in Box 32-7 . Treatment should begin after chest auscultation to confirm that there are bilateral breath sounds, and therefore no mainstem intubation. The first step includes increasing the inhaled concentration of oxygen and deepening the level of anesthesia with volatile anesthetics, or administering intravenous ketamine (0.5 to 2.0 mg/kg), a known bronchodilator ( Corssen et al., 1972 ; Hirshman et al., 1979 ). Lidocaine (1 mg/kg) may also be given intravenously to reduce airway reactivity at the earliest sign of bronchospasm. Administration of muscle relaxant and suctioning of the ETT may be performed if the patient is intubated. The second step consists of the administration of β2 agonists given by a metered-dose inhaler and a nebulizer chamber through the endotracheal tube followed by squeezing the anesthesia bag manually to provide a vital capacity maneuver to distribute the bronchodilator mist to the tracheobronchial tree. This maneuver should be repeated two to three times. If the nebulization chamber is not readily available, 4 to 8 puffs of a β2-agonist may be administered through the endotracheal tube, because only 5% to 10% of the administered dose may reach the end of the endotracheal tube and contact the airway. Parasympatholytic agents (atropine, 0.02 to 0.03 mg/kg) or antihistamines (Benadryl, 0.5 mg/kg) are indicated when wheezing is associated with increased vagal tone or histamine release, respectively. The development of hypotension and urticaria or flushing should lead to the consideration of anaphylaxis. Corticosteroids (e.g., 2 mg/kg of intravenous hydrocortisone) should be given and circulation supported with appropriate vasoactive agents (see Chapter 18 , Anesthesia for Pediatric Neurosurgery).

BOX 32-7 

Treatment of Intraoperative Bronchospasm



Confirm the diagnosis (exclude main stem bronchus intubation, mucus plug, pneumothorax, anaphylaxis, congestive heart failure).



Deepen anesthesia with a volatile agent.



Administer inhaled β-agonists and ipratropium.



Consider propofol or ketamine to further deepen anesthesia.



Consider intravenous lidocaine or atropine, or both.



Administer an intravenous corticosteroid.



Modify ventilation to avoid stacking breaths, gas trapping, and barotrauma.

Techniques of Extubation

At the conclusion of surgery and anesthesia, the asthmatic patient can be extubated “deep” or “awake” to avoid laryngospasm. Upper airway obstruction caused by soft tissue collapse in the pharynx is the major disadvantage of deep extubation. Deep extubation can be accomplished safely provided the maintenance of upper airway patency was satisfactory during the induction of anesthesia before intubation and there are no excessive secretions or blood in the airway. If maintaining airway patency was difficult during induction, the patient may become obstructed during the time of emergence from anesthesia. If this was the case, airway patency may be facilitated by prophylactic placement of an oropharyngeal or nasopharyngeal airway, well lubricated with lidocaine jelly when the patient is still deeply anesthetized. Successful deep extubation is facilitated by the achievement of spontaneous breathing before attempted extubation.

For a successful “awake” extubation, prophylactic treatment with the inhalation of a β2-agonist must be given even if a dose was previously given during or after the induction of anesthesia. Tracheal suction of any secretions before emergence may decrease coughing due to migration of mucus plugs. Lidocaine (1 mg/kg) given intravenously on emergence is helpful in minimizing tracheal stimulation as the patient awakens. The use of intravenous atropine (0.02 mg/kg), given for its vagolytic and bronchodilator effects, may be an additional safety precaution before extubation.


BPD is a chronic disease of lung parenchyma and small airways with chronic respiratory insufficiency in prematurely born infants (see Chapter 16 , Anesthesia for Neonates and Premature Infants). As originally described by Northway and others (1967) , BPD developed after a period of acute and subacute ventilator-induced lung injury and oxygen toxicity, in prematurely born infants with severe respiratory distress syndrome ( Hazinski, 1990 ). Although Northway's original series involved infants born at a mean gestational age of 34 weeks, all of whom had received excessive concentrations of oxygen during mechanical ventilation with a primitive ventilator by modern standards, over time, BPD has been seen in infants who had prolonged barotrauma (or volutrauma) in the absence of “excessive” oxygen. Early series were characterized by a high incidence of mortality with persistent respiratory symptoms and oxygen requirement beyond 4 weeks of age. Chest radiographs were abnormal and characterized by hyperinflation of the lungs with focal areas of increased density. They called this condition bronchopulmonary dysplasia to “emphasize the involvement of all the tissues of the lungs in the pathologic process” ( Northway et al., 1967 ; Northway, 2001 ). The incidence of BPD has not decreased over the past 2 decades despite improved neonatal intensive care, probably because of the survival of more infants who are premature. However, the clinical picture has changed with the advent of antenatal steroids, the use of surfactant therapy, and advances in ventilatory strategies for reducing volutrauma and ventilator-induced lung injury, including noninvasive techniques. Most infants who develop BPD are born at 24 to 28 weeks' gestation and rarely are older than 32 weeks' gestation (Hazinski, 1990 ), whereas the mean gestational age of Northway's original series was 34 weeks. Due to these changes in neonatal intensive care and affected patient population, many aspects of BPD have changed, including the definition, theories of pathogenesis, pathology, and clinical picture ( Jobe and Ikegami, 2000 ; Jobe and Bancalari, 2001 ).

Infants with BPD today are likely to have a minimal respiratory distress syndrome that does not progress after surfactant administration. The reason for prolonged ventilation in these very premature infants is more frequently apnea or poor respiratory effort, which may be related to immaturity of central respiratory control mechanisms. These infants rarely require the high airway pressures and high oxygen concentration that led to the “old” BPD. This newer clinical picture had been referred to as chronic lung disease or new BPD, but it is now simply called BPD. The current definition of BPD is oxygen dependence at 36 weeks postconceptual age (with a total duration of oxygen therapy of more than 28 days) in infants with birth weights between 500 and 1500 g. Prevalence varies between 67% in the smallest weight group to 1% in the largest ( Bancalari et al., 2003 ).


In the past, the development of BPD was associated with a condition that caused respiratory failure in the neonatal period (e.g., prematurity with respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia). Mechanical ventilation with high concentrations of oxygen (i.e., an acute insult to immature lungs) was employed, usually lasting more than 1 week. Oxygen free radicals, which are not well handled by an immature antioxidant host-defense system in the neonatal lungs, can cause direct cellular injury ( Ackerman, 1994 ). Although much lower concentrations of oxygen are now used than in the past, even room air (21% oxygen) is relatively hyperoxic for a premature infant whose in utero PO2 is less than 30 mm Hg ( Hazinski, 1990 ). Excessive hydration and patent ductus arteriosus with increased pulmonary fluid have been recognized as additional important factors contributing to the development of BPD ( Gerhardt and Bancalari, 1980 ; Van Marter et al., 1992 ). The current theory of the mechanism of injury in BPD also emphasizes the role of infection and inflammation ( Gonzalez et al., 1996 ; Sadeghi et al., 1998 ). Recurrent bacterial or viral infections in these infants may cause persistent alveolitis, which worsens alveolar and airway damage ( Rojas et al., 1995 ; Hannaford et al., 1999 ). Multiple markers of inflammation (e.g., lipid mediators, proteases, oxygen free radicals, cytokines) are elevated ( Groneck et al., 1994 ; Pierce and Bancalari, 1995 ). Nutritional deficiencies may also play a role ( Sosenko et al., 2000 ).

Immature, inflamed lungs with decreased compliance are most susceptible to high-volume trauma (i.e., volutrauma) and low-volume trauma (i.e., shear stress trauma) with marked distortion and distension of terminal bronchioles at high positive pressures ( Hazinski, 1990 ). In earlier pathologic examination in lungs of infants dying with BPD, peribronchiolar fibrosis and smooth muscle thickening were seen. This has also been found in animal models exposed to prolonged positive pressure ventilation and hyperdistention (Coalson et al., 1999). The pathology now seen in extremely premature infants reflects the very immature state of their pulmonary parenchyma, with enlarged and simplified alveolar structure and a reduced number of capillaries, which are dysmorphic in appearance. Fibroproliferation may still occur but is more variable. Changes in larger blood vessels are less prominent with less indication of pulmonary hypertension than seen in “old BPD.” Airway smooth muscle hyperplasia may still occur but is more variable (Coalson, 2000). After this damage has occurred to immature lungs, infants may require prolonged mechanical ventilation and high oxygen concentration for weeks or months, despite having not required high oxygen concentrations in the first few weeks of life. Although less common than with “old BPD,” progressive respiratory failure with associated pulmonary hypertension with or without cor pulmonale may follow.

Even after the perinatal period, RAD persists in infants with BPD. Mallory and others (1991) studied lung function in infants with moderate to severe BPD longitudinally during the first 4 years of life with the forced deflation technique and found that airway hyperresponsiveness or hyperreactivity continued to be present in all children studied. They postulated that airway hyperreactivity is an important etiologic factor for the pathogenesis of lower airway obstruction in BPD.

Preanesthetic Considerations

Most infants with moderate to severe BPD remain oxygen dependent, with or without continuous positive airway pressure, or ventilator dependent beyond 4 weeks of age. They have persistent lower airway obstruction and airway hyperreactivity ( Mallory et al., 1991 ). Tachypnea and dyspnea may be intermittently or chronically present. Growth failure because of chronic hypoxia despite oxygen therapy andcor pulmonale associated with pulmonary hypertension may occur ( Hazinski, 1990 ). Wheezing may or may not be present on auscultation because the site of airway hyperreactivity is primarily in the periphery of the lungs. The chest wall may appear hyperinflated or flat ( Edwards and Hilston, 1987 ). In addition to lower airway obstruction primarily involving small airways, infants who were intubated for prolonged periods sometimes develop large airway disease such as subglottic stenosis (which may or may not be recognized), tracheomalacia, and bronchomalacia ( Miller et al., 1987 ; McCubbin et al., 1989 ). A later study also found a greater degree of upper airway obstruction in children with a history of BPD compared with age-matched children with asthma ( Sadeghi et al., 1998 ).

Infants with mild forms of BPD improve with age and may become asymptomatic, but airway hyperreactivity may persist. Parents of the infant may not be aware of the history of BPD even when their child received prolonged mechanical ventilation as a neonate. It is appropriate, therefore, to assume that a child has or had BPD and has RAD if he or she was born prematurely and was mechanically ventilated for more than 1 week during the neonatal period. Inguinal hernia is often present in infants with BPD, probably as the result of prematurity and continually increased abdominal pressure resulting from airway obstruction and increased inspiratory effort. Prematurely born infants may require postoperative admission for monitoring because they have an increased risk of postoperative apnea, as discussed inChapters 2 (Respiratory Physiology) and 16 (Anesthesia for Neonates and Premature Infants).

As with asthmatic patients, careful history taking is of utmost importance before anesthetizing an infant with BPD or a history of BPD. These patients may have failure to thrive (a sign of chronic hypoxia), worsening of symptoms, or even respiratory failure with lower respiratory tract infection. The patient may be taking β2-agonists or other treatments for asthma. Other medications may include diuretics. A family history of allergy and asthma is significant because premature birth may be linked to smooth muscle hyperresponsiveness and asthma ( Bertland et al., 1985 ). Relatively common surgical conditions in infants and children with BPD or a history of BPD include inguinal hernia, direct laryngoscopy and bronchoscopy for subglottic stenosis, and surgical procedures of the larynx for the complications of prolonged intubation or tracheostomy (e.g., excision of granuloma, laryngotracheoplasty).

Anesthetic Management

Anesthetic management of infants and children with BPD or a history of BPD is similar to those with asthma. Before anesthetizing the child with a history of BPD, it is imperative to obtain a baseline oxygen saturation measurement with a pulse oximeter (SpO2), although a normal oxygen saturation level does not necessarily guarantee the absence of lung dysfunction. Many infants and young children with a history of BPD maintain remarkably good SpO2 values, presumably because of hypoxic pulmonary vasoconstriction (HPV). The infant with BPD with near normal SpO2 in room air may develop marked desaturation after induction with halothane or sevoflurane, presumably due to a loss of HPV under general anesthesia, although HPV in healthy human volunteers may be insignificant ( Benumof, 1994 ). If this occurs, oxygen saturation may be maintained better with intravenous techniques using opioids and propofol. Prophylactic treatment with a β2-adrenergic agonist by a metered-dose inhaler may be beneficial for patients with possible airway hyperreactivity to prevent perioperative bronchoconstriction. For intubating a child with a history of mechanical ventilation, it is prudent to start with an endotracheal tube one size (0.5 mm inner diameter) smaller than the appropriate size for the age for subglottic narrowing, which may be the result of prolonged intubation. If rapid sequence intubation is required due to fasting violation or intestinal obstruction, desaturation may be rapid when apnea occurs, and gentle ventilation by mask with maintenance of cricoid pressure may be necessary to maintain saturation if intubation is not rapidly accomplished.


Cystic fibrosis (CF), an autosomal recessive disorder, is the most common lethal inherited disorder among whites ( Wood et al., 1976 ). In the United States, the gene frequency (heterozygotes) in whites is about 1 in 25; it is uncommon among Hispanics (1 in 46) and African Americans (1 in 65) and lowest among Asians and Native Americans (1 in 90). The disease incidence among whites is approximately 1 in 2500 live births. With early diagnosis and aggressive treatment over the past 40 years, the mean survival of a CF patient has increased to 31 years by 2000.

In 1985, Tsui and others localized the gene responsible for the manifestation of CF to 250 kilobases on the long arm of chromosome 7 ( Kerem et al., 1989 ). The deletion of three base pairs removing a phenylalanine residue at position 508 (d508) from a 1480-amino acid protein called cystic fibrosis transmembrane conductance regulator, a cAMP-dependent chloride ion channel, accounts for approximately 70% of CF chromosome abnormalities ( Cystic Fibrosis Genetic Analysis Consortium, 1990 ). The remaining cases are accounted for by more than 700 mutations ( Mickle and Cutting, 1998), of which 20 account for most of the remaining 30% of cases.


The disease is characterized by exocrine gland dysfunction resulting in chronic pulmonary disease, pancreatic dysfunction, and abnormalities in electrolyte reabsorption in the sweat ductwith increases in sweat sodium and chloride concentrations and electrolyte imbalance. CF patients have sweat chloride levels in excess of 60 mEq/L (normal < 40 mEq/L) as measured by pilocarpine iontophoresis. In addition to pulmonary disease, other significant clinical manifestations of CF include those listed in Table 32-10 .

TABLE 32-10   -- Organ system involvement in cystic fibrosis

Organ System

Incidence (%)


Pneumothorax due to bleb rupture

5 to 8

Obstructive lung disease


Ear, nose, and throat


90 to100

Nasal polyps



Pancreatic enzyme deficiency

85 to 90

Diabetes, second-degree pancreatic failure



Meconium ileus (newborn)

7 to 20

Distal intestinal obstruction syndrome (includes intussusception)

10 to 30

Rectal prolapse


Gastroesophageal reflux disease


Hepatic Liver failure

5 to 20

Coagulopathy due to vitamin K deficiency

100 if untreated



Pulmonary disease is the most common cause of death. Enhanced absorption of sodium across the airway epithelium and failure to secrete chloride and fluid toward the airway lumen is thought to lead to dehydration and thickening of airway mucus and abnormal mucociliary clearance. The patients are initially colonized with Haemophilus influenzae and then by Staphylococcus aureus, and eventually by the mucoid variant of Pseudomonas aeruginosa. Colonization with Aspergillus and atypical mycobacteria may occur. The chronic infection in the periphery of the tracheobronchial tree results in bronchiolitis, which may lead to airway hyperresponsiveness, bronchiectasis, lobar or segmental atelectasis, and pneumothorax. Hemoptysis, and eventually cor pulmonale and respiratory failure, ensues ( Aitken and Fiel, 1993 ).

Small airways obstruction, hyperinflation, and ventilation-perfusion imbalance are the most common and important pulmonary changes in children with moderate to severe CF. The early signs of lung dysfunction include a reduction in maximum expiratory flow rates at low lung volumes (e.g., FEF25-75, FEF50, FEF75) and an increase in residual volume to total lung capacity (RV/TLC) ratio (see Chapter 2 , Respiratory Physiology in Infants and Children). Airway hyperreactivity is often present, probably in response to airway inflammation. Some patients have good response to bronchodilators but others have inconsistent or even paradoxical responses, sometimes worsening airway function because of the relaxation of airway smooth muscles and resultant increases in airway collapsibility ( Pattishall, 1990).


Patients with CF take multiple medications, including pancreatic enzyme replacement. Patients with a prominent bronchospastic component will be on β2-agonist therapy. They frequently take inhaled or oral antibiotics for prophylaxis or treatment of pulmonary infection. Patients infected with Pseudomonas aeruginosa frequently take aerosolized tobramycin, which, when administered on an every-other-month basis, has been shown to preserve pulmonary function and reduce hospitalization ( Ramsey et al., 1999 ). Patients with infectious exacerbations are treated with intravenous antibiotics in hospital or at home. Chest physiotherapy several times a day is a mainstay of CF treatment. Inhaled mucolytics (N-acetylcysteine-Mucomyst) have long been used to decrease the viscosity of pulmonary secretions, but there is little in the literature documenting its efficacy ( Duijvestijn and Brand, 1999 ). Pulmozyme (i.e., human recombinant DNase), which dissolves DNA released from neutrophils, has improved pulmonary function and reduced the frequency of infection ( Fuchs et al., 1994 ).

Preanesthetic Considerations

Common surgical indications in infants and children with CF are listed in Table 32-11 . Management of children with CF is a challenge to the anesthesiologist. These patients are often frail and malnourished. Decreased plasma albumin levels may affect anesthetic potency. Intravascular volume may be diminished because of chronic diarrhea, poor oral intake, and diuretic therapy. Electrolyte imbalance may result from excessive chloride and sodium losses. Pulmonary function ranges from near normal without airway obstruction to severe obstruction, air trapping, hypoxemia, and hypercapnia. Copious secretions and resultant ventilation-perfusion imbalance may prolong mask induction with volatile anesthetics. Nasal polyps may block the nasal airway completely during mask induction. Secretions may irritate the larynx and precipitate laryngospasm. Pathophysiologic considerations in patients with CF that may affect anesthetic management are listed in Table 32-12 .

TABLE 32-11   -- Surgical indications for patients with cystic fibrosis


Typical Age Range

Meconium ileus or equivalent

1 day to 3 years

Nasal polyps or sinusitis

10 to 18 years

Other procedures

10 to 18 years



 Feeding gastrostomy; port-A-Cath or


 PICC venous access


 Lobectomy; thoracoplasty or thoracoscopy


 Organ transplantation (double lungs; heart-lungs)


PICC, peripherally inserted central catheter.




TABLE 32-12   -- Pathophysiology of cystic fibrosis: Effect on anesthetic management


Possible Outcome

Pulmonary dysfunction

 Airway obstruction

Prolonged mask induction

 V/Q imbalance

Prolonged mask induction

 Copious secretions

Laryngospasm, bronchospasm

 Airway hyperreactivity

Laryngospasm, bronchospasm

 Nasal polyps

Upper airway obstruction

Gastrointestinal and hepatobiliary disorders

Upper airway obstruction

 Decreased serum albumin levels

Increased drug potency


Increased bleeding

 Diabetes or glucose intolerance

Hyperglycemia, acidosis

Abnormal sweat gland function

Electrolyte imbalance

Cor pulmonale

Hemodynamic instability; arrhythmia



The preoperative evaluation should include the assessment of pulmonary function by history, physical examination, and pulmonary function testing. The pulmonary function testing should include lung volume measurements and response to bronchodilators. An increase in TLC and the RV/TLC ratio with decreased vital capacity indicates the presence of hyperinflation and air trapping. Lower airway obstruction with small airway involvement is demonstrated when FEF25-75, FEF50, and especially FEF75 are markedly decreased from predicted values. A preoperative chest radiograph is needed in patients with moderate to severe pulmonary disease. Preoperative oxygen saturation should be obtained by means of pulse oximetry in room air for postoperative comparison. Recent tracheal culture results should be reviewed as a guide to choice of perioperative antibiotic therapy. In patients with significant lower airway obstruction andair trapping, preoperative arterial blood gas measurement is recommended to assess the degree of hypoxemia more accurately and to evaluate acid-base status and the presence of hypercapnia. In those with long-standing hypoxemia, pulmonary hypertension and cor pulmonale should be suspected. These patients should have preoperative electrocardiography and echocardiography to evaluate myocardial function and reserve. Blood sugar, liver function tests, and coagulation studies may be indicated.

The child with CF and his or her family are exceedingly knowledgeable regarding the pathogenesis and treatment of the disease. A lack of knowledge of CF in general and of the patient's past history and present conditions in particular at the time of the preoperative visit could quickly undermine the confidence of the family in the anesthesiologist. More importantly, the CF patient is often petrified by the thought of death under anesthesia. It is therefore prudent for the anesthesiologist to gain the patient's and his or her parents—confidence and administer preoperative sedation, such as oral benzodiazepine (Lamberty and Rubin, 1985 ). Opioid premedication should be avoided in severe cases because of possible respiratory depression and hypoxemia.

Anesthetic Management

Because of copious secretions in affected patients, it is preferable to schedule surgery later in the day to allow enough time for ambulation and chest physiotherapy in the morning to facilitate expectoration of secretions retained overnight. The baseline oxygen saturation in room air is measured with a pulse oximeter before administering oxygen and anesthetics.

In patients with significant pulmonary involvement, intravenous access should be established before the induction of anesthesia because of prolonged mask induction and possible nasal obstruction from nasal polyps. An anticholinergic may be given during induction. Concern about excessive drying of secretions is unfounded because atropine decreases secretions without changes in viscosity and has not been a significant problem in clinical practice ( Lamberty and Rubin, 1985 ). Intravenous propofol may be preferred to thiopental because it is less irritating to the upper airways and actually causes bronchodilation. Ketamine, despite its bronchodilating properties, is relatively contraindicated because it tends to increase secretions and may cause laryngospasm. Fifty percent of children with CF have gastroesophageal reflux disease (GERD) and may require rapid sequence intubation. Inhalation induction is usually satisfactory in young children with mild lung disease. Anesthetic gases should be heated and humidified to prevent irritation of the upper airways and laryngospasm, and to avoid drying and inspissation of secretions. Nitrous oxide should be avoided in patients with suspected or pulmonary function test-proven trapped gas volume to prevent its expansion and the potential danger of bleb rupture.

Endotracheal intubation with muscle relaxation is mandatory in patients with severe respiratory involvement, although the anesthesiologist should be exceedingly careful not to hyperdistend already air-trapped lungs. When a nondepolarizing muscle relaxant is chosen, the effect of aminoglycoside antibiotics to prolong the duration of action of such drugs must be kept in mind and monitoring of train-of-four used to guide relaxant administration. It is also mandatory to carefully monitor end-tidal pCO2 to prevent hyperventilation and maintain preoperative arterial pCO2 levels, which may be elevated. Sudden hypocapnia in a chronic hypercapnic patient can be disruptive of the patient's ventilatory control mechanisms, increasing the chance that the patient might require postoperative ventilation. After intubation, tracheobronchial suction should be performed and repeated at intervals throughout surgery and before extubation to improve pulmonary gas exchange. Although the use of an LMA might be an option for short cases, disadvantages include inability to suction secretions, obstruction of the LMA “grate” by thick secretions, risk of laryngospasm, and risk of aspiration in patients with GERD. Intraoperatively, glucose should be monitored in patients with glucose intolerance. Care should be taken to conserve heat in these patients with reduced body fat.

Regional anesthesia should be considered whenever applicable. Although regional anesthetic techniques without general anesthesia might be useful in some situations, these techniques should be carefully considered in children with severe pulmonary disease. Depression of abdominal and intercostal muscle function by thoracic levels of spinal or epidural anesthesia may not be tolerated. Pediatricians and pulmonologists often request regional anesthesia instead of general anesthesia because of fear that severely afflicted CF patients will not tolerate general anesthesia or may become ventilator dependent after endotracheal intubation. However, most of these sick CF patients, dyspneic or orthopneic with hypercapnia and oxygen dependence, may not tolerate even a short surgical intervention, such as central venous catheter or MediPort insertion, with local anesthesia and sedation. Instead, general endotracheal anesthesia with an inhaled agent, supplemented by caudal, lumbar, or thoracic epidural anesthesia for abdominal or thoracic procedures, is much better tolerated, safer, and provides good operative conditions, rapid emergence, and a pain-free postoperative state ( Dalens et al., 1986 ). If epidural anesthesia is to be used, coagulopathy should be ruled out, and the appropriate concentration of local anesthetic drugs chosen to minimize motor block. Continuous caudal or epidural anesthesia with local anesthetic with or without carefully chosen doses of an opioid provides prolonged postoperative pain relief and facilitates coughing and deep breathing after upper abdominal or thoracic procedures. If regional anesthesia is not appropriate, judicious use of inhalation agents and short-acting opioids and wound infiltration with local anesthetic by the surgeon should facilitate early extubation, which is desirable in most cases. After surgeries without a high risk of postoperative bleeding, the use of NSAIDs may be effective in reducing the amount of opioid needed for analgesia.

Cystic Fibrosis and Lung Transplantation

For patients with end-stage pulmonary disease, lung transplantation may be the final surgical option. In general, CF patients with an FEV1 less than 30%, PaO2 less than 55 mg Hg, or PaCO2 more than 50 mm Hg have a 50% 2-year survival ( Kerem et al., 1992 ) and may be candidates for lung transplantation (i.e., double-lung or heart-lung procedure). The 3-year survival rate is 60%, which is similar to that seen in non-CF patients ( Sweet et al., 1997 ). Twenty-seven percent of lung transplant patients develop bronchiolitis obliterans, which is responsible for 64% of the late deaths. Among the survivors of lung transplantation, there has been no recurrence of CF in the transplanted lungs measured by the transepithelial potential differences ( Alton et al., 1991 ). The management of end-stage CF patients for lung transplantation is described in Chapter 2 (Respiratory Physiology) and Chapter 28 (Anesthesia for Organ Transplantation).

Copyright © 2008 Elsevier Inc. All rights reserved. -

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

Copyright © 2005 Mosby, An Imprint of Elsevier


Cardiovascular disorders are commonly encountered in the pediatric population. The baseline incidence of congenital heart disease is approximately 0.8 in 100 births, on which is superimposed an incidence of acquired heart disease. Congenital and acquired diseases have the ability to affect myocardial function, valve function, and conduction tissue, all of which can be affected by anesthetics. Anesthetic effects on vascular tone can also have a positive or negative impact on myocardial function and shunting of blood through intracardiac defects.

Patients with cardiac disease should be identified preoperatively. Although children with congenital heart disease having noncardiac surgery should generally do well with appropriate anesthetic and perioperative care, there is preliminary information that, in the aggregate, congenital cardiac disease of even a moderate degree can negatively impact mortality after noncardiac surgery ( Baum et al., 2000). Certainly even hemodynamically insignificant lesions can alter perioperative management as children with such abnormalities can require perioperative antibiotics for endocarditis prophylaxis; however, not all surgical procedures or all children with cardiac disease require endocarditis prophylaxis. Recommendations are outlined in Tables 32-13 and 32-14 [13] [14], in Boxes 32-8 and 32-9 [8] [9], and on the Internet (

TABLE 32-13   -- Endocarditis prophylaxis regimens for dental, oral, respiratory tract, or esophageal procedures




Standard general prophylaxis


50 mg/kg PO 1 hr before procedure (adults, 2 g)

Unable to take orally


50 mg/kg IM or IV within 30 min of procedure (adults, 2 g)[*]

Allergic to penicillin


20 mg/kg PO 1 hr before procedure (adults, 600 mg)


or Cephalexin or cefadroxil

50 mg/kg PO 1 hr before procedure (adults, 2 g)


or Azithromycin or clarithromycin

15 mg/kg PO 1 hr before procedure (adults, 500 mg)

Allergic to penicillin and unable to take orally


20 mg/kg IV within 30 min of procedure (adults, 600 mg)[*]


or Cefazolin

25 mg/kg IM or IV within 30 min of procedure (adults, 1 g)[*]

Adapted from Dajani AS, Taubert KA, Wilson W, et al.: Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 277:1794, 1997.

IM, intramuscularly; IV, intravenously; PO, orally.



The pediatric dose should not exceed the adult dose. It is appreciated that many children do not have intravenous access before surgery. Intravenous antibiotics should be given as soon as possible after induction and intravenous catheter placement and before the surgical incision is made.



TABLE 32-14   -- Endocarditis prophylaxis regimens for genitourinary and gastrointestinal (excluding esophageal) procedures




High-risk patients[*]

Ampicillin + gentamicin

Ampicillin, 50 mg/kg IM or IV, plus gentamicin, 1.5 mg/kg within 30 min of starting the procedure;[†] 6 hr later: ampicillin, 25 mg/kg IM or IV, or amoxicillin, 25 mg/kg PO Adults: ampicillin, 2 g, and gentamicin, 1.5 mg/kg (up to 120 mg); 6 hr later: ampicillin, 1g IM or IV, or amoxicillin, 1 g PO

High-risk patients[*] allergic to penicillin

Vancomycin + gentamicin

Vancomycin, 20 mg/kg by slow IV infusion, plus gentamicin, 1.5 mg/kg IM or IV, to be completed within 30 min of starting the procedure[†]



Adults: vancomycin, 1 g, and gentamicin, 1.5 mg/kg (up to 120 mg)

Moderate-risk patients[*]

Amoxicillin or ampicillin

Amoxicillin, 50 mg/kg PO 1 hr before the procedure, or ampicillin, 50 mg/kg IM or IV within 30 minutes of starting the procedure[†]



Adults: amoxicillin, 2 g, or ampicillin, 2 g

Moderate-risk patients[*]allergic to ampicillin or amoxicillin


Vancomycin, 20 mg/kg by slow IV infusion, completed within 30 min of starting the procedure[†]



Adults: 1 g

Adapted from Dajani AS, Taubert KA, Wilson W, et al.: Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 277:1794, 1997.

IM, intramuscularly; IV, intravenously; PO, orally.



See Box 32-8 for definitions of medium-risk and high-risk groups.

The pediatric dose should not exceed the adult dose. It is appreciated that many children do not have intravenous access before surgery. Intravenous antibiotics should be given as soon as possible and before the surgical incision is made.



BOX 32-8 

Cardiac Conditions Requiring Antibiotic Endocarditis Prophylaxis

Prophylaxis Recommended



Prosthetic valves (i.e., bioprosthetic and homograft)[*]



Previous bacterial endocarditis[*]



Complex cyanotic heart disease[*]



Systemic-pulmonary shunts (e.g., Blalock-Taussig)[*]



Most cardiac structural abnormalities not delineated above or below[†]



Acquired valve dysfunction (e.g., rheumatic)[†]



Hypertrophic cardiomyopathy[†]



Mitral valve prolapse with insufficiency[†]

Prophylaxis Not Required[‡]



Isolated secundum atrial septal defect



Surgical repair beyond 6 months without residua



Secundum atrial septal defect



Ventricular defect



Patent ductus arteriosus



Mitral valve prolapse without insufficiency



Cardiac pacemaker (i.e., intravenous and epicardial)



Functional murmur

(Adapted from Djinni AS, Aubert KA, Wilson W, et al.: Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 277:1794, 1997.)


*  High risk.

†  Moderate risk.

‡  Endocarditis risk no higher than for the general population.

BOX 32-9 

Procedures for Which Endocarditis Prophylaxis Is Not Recommended



Orotracheal intubation



Injection of intraoral anesthetics



Tympanostomy tube placement



Flexible bronchoscopy with or without biopsy[*]



Cardiac catheterization



Endoscopy with or without biopsy[*] (includes transesophageal echocardiography)



Cesarean section



In the absence of infection: urethral catheterization, dilatation and curettage, uncomplicated vaginal delivery,[*] therapeutic abortion, sterilization procedures, insertion or removal of intrauterine devices



Cardiac catheterization



Implanted pacemakers



Incision or biopsy of surgically scrubbed skin




(Adapted from Djinni AS, Aubert KA, Wilson W, et al.: Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 277:1794, 1997.)


*  Prophylaxis is optional in the high-risk group (see Box 32-8 for delineation of high-risk patients).


Although the specifics of the anesthetic management of individual cardiac problems are discussed in Chapter 17 (Anesthesia for Cardiovascular Surgery), the following general areas should be emphasized.

Preoperative Period

Prolonged preoperative fasting should be avoided in cyanotic children with significant erythrocytosis to avoid dehydration and further exaggeration of the elevated hematocrit and blood viscosity. Small infants with clinically significant heart failure and failure to thrive can have inadequate glycogen reserves and are at risk for hypoglycemia if fasted for many hours. Otherwise appropriate preoperative sedation is in no way contraindicated in children with cyanotic or acyanotic heart disease unless the child has profound heart failure. DeBock and others (1990) demonstrated that SpO2 frequently increases with preanesthetic medication in children with cyanotic and acyanotic heart defects.

Intraoperative Period

Although much discussion is appropriately given to the specifics of cardiac pathophysiology, most children with congenital heart disease who develop problems during anesthesia do so for primarily noncardiac reasons, particularly airway compromise. Cyanotic infants, in particular, begin with decreased oxygen saturation, and can rapidly desaturate with transient interruption in breathing, whether due to apnea or airway obstruction with failure to establish effective ventilation. Children with severe congestive failure or cyanosis will have a decreased margin of safety and will tolerate failures of respiratory or hemodynamic management poorly.

Much time is often spent discussing the effects of left to right and right to left shunts on the onset time of intravenous and volatile anesthetics. Although there are differences, they usually are so small as to be clinically irrelevant. In the absence of a complication such as loss of the airway or the development of a hypercyanotic “tet” spell in children with tetralogy of Fallot or variants, oxygen saturation in cyanotic children almost invariably increases with the induction of anesthesia ( Greeley et al., 1986 ; Laishley et al., 1986 ). There are several possible reasons for this, one of the most likely being a decrease in oxygen consumption causing an increase in mixed venous oxygen saturation, and subsequently higher arterial oxygen saturation when some of this blood is shunted right to left.

Minimization of right-to-left shunting at the atrial level is primarily addressed by increasing intravascular volume. Minimizing shunt at the ventricular and great vessel levels is primarily modulated by changes in pulmonary and systemic vascular resistance. Increasing systemic resistance or decreasing pulmonary resistance will increase left to right shunting (or decrease right to left shunting) and vice versa.

Nitrous oxide is a mild myocardial depressant. In adult patients, it can increase pulmonary vascular resistance (PVR), particularly in patients in whom PVR is already elevated ( Schulte-Sasse et al., 1982 ). In children, however, no significant increase in PVR has been observed with 50% nitrous oxide regardless of the preexisting PVR ( Hickey et al., 1986 ).

Cyanotic patients and patients with elevated central venous pressure, in particular, are at risk for increased perioperative blood loss and require adequate intravenous access. Not only do all cyanotic patients require that intravenous catheters be kept clear of air bubbles to avoid systemic air emboli, but there can also be small amounts of right-to-left shunting during the cardiac cycle even with lesions thought of as left-to-right shunting lesions. Therefore, all intravenous catheters and tubings need to be cleared of air for all patients with shunt lesions, regardless of predominant direction of shunt flow. Stopcocks are common sites for air to be introduced inadvertently.

End-tidal PCO2 correlates with arterial PCO2 in acyanotic patients. However, in children and adults with cyanotic congenital heart disease end-tidal PCO2 tends to underestimate arterial PCO2 in patients with normal, decreased, or increased total pulmonary blood flow ( Burrows, 1989 ).

Postoperative Period

The specific length of observation in a postanesthesia care unit depends on the patient and the surgical procedure and cannot be generalized. Patients with good hemodynamic function may undergo relatively minor noncardiac surgery on an ambulatory basis and are not automatically excluded because of their cardiac disease.

When not under anesthesia, patients with cyanotic heart disease have little increase in systemic oxygen saturation in response to supplemental oxygen. Similarly, oxygen saturation will not be markedly decreased by removing supplemental oxygen (other causes for postoperative hypoxemia being absent). Knowledge of the patient's normal preoperative range of oxygen saturation will avoid unnecessary prolongation of the PACU stay because of a fear of removing supplemental oxygen.

Hypovolemia from continued surgical blood or fluid loss postoperatively can worsen right-to-left shunting in cyanotic patients, and it should be rapidly corrected. The onset of hypovolemia can be insidious if caused by gradual oozing from surgical drains. Cyanotic patients should have hematocrit levels measured serially after surgery, especially after significant blood loss. They may require a higher than normal hematocrit level to ensure adequate oxygen delivery. In general, a level similar to the preoperative hematocrit should be maintained.

Patients with labile pulmonary arterial hypertension would particularly benefit from good postoperative analgesia. Even cyanotic patients have a normal ventilatory response to hypercarbia and respond in a normal fashion to appropriate doses of parenteral, intrathecal, or epidural opiates, and age- and weight-appropriate doses of analgesic drugs should be given. Patients who have had a Glenn or Fontan procedure (i.e., single-ventricle physiology) depend on low pulmonary vascular resistance for maintenance of adequate pulmonary blood flow. If these patients require postoperative ventilatory support, pulmonary vascular resistance should be minimized by limiting positive inspiratory pressure and by using low levels of PEEP to optimize functional residual capacity, which minimizes pulmonary vascular resistance.


Cardiac murmurs are exceedingly common in normal children with an overall incidence of about 80%. Most of these are the somewhat inappropriately called functional murmurs (also called innocent). The incidence of functional murmurs is highest at about 3 to 4 years of age. Functional murmurs represent the sound of blood flowing through a structurally normal heart ( Fig. 32-5 ). There is no anesthetic concern about these murmurs, other than reassurance to the family. There are several commonly recognized functional murmurs. Almost all are short, soft, and louder when supine. Most functional murmurs will become louder with increased cardiac output, as would occur with anemia, fever, exercise, or anxiety. The most common is Still's murmur. This has a very typical musical or vibratory quality and is a mid-systolic murmur heard between the mid-left sternal border and the apex. Soft pulmonary flow murmurs at the upper left sternal border are commonly heard in thin-chested older children and adolescents. The murmur is softer than true pulmonic stenosis and is unaccompanied by a systolic ejection click. Peripheral pulmonic stenosis generates an ejection murmur from the left upper sternal border to the axillae and back in neonates. It is generated by turbulent flow when blood passes from the main to the branch pulmonary arteries. In the neonate, the branch pulmonary arteries, unaccustomed to accommodating large amounts of pulmonary blood flow in utero, form an acute angle with the main pulmonary artery. By about 6 months of age, the vessels remodel and the murmur disappears.


FIGURE 32-5  Description of innocent murmurs. A, aortic; LLSB, lower left sternal border; P, pulmonic; PPPS, physiologic peripheral pulmonic stenosis; ULSB, upper left sternal border; 1 and 2, first and second heart sounds.  (From Hoffam JE: Cardiovascular examination. In Rudolph AM: Rudolph's pediatrics, 19th ed. Norwalk, CT, 1991, Appleton and Lange.)




Less common innocent murmurs are the venous hum and the mammary souffle. Both of these are continuous murmurs and are exceptions to the rule that diastolic murmurs are always pathologic. The venous hum represents blood draining down the jugular into the subclavian veins. It is heard over the left or right upper chest with the patient upright. It disappears when the patient lies down, with gentle compression of the jugular vein, or with a Valsalva maneuver. The mammary souffle can be heard over the breasts of lactating women. Unlike functional murmurs, pathologic murmurs are generated by a normal amount of blood across an abnormal valve or opening, or an abnormal amount of blood passing through normal valves.

Occasionally, children arrive for a preanesthetic evaluation, and a murmur is identified for the first time. The exact method of evaluation remains somewhat controversial ( Yu et al., 2002 ). Isolated chest radiographs and electrocardiograms are generally a poor investment ( Yu et al., 2002 ). In any event, electrocardiograms interpreted by computer or an adult cardiologist may need to be reinterpreted using age-corrected normal values.

In general, children who are acyanotic and growing well, with a soft systolic murmur and good exercise tolerance, will tolerate anesthesia well. Signs of heart disease in infants differ somewhat from adults and older children. Perioral cyanosis can be a normal finding in neonates, especially with crying, and needs to be differentiated from central cyanosis (confirmed by pulse oximetry). Heart failure often manifests in young infants by tachypnea, diaphoresis with eating (in excess of the normal sweating of the head many infants have), and hepatomegaly. Increased pulmonary blood flow can impinge on small bronchioles, causing airway obstruction and expiratory wheezing (“cardiac asthma”). Peripheral edema due to congestive heart failure is distinctly uncommon in children. Blood pressure measurements in both arms and a leg can confirm or exclude coarctation of the aorta. When caring for children with known heart disease or a history of cardiac surgery, the child's pediatrician or cardiologist should be contacted and a copy of the most recent evaluation obtained.


Long-standing cyanotic and acyanotic congenital disease can have effects on the function of a variety of other organ systems. Some of these may not become clinically apparent until years after surgical correction of the underlying cardiac defect. These are summarized in Table 32-15 .

TABLE 32-15   -- Potential noncardiac manifestations of congenital heart disease

Organ System and Manifestations


Pulmonary or Thoracic

Decreased dynamic lung compliance

Occurs in lesions with increased pulmonary blood flow (i.e., left-to-right shunting)


Pulmonary venous obstruction


Can require higher airway pressure for ventilation


Can impinge on small airways, resulting in air trapping, wheezing


More common with cyanotic lesions


Can manifest in adolescence, years after corrective cardiac surgery


Can occur in end-stage Eisenmenger syndrome (i.e., pulmonary hypertension due to prolonged excessive pulmonary blood flow)

Phrenic nerve injury

From prior surgery


Particularly after surgery at the apices of the thorax (e.g., patent ductus arteriosus ligation, coarctation, pulmonary artery banding, Blalock-Taussig shunt)

Recurrent laryngeal nerve injury

From prior surgery or from an enlarged hypertensive pulmonary artery

Blunted ventilatory response to hypoxemia

In cyanotic patients


Normalizes after surgical repair


Normal ventilatory response to hypercarbia


Symptomatic hyperviscosity

Occurs with hematocrit higher than about 65% (or lower if iron deficient)


May cause neurologic symptoms

Bleeding diathesis

Abnormalities of many factors have been described in cyanotic patients, with no consistent pattern


Elevated central venous pressure can cause increased operative bleeding, as can increased tissue vascularity with cyanotic disease (collateral blood vessel formation)


Increased risk of bleeding with prior thoracic surgery during repeat thoracic procedures


Calcium bilirubinate stones from increased heme turnover in cyanotic disease


Symptomatic years after corrective cardiac surgery


Paradoxical emboli to central nervous system

Occur with right-to-left intracardiac shunts


Occur even with a predominantly left-to-right shunt lesion

Brain abscess in patients with right-to-left shunts

Can present with seizure focus years later

Cerebral thrombosis

Polycythemia in children


Femoral vein complications

Thrombosis or ligation from prior cardiac catheterization

Reduced lower extremity blood pressure

Coarctation of the aorta; left arm involvement is variable

Reduced upper extremity blood pressure

With classic Blalock-Taussig anastomosis


Stenosis of the subclavian artery after modified Blalock-Taussig anastomosis

Artifactually elevated right arm blood pressure

Supravalvar aortic stenosis (i.e., Coanda effect)




Originally named mucocutaneous lymph node syndrome after its major manifestations, Kawasaki disease is the most common cause of acquired heart disease in children in the United States. The cause has yet to be determined. In the United States, the peak incidence is between 13 and 24 months of age. Current diagnosis and therapy have been reviewed in detail ( Mason and Takahashi, 1999) . The acute illness is associated with fever, intense conjunctival injection, red cracked lips, lymphadenitis of the neck, and erythema of the palms and soles followed weeks later by desquamation of the fingers and toes. The most concerning feature of the disease is that it causes an infantile periarteritis nodosa-like vasculitis of medium and large arteries in 10% to 15% of children. Of particular concern is involvement of coronary arteries ( Fig. 32-6 ) with the risk of subsequent thrombosis or, less commonly, rupture. The risk of coronary artery aneurysms is higher in infants. The acute phase of the illness can also be associated with myocarditis, usually mild, but sometimes associated with heart failure. Myocarditis is usually transient, lasting several weeks. Laboratory findings during the acute phase include elevated sedimentation rate, C-reactive protein, and thrombocytosis to more than 800,000/mm3.


FIGURE 32-6  Large aneurysms of the left main coronary artery in a child with Kawasaki syndrome.  (Courtesy of Jonathan Rome, M.D.)


Coronary artery aneurysms will become apparent within the first two weeks of disease in about 5% of children who have been treated with intravenous injection of gamma globulin (IVIG), and in 20% to 25% of children who have not. Early aneurysms can resolve spontaneously or progress.

Treatment in the acute phase includes IVIG and aspirin (acetylsalicylic acid) for 4 days, followed by aspirin for 6 to 8 weeks. If IVIG therapy fails, children are at high risk for the development of coronary artery complications, which may be treatable with corticosteroids.

If coronary artery aneurysms do develop, about one half regress within 1 to 2 years, and about one fifth develop coronary stenoses. Smaller aneurysms (<8 mm in diameter) and fusiform aneurysms are more likely to regress than larger or saccular aneurysms. Larger aneurysms can develop thromboses or stenosis with subsequent ischemia, or can rupture. Rupture is rare and usually occurs within the first month or two of disease. Ischemia can develop years after the acute illness. Even if aneurysms regress, intimal proliferation can result in endothelial dysfunction ( Furuyama et al., 2003 ). Warfarin has been used in some centers to treat children with giant aneurysms. Angioplasty has been attempted in several centers with mixed results, and surgical bypass grafting has been done on occasion for high-grade obstruction of the left main coronary artery or at least two of the major coronary arteries. Due to the young age of the patients, grafting is done with arterial rather than venous grafts ( Kitamura et al., 1994 ).


This vasculitis of the aorta and its major branches, sometimes known by its catchy synonym “pulseless disease,” is an uncommon disease of children. However, 75% of patients begin to develop symptoms during their teenage years, and it is an important cause of hypertension in adolescents in Asia, where it is more common. It occurs eight times more often in females. Narrowing of major arteries results in limb claudication or end-organ disease. Limb blood pressures can be artifactually low or unobtainable. Early vessel inflammation is followed by fibrosis. Headaches are a common symptom. The subclavian artery is involved in 90% of cases, and two thirds involve the supradiaphragmatic and infradiaphragmatic aorta. The carotid artery, usually the left, is involved in one half of the cases. Stenoses are more common than occlusion, and occlusion is more common than aneurysm formation. There is mural inflammation and thickening. Both coronary arteries and pulmonary arteries are uncommonly affected. Initial treatment is with corticosteroids. Long-term therapy is often required, and cytotoxic drugs are sometimes added. After fibrosis has occurred, the treatment is stenting or surgery ( Rigby et al., 2002 ).

Copyright © 2008 Elsevier Inc. All rights reserved. -

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

Copyright © 2005 Mosby, An Imprint of Elsevier



Hemoglobin Structure, Development, and Function

Hemoglobin (Hb) is composed of two pairs of subunits containing protoheme and globin ( Box 32-10 ). The globin imparts the spatial structure responsible for many characteristics of hemoglobin, including oxygen affinity. The various globin chains differ in the number and sequence of amino acids and are designated by α, β, γ, γ, ε, ζ, and ϑ. Normal adult red blood cells (RBCs) have three types of hemoglobin: HbA (α2β2), approximately 95%; HbA2 (α2γ2), approximately 2.5%; and HbF (α2γ2) ( Table 32-16 ) ( Lane, 1996 ). The intricate spatial relationship of the four subunits determines oxygen affinity and changes in affinity during oxygen loading and unloading, as well as physical properties such as hemoglobin solubility.

BOX 32-10 

Hemoglobinopathies: Glossary of Terms


cerebrovascular accident


hemoglobin A


hemoglobin A2


hemoglobin F


hemoglobin S


sickle cell trait


sickle cell C disease


irreversibly sickled cell


sickle cell disease

TABLE 32-16   -- Common sickle cell syndromes: diagnostic testing and clinical severity









Neonatal Screen[*]

HbA (%)

HbS (%)

HbF (%)

HbA2 (%)

HbC (%)

Solubility Test[†]

Sickle cell anemia (HbSS)






80 to 95

2 to 20




Sickle β0 thalassemia[‡]






80 to 92

2 to 15

3.5 to 7



Sickle Hb C disease (HbSC)






45 to 50

1 to 5


45 to 50


Sickleβ+ thalassemia[‡]




FSA or FS[‖]

5 to 30

65 to 90

2 to 10

3.5 to 6



Sickle trait





50 to 60

35 to 45










95 to 98






From Lane PA: Sickle cell disease. Pediatr Clin North Am 43:639, 1996.


Hemoglobin reported in order of quantity (e.g., FSA=F>S>A); F, fetal hemoglobin; S, sickle hemoglobin; C, hemoglobin C; A, hemoglobin A.

False-negative results occur during infancy in all sickle syndromes.

β0 Indicates thalassemia mutation with absent production of β-globin; β+ indicates thalassemia mutation with reduced (but not absent) production of β-globin.


Quantity of HbA2 cannot be measured in presence of HbC.

Quantity of HbA at birth is sometimes insufficient for detection.



At birth, RBCs contain 70% to 90% HbF, which is predominant until 2 to 4 months of age in normal patients. β-Chain production begins before birth, and γ-chain production wanes, resulting in a normal adult profile by age 4 months. Disorders of the β chain do not manifest in the first few months and are not identified by precipitation screening tests. HbF persists in many conditions and offers a protective effect when present in many hemoglobinopathies. Some experimental interventions to treat sickle cell patients attempt to stimulate HbF production.

Hemoglobinopathies can result from production of an abnormal hemoglobin molecule or by underproduction of a given chain. The most common mechanism of the former type is the result of a single substitution of one amino acid for another on the protein chain. Underproduction of a given chain results in thalassemia.

Sickle Cell Disease

Sickle cell disease (SCD) is an autosomal recessive inherited disease. Eight percent of the African American population of the United States are carriers (HbSA, sickle trait), and 1 in 625 has the disease (HbSS, SCD).

Sickle cell disease results from a single amino acid substitution on position 6 of the β chain (Glu ➙ Val). The SCD patient has two normal α chains and two abnormal β chains in the S hemoglobin, which makes up roughly 90% of the hemoglobin. The remainder is HbF and HbA2. The substituted amino acid (valine) increases the rate of polymerization (gel formation). This decreases the hemoglobin solubility. Polymerization is increased by increases in temperature and H+ concentration and is decreased by oxygen and other non-S hemoglobin. As oxygen is unloaded, polymerization increases in a single direction, and subsequent alignment of multiple polymers results in sickling. Some sickled cells can regain normal conformation and some do not (i.e., irreversibly sickled cells). The irreversibly sickled cells are rigid, viscous, and more adherent to endothelium and result in arteriolar and capillary vaso-occlusion. This pathology results in acute crisis and in long-term chronic problems, which the anesthesiologist must consider. Table 32-16 provides information on diagnostic findings and relative severity of the spectrum various sickle variants ( Lane, 1996 ).

Acute Crisis

Although the most important crises to consider during the perioperative period are the vaso-occlusive crises in the form of acute chest syndrome and stroke, the physician should also be aware of the other crises. Acute splenic sequestration may occur from 5 months to 2 years of age. Acute pooling of large amounts of blood results in profound anemia and shock. Aplastic crisis manifests as an acute decrease in RBC production, usually as a result of infection (e.g., parvovirus B19). Hyperhemolytic crises may result from infection or G6PD deficiency.

The vaso-occlusive crises are episodes of ischemia, pain, and infarctions of various organs. Those commonly seen are painful crisis (hand-foot syndrome in infancy), cerebrovascular accident (infarctive in infants and hemorrhagic in older patients), acute chest syndrome, and priapism. Vaso-occlusive crises occur with greater frequency during the perioperative period and prevention of these episodes is the primary goal when deciding the best transfusion and anesthetic approach.

Acute chest syndrome is a common and important perioperative complication of complex pathophysiology likely resulting at least in part from pulmonary vaso-occlusion due to sequestration of sickled cells in small pulmonary vessels. Symptoms of fever, tachypnea, pleuritic pain, and cough are difficult to distinguish from pneumonia and may begin as pneumonia. Infection or fat emboli may lead to vaso-occlusion and sequestration. Chest radiograph can range from normal to complete opacification but usually demonstrates a new lobar infiltrate. The mortality rate of patients with acute chest syndrome is from 2% to 12% depending on the series (Vichinsky et al., 1994, 1997 [520] [522]). It is the second most common cause of hospitalization and accounts for 25% of deaths in sickle cell patients. Patients may rapidly develop respiratory failure and should be treated with hydration, oxygen, antibiotics, and in many cases exchange transfusion. There may be a role for inhaled nitric oxide in treating severe cases ( Sullivan et al., 1999 ).

Chronic Problems

A lifetime of intermittent vaso-occlusion and endothelial damage results in a host of chronic problems in many patients. These include decreased growth and maturation, increased nutritional requirements, retinopathy, hearing loss, stroke, high output cardiac failure, pulmonary insufficiency, loss of renal concentrating ability, jaundice, bone and joint destruction, leg ulceration and splenic infarction (infection risk). Cardiomegaly and high output failure from anemia are common. Increased left ventricular end-diastolic volume and increased cardiac index have been reported in symptomatic children ( Rees et al., 1978 ).

Survival of sickle cells in vivo is 5 to 15 days, compared with 120 days for RBCs containing hemoglobin A. The oxygen-dissociation curve in SCA is shifted to the right (i.e., the hemoglobin molecules—affinity for oxygen is less), and theoretically, the cells are predisposed to sickling ( Bromberg et al., 1967 ; Milner, 1974 ). The cause of this rightward shift is unknown, but it is probably related to increased 2,3-diphosphoglycerate levels and to increased mean corpuscular hemoglobin concentration. Of interest is the heterogeneous nature of the P50 value among the cells with HbS, which varies from 27 to 42 mm Hg ( Fig. 32-7 ).


FIGURE 32-7  Oxygen hemoglobin dissociation curves from top and bottom layers of HbS red blood cells. Notice the heterogeneous nature of the P50 values.  (From Seakins M, Gibbs WN, Milner PF, et al.: Erythrocyte Hb-S concentration. An important factor in the low oxygen affinity of blood in sickle cell anemia. J Clin Invest 52:422, 1973.)




Renal dysfunction is frequent in patients with sickle cell disease. Hematuria and hyposthenuria are hallmark findings in patients with SCA. Because sickle cell patients are unable to concentrate their urine, intravenous hydration should be started the night before surgery ( Buckalew and Someren, 1974 ).

Neurologic impairment can be a devastating consequence of this disease. Cerebrovascular disease occurs in approximately 8% of children with sickle cell disease. Transfusion programs aimed at maintaining HbS levels at less than 30% reduce the risk of recurrent stroke from 60% to 70% to less than 10% ( Lane, 1996 ). Evidence of a stroke or residual hemiparesis should be documented, and neuromuscular monitoring on the affected extremities should be avoided, because increased twitch responses may falsely minimize the degree of neuromuscular blockade. This can be considered to be as much an endothelial disease as an RBC disease. Every vascular bed is affected.

Anesthetic Management

Preoperative Transfusion.

Surgical morbidity and mortality rates are increased for sickle cell patients. Early reviews reported mortality rates as high as 10% and complication rates as high as 50% ( Holzmann et al., 1969 ). In later reviews, Platt and others (1994) reported some interesting statistics on mortality of patients with sickle cell disease. The perioperative mortality rate for sickle cell patients was 1.1%, clearly above that of the general population, and 7% of the deaths reviewed were surgically related. The mean age of death for sickle cell patients was 42 years.

Griffin and Buchanan (1993) reported their experience with nontransfused children with sickle cell disease having elective surgery. Although there were no intraoperative complications or perioperative deaths among 54 children undergoing 66 procedures, 26% experienced postoperative complications. They concluded that preoperative transfusion could be avoided in patients having low-risk procedures and that those having high-risk procedures (i.e., thoracotomy, laparotomy, or tonsillectomy and adenoidectomy) should receive preoperative transfusion.

The Cooperative Study of Sickle Cell Disease group observed nearly 4000 patients over a 10-year period and reported a 1.1% mortality rate when 717 patients underwent 1079 procedures ( Koshy et al., 1995 ). This was a descriptive report without randomized comparisons, and it provided little insight about how differences in practice affect outcomes.

Because of these concerns, most anesthesiologists adopted some form of aggressive transfusion therapy for certain subgroups of patients or procedures when they thought the patients were at high risk for complications. This aggressive therapy often included a hypertransfusion protocol or acute exchange transfusion to a predetermined Hb and HbS level. Frequently, the goal of transfusion was to attain an Hb level of 9 to 10, with HbS accounting for less than 30%. Until recently, the value and consequence of such aggressive therapy was unknown.

In 1995, the results of the Preoperative Transfusion in Sickle Cell Disease Study Group were published ( Vichinsky et al., 1995 ). This group, consisting of 36 centers, randomized 604 cases into a “simple transfusion arm” and an “aggressive transfusion arm.” The former group received a simple transfusion to a hemoglobin level of 10 g/dL, and the later group received transfusions sufficient to attain an HbS level of less than or equal to 30% and a hemoglobin level of 10 g/dL ( Table 32-17 ). Only higher-risk surgery and the existence of pulmonary disease were associated with serious complications. Most complications were in the postoperative period.

TABLE 32-17   -- Aggressive versus simple transfusion protocols for sickle cell patients


Aggressive Arm

Simple Arm

Hemoglobin S (HbS)



Hemoglobin (Hb)

11.1 g/dL

10.6 g/dL

Units transfused



Hospital days (for transfusion)









Acute chest syndrome






Data from Vichinsky EP, Haberkern CM, Neumayr L, et al.: The preoperative transfusion in sickle cell disease study group: A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. N Engl J Med 333:206, 1995.




Since this study, anesthesiologists and hematologists have meaningful data on which to base transfusion guidelines. However, if a physician were to adopt a simple transfusion practice as described in this study, it would be prudent to adopt similar preoperative, intraoperative, and postoperative practice guidelines for the nontransfusional care of these patients. Each center should review the literature and adopt guidelines with guidance from the hematologists and transfusion medicine specialists in their own institution.

Sickle cell patients come to the operating room most often for cholecystectomy. Haberkern and others (1997) described the 364-patient subset of the Preoperative Transfusion in Sickle Cell Disease Study Group that was undergoing this procedure. As in the parent study, complications were similar in the aggressive versus simple transfusion. However, the nonrandomized, nontransfused group had the highest incidence of sickle cell-related complications, including a 19% incidence of acute chest syndrome. This rate was twice that of the transfused groups. This perhaps provides the most compelling data that some form oftransfusion practice is prudent in patients with sickle cell disease undergoing surgery.

Recommendations for preoperative preparation for most patients include hydration and simple transfusion for correction of anemia. Very-high-risk patients, such as those with stroke or recent or frequent acute chest syndrome, will likely require a more aggressive transfusion regimen. Communication between the hematologist, anesthesiologist, and surgeon is essential to prepare these children for surgery. For patients who require transfusion, it is extremely important to keep the hemoglobin level less than 12 mg/dL to avoid potentially devastating problems, such as stroke, which may be associated with hyperviscosity.

Intraoperative Management.

No particular anesthetic or technique has proved to be more or less advantageous for sickle cell disease patients. Arguments can be made for and against regional techniques for sickle cell patients. In the Cooperative Study of Sickle Cell Disease series, the non-sickle cell disease-related outcomes of fever and infection were higher in the regional group ( Koshy et al., 1995 ). However, this group contained a large portion of obstetric patients receiving epidural anesthesia. This subpopulation is known to have a higher complication rate than other surgical groups. Some physicians suggest that the compensatory vasoconstriction in nonblocked areas, lack of control of ventilation, and potential for stasis during regional anesthesia create an environment in which sickling can occur ( Scott-Conner and Brunson, 1994 ). Others feel that regional techniques do not create this milieu. In one series, epidural anesthesia and analgesia was successfully used to treat painful vaso-occlusive crisis ( Yaster et al., 1994 ). Suffice it to say that the technique of anesthetic is likely much less important than the meticulous attention to detail in the areas of perioperative hydration, perfusion, oxygenation, and temperature control.

The advisability of tourniquet use in patients with sickle cell disease has been debated. Although no prospective studies have been performed to address this issue, there are several small retrospective reports touting its safety ( Adu-Gyamfi et al., 1993 ). If one chooses to use a tourniquet, the extremity should be carefully exsanguinated before inflation. The value of administering sodium bicarbonate or creating mild respiratory alkalosis before deflation has not been critically evaluated.

Postoperative Management.

Most of the serious sickle cell disease-related complications occur in the postoperative period ( Holzmann et al., 1969 ; Goodwin, 1998 ), the most common of which are vaso-occlusive crises (painful crisis, acute chest syndrome, and stroke). For these reasons, it is important to comply with the regimen used by the Preoperative Transfusion in Sickle Cell Disease Study Group ( Vichinsky, et al., 1995) , which includes postoperative oxygen supplementation, hydration, and pulse oximeter monitoring. This has obvious implications with respect to advisability of outpatient surgery for these patients.


In a later report, the Study Group compared perioperative morbidity in children having tonsillectomy, adenoidectomy, or myringotomy ( Waldron et al., 1999 ). Most of the children having myringotomy received the same preoperative and postoperative care as described previously. There were no differences in the aggressive versus simple transfusion regimens. Four of 11 randomized, transfused patients had complications (recurrent cerebrovascular accident, 1; airway obstruction, 2; URI, 1). Of 18 nonrandomized children, 14 were not transfused. In this group, one child had a vaso-occlusive event on postoperative day 10, and one had an aplastic event on day 23. In the transfused group, a single patient had a complication of a period of bradycardia in the recovery room. Eight of 29 patients having myringotomy had at least one serious perioperative complication. Realizing that this was not specifically studied, the Study Group speculated that transfusion before myringotomy may not improve outcome. They emphasize, however, that the physician should give attention to hydration, oxygenation, and temperature control during the preoperative and postoperative period.

Sickle Trait

By definition, patients with sickle trait (HbSA) have at least 50% HbA. Under physiologic conditions, problems are rare. Intracellular polymerization begins below oxygen saturations of 85% in HbSS, but this does not occur in HbSA until saturations are below 40%. It is generally accepted that children with sickle trait do not require transfusions. However, attention to hydration, perfusion, ventilation, and temperature control is prudent.

Sickle Hemoglobin C Disease

In general, patients with HbS and HbC (HbSC or S-C disease) have less frequent and usually milder vaso-occlusive episodes. In the Preoperative Transfusion in Sickle Cell Disease Study Group, there were 92 patients with HbSC disease. This group was reported separately ( Neumayr et al., 1998 ). Nontransfused patients undergoing intraabdominal procedures had a higher incidence of sickle cell-related complications (35%) compared with those who were transfused (0%). There were two deaths in the nontransfused group and none in the transfused group. The investigators concluded that transfusion appears to be beneficial in HbSC disease patients undergoing abdominal procedures but is not necessary in minor procedures. Because these patients are usually only mildly anemic, partial exchange transfusions may be required to keep hemoglobin levels to less than 12 mg/dL.



Underproduction of a given chain results in thalassemia. α-Thalassemia represents defective α-chain production of which there are four types. The severity of the syndrome depends on how many of the four α-globulin genes are absent (one had the trait, two had mild anemia, three had thalassemia intermedia-like syndrome [HbH disease], and four were stillborn).

β-Thalassemia results from an underproduction of β chains and has 60 forms. The gene is commonly seen in countries bordering the Mediterranean Sea. Homozygotes (β0) have a profound, transfusion-dependent anemia known as thalassemia major, Cooley's anemia, or β-thalassemia. However, a patient can be homozygous for a milder form (β-) and have mild to moderate anemia (i.e., thalassemia intermedia). These patients do produce β chains but in lower amounts. Heterozygotes for β- or β0 (i.e., thalassemia minor) demonstrate a mild hypochromic microcytic anemia.

Anemia and problems associated with chronic anemia and frequent transfusions are the issues facing the anesthesiologist. These patients will not recover from blood loss during surgery as would otherwise be expected. Patients can be heterozygous for two disorders such as sickle cell disease and β-thalassemia. Those with sickle β0-thalassemia have no normal HbA, and those with sickle β--thalassemia have some normal HbA (see Table 32-16 ).


Many U.S. states include hemoglobin testing as part of the newborn screening blood tests. The degree to which parents are aware and understand the results is variable. Because the postoperative mortality and morbidity of SCD patients are significantly greater, many centers choose to screen patients at risk for sickle cell disease. This can be done with the newborn screen or with rapid prep tests with follow-up electrophoresis on positive prep tests to distinguish trait from disease. Ninety percent of SCD patients have some clinical manifestation by their 10th birthday.

With the completion of the Preoperative Transfusion of Sickle Cell Disease Study Group data, there are now reasonable guidelines to approach most surgical situations. It seems prudent to adopt the standard practices of preoperative hydration, intraoperative vigilance, and postoperative oxygen supplementation and oximetry monitoring, employed by the Study Group. Special circumstances of high-risk procedures and high-risk patients will continue to require careful consideration and consultation. Only through effective communication between surgery, anesthesiology, and hematology specialists will the individual unique patient considerations be appropriately managed.



Each year in the United States, 1 in 7000 children younger than age 20 years is diagnosed with a new cancer. Childhood cancer remains the leading cause of disease-related mortality in children 1 to 14 years old. Acute lymphoblastic leukemia and CNS tumors are the two most common types of neoplasm in children. They comprise 23.5% and 22.1%, respectively, of cancer diagnosis ( Fig. 32-8 ). Five-year survival rates have improved dramatically over the past several decades ( Fig. 32-9 ).


FIGURE 32-8  Distribution of specific cancer diagnosis for children (0 to 14 years) and adolescents (15 to 19 years) for 1990 to 1997. Percent distribution is given by international classification of childhood cancer diagnostic groups and subgroups for those younger than 15 to 19 years old (all races and both sexes). CNS, central nervous system; RMS, rhabdomyosarcoma; STS, soft tissue sarcoma.  (Incidence data are from the Surveillance, Epidemiology and End Results program, National Cancer Institute; redrawn from Smith MA, Rloeckler Ries LA: Childhood cancer: Incidence, survival and mortality. In Pizzo PA, Poplack DG, editors: Pediatric oncology, 4th ed. Philadelphia, 2002, Lippincott, Williams & Wilkins, p 2.)





FIGURE 32-9  Five-year survival rate for all childhood cancers diagnosed between 1960 and 1995.  (Data from Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics, 2000. CA Cancer J Clin 2000;50:7; redrawn from Balis FM, Holcenberg JS, Blaney SM: In Pizzo PA, Poplack DG, editors: Pediatric oncology, 4th ed. Philadelphia, 2002, Lippincott, Williams & Wilkins, p 238.)




From the time a child is first diagnosed with a malignancy to the end of a successful treatment course, the anesthesiologist assumes a very important role in his or her care. Historically painful procedures such as lumbar punctures and bone marrow aspirations were performed under local anesthesia with or without sedation. This was only minimally effective in reducing pain and anxiety. Parents had to deal with the anguish and uncertainty of the cancer diagnosis and the horror of watching their children suffer through multiple painful procedures. In many centers, an anesthesiologist is present when diagnostic procedures are performed, when central venous access devices are implanted, when a tumor is removed, when the radiation treatments are performed, through all of the surveillance procedures, and when the central venous devices are removed after a cure is effected. Anesthesiologists individually and entire departments often develop close relationships with these children and their families. The anesthetic management in off-site venues and for specific malignancies is discussed in Chapter 25 (Anesthesia for Procedures Outside the Operating Room). In the following section, we review the anesthetic implications of cancer chemotherapy.

Anesthetic Implications of Cancer Chemotherapy

General Toxicity

Acute toxicities common to most agents include myelosuppression, alopecia, nausea, vomiting, mucositis, and liver dysfunction. Myelosuppression produces pancytopenia. Profoundly neutropenic patients may require protective isolation. These children may be better served by avoiding the preoperative holding area and being recovered in a separate area. Rectal temperatures and medications should be avoided in neutropenic children. The need for platelet transfusion in thrombocytopenic children depends on the type of procedure and the function of the existing platelets. Neuraxial anesthesia may be contraindicated in patients with platelet counts of less than 80,000. These issues should be decided with consultation from, and in partnership with, the hematologist-oncologist before the procedure. The decision as to when and how to transfuse RBCs should also be discussedwith the hematologist. RBCs may require irradiation to prevent graft-versus-host disease and should be screened for cytome-galovirus and other known viruses. Individual drugs produce unique toxicities ( Table 32-18 ). Those that produce cardiac and pulmonary injury are of special interest to the anesthesiologist and warrant discussion.

TABLE 32-18   -- Toxicity of chemotherapeutic agents

Organ or System Effect

Drug Examples

Comments and Anesthetic Implications

Bone marrow suppression

All cytotoxics

Anemia, leukopenia, and thrombocytopenia occur to a variable degree

Nonthrombocytopenic bleeding


Hemorrhagic pancreatitis

Lungs: fibrosis or pneumonitis


Oxygen toxicity particularly associated with high doses; postoperative adult respiratory distress syndrome reported with high inspired oxygen concentrations and excessive intravenous fluids; synergistic with radiotherapy

Mitomycin C

Carmustine (BCNU)


Heart: cardiomyopathy, electrocardiographic, and echocardiographic changes


Acute cardiomyopathy; cardiomyopathy months after therapy; echocardiographic changes may occur





Rarely cardiotoxic

Central nervous system


Corneal effects


Cerebellar ataxia


Encephalopathy, impaired sensorium, lethargy, convulsions, stroke, syndrome of inappropriate secretion of antidiuretic hormone (SIADH)





Peripheral nervous system: neuropathy

Vincristine, vinblastine


Cisplatin, procarbazine


Autonomic nervous system


Can lead to surgical abdominal crisis

















All drugs

Uric acid nephropathy at start of treatment. Prophylactic allopurinol and fluid therapy necessary


Tubular and glomerular damage








Glomerular damage, dose related


Glomerular and tubular damage, dose related; low calcium and magnesium blood levels possible

Gastrointestinal epithelium


Stomatitis, diarrhea, cachexia, mucous membrane ulceration





Eruption may parallel pulmonary toxicity






Possible increased requirement for nondepolarizing relaxants


Alkylating agents

Inhibition of plasma cholinesterase


Possible increased apnea from suxamethonium


Electrolyte disturbances





MAO inhibitor effects; care with vasopressors, sedatives, narcotics; influenza symptoms can manifest

Adapted from Hain WR, Jones SEF: Diseases of blood. In Katz J, Steward DJ, editors: Anesthesia and uncommon pediatric diseases, 2nd ed. Philadelphia, 1993, WB Saunders, p 665.



Cardiac Toxicity

Several chemotherapeutic agents have cardiac toxicities that may be acute, chronic, or both. The most notorious agents for cardiac toxicity are the anthracycline agents: doxorubicin (Adriamycin), daunorubicin (Cerubidine), and idarubicin ( Giantris et al., 1998 ; Singal and Iliskovic, 1998 ; Balis et al., 2002 ). These agents can cause acute alterations in the electrocardiogram (e.g., decreased QRS amplitude, nonspecific ST and T wave changes) and rhythm disturbances (e.g., supraventricular tachycardia, premature ventricular contraction). Another acute complication in children is a reduction in ventricular function reaching a nadir at 24 hours after administration. A rare form of this is the myocarditis-pericarditis syndrome. This can occur after one to three doses of doxorubicin and results in CHF with a variable course from complete recovery to cardiogenic shock.

Chronic toxicity may occur weeks, months (early form), and years (late form) after administration. The early form causes histopathologic changes within the myocyte, including cytoplasmic vacuolization and myofibrillary lysis, with degeneration of nuclei and mitochondria. Oxygen free radicals generated by metabolism of the drug are thought to be responsible for these changes. Myocardial dysfunction may cause congestive heart failure that is poorly responsive to inotropic medications. Its incidence correlates with cumulative dose. The incidence of congestive heart failure increases when doses exceed 450 mg/m2 for doxorubicin and 700 mg/m2 for daunorubicin. However, cardiac toxicity has occurred with doxorubicin doses as low as 220 mg/m2. The cumulative toxic dose of idarubicin is not known, but a dose of 150 mg/m2 appears to be well tolerated. The risk is also increased with mediastinal irradiation ( Table 32-19 ) ( Allen, 1992 ). Late cardiotoxicity is more common in children and may be related to the inability of the heart to grow with the child. Although this complication was thought to occur primarily with doses of doxorubicin greater than 300 mg/m2, some children suffer this complication at lower doses. Cardiac dysfunction may occur from 7 to 14 years after therapy. Children seem to have a higher incidence at lower doses than adults. Children treated with these medications should receive pretreatment echocardiograms and serial follow-up monitoring studies for many years after treatment.

TABLE 32-19   -- Risk factors and effects of anthracycline cardiac toxicity

Risk Factor

Incidence and Effects

Cumulative dose

<1%: <300 mg/m2 5% to 10%: 350 to 450 mg/m2 30%: >550 mg/m2

Schedule of administration

Risk greatest with bolus administration Less risk with continuous infusion Less risk with dexrazoxane

Mediastinal irradiation

Strong association with increasing risk

Cardiac disease

Preexisting coronary artery disease, valvular heart disease, hypertension


Young children


Adults >70 yr

From Swafflor J, Gibbs HR: Cardiac complications of cancer treatment. Anesthesiol Clin North Am 16:598, 1998.




Cyclophosphamide, especially in high doses (excess of 100 to 200 mg/kg) can cause severe CHF from hemorrhagic myocarditis. Cardiac tamponade from pericardial effusions has been reported with cardiotoxicity from this agent. Toxicity may occur at lower doses in children who have also received anthracyclines.

Radiation applied to thoracic tumors can result in cardiac toxicity. Early toxicity may cause pericarditis with effusion and possible tamponade. Most long-term effects occur with cumulative doses exceeding 4000 cGy, and they may not manifest for up to 10 years after treatment ( Applefield et al., 1982 ). The dose of radiation absorbed is defined as energy expressed in units of joules deposited per kilogram (J/kg), which is denoted as gray (Gy) units. One Gy is equal to 100 rad in the old system, and 1 rad is equal to 1 cGy.

Preoperative assessment of many of these patients will include a cardiology consultation and echocardiogram in high-risk patients. Selection of induction and maintenance agents will obviously be influenced if ventricular dysfunction is present or suspected. Intraoperative fatalities have occurred in children with chemotherapy-induced cardiomyopathy in the presence of potent inhaled anesthetics (McQuillan et al., 1988 ). This has been most marked with halothane, because of its myocardial depressant effects on an already compromised myocardium.

Pulmonary Toxicity

Many, if not most, cancer chemotherapeutic agents cause some degree of pulmonary toxicity. Because immunosuppressed children are predisposed to lung infections, it is often difficult to sort out toxicity from infectious and toxic inflammatory processes. Because multimodal chemotherapy and radiation therapy are used to treat many forms of cancer, it is often difficult to pinpoint the specific causative agent.

Alkylating agents such as busulfan, cyclophosphamide, melphalan, and chlorambucil are associated with cytotoxic lung injury. Busulfan may cause lung injury when given as a single agent; the others do so only when given in high doses or as part of multi-drug therapy. Busulfan lung injury occurs 6 weeks to 10 years after therapy with an average time interval from treatment to symptoms of 3 years. Dyspnea, fatigue, nonproductive cough, weight loss, unexplained fever, and bi-basilar reticular infiltrates are hallmarks of this complication. This pulmonary fibrosis carries a poor prognosis. Toxicity appears to be idiosyncratic and is not dose dependent.

Cytotoxic antibiotics such as bleomycin and its analogs, peplomycin and talisomycin S10b, as well as mitomycin, an alkylating agent, have pulmonary toxicities. Bleomycin lung injury has become the prototype for interstitial pneumonitis and pulmonary fibrosis. A synergistic relationship exists between high inspired oxygen concentration and bleomycin toxicity. Although the exact mechanism is unclear, oxygen concentrations above 30% can rapidly precipitate acute lung injury and acute respiratory distress syndrome ( Mathes, 1995 ; Maher and Daley, 1993 ). Mortality from this injury ranges from 13% to 83% in various studies. High dose corticosteroids may have a beneficial effect in this lung injury ( Maher and Daley, 1993 ).

Antimetabolites such as cytosine arabinoside (ara-C), fludarabine, methotrexate, and 6-mercaptopurine also cause various degrees of lung injury. In general, these are dose-related toxicities and usually carry a better long-term prognosis.

Thoracic radiation causes clinically significant lung injury in 5% to 15% of patients who receive this treatment. Several phases of lung injury are described. The latent or early phase occurs within 1 to 2 months of exposure. The exudative or intermediate phase is 4 to 6 months after this; symptoms of pneumonitis develop. The late phase brings the development of pulmonary fibrosis and occurs from 6 to 12 months after exposure. Factors that influence the risks of this complication include the total dose of irradiation, volume of lung treated, and fraction size. Pulmonary toxicity has decreased significantly over the past decade because of refined techniques in radiotherapy ( Hassink et al., 1993 ). Toxicity does not usually occur until more than 3000 cGy is delivered to more than 50% of the lung when radiation therapy alone is used in adult patients. The mechanism of injury appears to be different in children younger than 3 years, in whom interference with growth of the lung and chest wall may occur ( Miller et al., 1986 ). In these children, restrictive lung disease has occurred with doses of 1100 to 1400 cGy.

Children who have received multimodal chemotherapy with and without thoracic radiation may be at risk for pulmonary toxicity. Preoperative assessment may include chest roentgenograms in selected patients. Determination of oxygen saturation with the patient breathing room air will identify those with intrapulmonary shunting and diffusion abnormalities. Children at risk for pulmonary toxicity should receive the minimum inspired oxygen concentration required to provide acceptable oxygen saturation values ( Klein and Wilds, 1983 ). This vigilance should be observed in the postoperative period as well.

Copyright © 2008 Elsevier Inc. All rights reserved. -

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

Copyright © 2005 Mosby, An Imprint of Elsevier


Coagulation abnormalities provide many challenges for the pediatric anesthesiologist. Children with known coagulation disorders require disease-specific perioperative management. Often the child in the operating room is to be treated for the complications of a bleeding diathesis. More challenging is the intraoperative investigation and management of children who develop coagulopathy in the operating room from preexisting but undiagnosed diseases or from acquired disorders. The following sections focus on the endogenous control of hemostasis, developmental changes in coagulation, and commonly inherited coagulopathies and their management ( Box 32-11 ).

BOX 32-11 

Coagulation: Glossary of Terms


activated clotting time


activated protein C


activated partial thromboplastin time


antithrombin III


ε-aminocaproic acid


platelet surface glycoprotein receptor IIb/IIIa


international normalized ratio


plasminogen activator inhibitor


proteins induced in vitamin K's absence


prothrombin time


recombinant factor VIIa


severe combined immune deficiencies syndrome


thrombin-activatable fibrinolysis inhibitor


transfusion-associated graft-versus-host disease




tissue factor


tissue factor pathway inhibitor


tissue plasminogen activator


transfusion-related acute lung injury


thromboxane A2


von Willebrand factor


The hemostatic system is designed to maintain blood in a fluid state until vessel injury occurs, at which point a rapid cascade of events is activated to terminate blood loss by sealing off the vascular defect. Hemorrhage occurs if the response is inadequate; thrombosis occurs if the response is dysregulated. The vascular endothelial cell is at the fulcrum of this delicate balance. The normal endothelial cell maintains blood in its fluid state by inhibiting platelet aggregation and blood coagulation through the production of prostacyclin, nitric oxide, and antithrombin III and by promoting fibrinolysis through the conversion of plasminogen to plasmin. Physically, the endothelial cell is a barrier between the platelets and procoagulant proteins derived from reactive components present in the deeper layers of the vessel wall. These components include collagen, fibronectin, von Willebrand factor (vWF), and tissue factor (TF), all of which stimulate platelet adhesion and aggregation and trigger the coagulation cascade.

Primary Phase of Hemostasis

The platelet is central to the primary phase of hemostasis. A graphic representation of the hemostatic mechanism is shown in Figure 32-10 . The normal circulating platelet count ranges from 150,000 to 400,000/mL. An additional 33% of all platelets are sequestered within the spleen. After vascular injury, the affected vessel constricts proximally, diverting blood flow away from the site of endothelial disruption. Extravasated blood is exposed to subendothelial structures and the platelets are stimulated by their exposure to collagen. The platelets become adherent to the subendothelial infrastructure, anchored through the binding of vWF to the platelet surface glycoprotein Ib. Once the platelet adhesion occurs, platelet activation results in (1) the release of platelet agonists, such as epinephrine and serotonin from the dense granules; (2) the synthesis of thromboxane A2 by cyclooxygenase (COX) from the conversion of arachidonic acid, released from the platelet lipid membrane; and (3) a 50% increase in the number of platelets and a conformational change in the platelet surface glycoprotein receptor IIb/IIIa (GPIIb/IIIa), which binds to fibrinogen, vWF, and fibronectin ( Shattil et al., 1998 ).


FIGURE 32-10  Regulation of coagulation. The coagulation cascade is regulated by a number of plasma proteins. The tissue-factor-pathway inhibitor forms a quaternary structure with tissue factor, factor VIIa, and factor Xa. The thrombomodulin–protein C–protein S pathway inactivates factors Va and VIIIa. Antithrombin III inactivates factors XIa, IXa, Xa, and IIa in a reaction that is accelerated by the presence of heparan sulfate. In the fibrinolytic pathway, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) convert plasminogen to plasmin. Once generated, plasmin proteolytically degrades fibrin.  (Redrawn from Rosenberg RD, Aird WC: Vascular bed specific hemostasis and hypercoagulable states. N Engl J Med 340:1555, 1999.)




Platelet activation increases fibrinogen's affinity for the GPIIb/IIIa receptor and results in clustering of receptors on the platelet surface. Platelet aggregation, through the linkage of GPIIb/IIIa to the GPIIb/IIIa on other platelets by bridging fibrinogen or vWF, increases the size of the initial platelet plug, creating a mass of aggregated platelets at the site of injury. Thromboxane A2 (TXA2) binds to a G protein-coupled receptor on the platelet surface leading to an increase in intracellular calcium and activation of protein kinase C. TXA2 induces aggregation of other platelets and promotes vascular smooth muscle constriction, producing local vasoconstriction, which limits blood loss and increases the effectiveness of the platelet plug by decreasing the effective surface area the platelet plug needs to cover. TXA2 amplifies the platelet's responses to weak agonists such as ADP and epinephrine ( Funk, 2001 ). The initial platelet plug is friable. It is stabilized by an increase in platelet cytosolic calcium that is mediated through platelet agonist exposure, which initiates actin filament turnover that modulates the cytoskeletal changes. These changes enable GPIIb/IIIa clustering and bindingof fibrinogen and vWF. The conformational change of GPIIb/IIIa, induced by ligand binding, exposes new ligand binding sites and additional merging of receptors on the platelet surface, resulting in clot retraction ( Wartlier et al., 2002 ).

Secondary Phase of Hemostasis

The exposure of subendothelial structures to circulating blood simultaneously activates the coagulation cascade (the secondary phase of hemostasis) to produce a cross-linked fibrin clot. Of the coagulation proteins, prothrombin (II), protein C, protein S and factors VII, IX, and X are synthesized as prozymogens and activated to serine proteases through a vitamin K-dependent hepatic enzyme ( Furie and Furie, 1990 ). This modification is required for calcium binding, serving as a bridge for binding the factors to the phospholipid surface.

New Model of Cell-Based Coagulation

In earlier schemes, the coagulation cascade had been divided into intrinsic (e.g., XII, XI, IX, VIII) and extrinsic pathways (e.g., TF, factor VII). This traditional scheme is depicted in Figure 32-11 . This model is primarily useful for the interpretation of in vitro laboratory tests, the activated partial thromboplastin time (aPTT), and the prothrombin time (PT). The common pathway of the clotting cascade is the production of factor Xa (FXa) that, in concert with FVa, cleaves prothrombin to thrombin resulting in fibrin production. It became apparent that deficiencies in the intrinsic pathway did not produce bleeding conditions, and that the concept was not clinically relevant.


FIGURE 32-11  Mechanism of hemostasis. HMWK, high-molecular-weight kininogen; vWF, von Willebrand factor.



In vivo, the critical component in the initiation of coagulation is TF, a membrane receptor for factor VII. TF is expressed constitutively on cells that are not in direct contact with blood, such as vascular smooth muscle, fibroblasts, and macrophages, forming a hemostatic envelope around the vascular endothelium ( Mann et al., 1998 ). In response to cytokine exposure, mononuclear cells and vascular endothelial cells can be induced to express TF ( Camerer et al., 1996 ; Levi et al., 2002 ). TF complexes with factor VII and activates it to factor VIIa. The TF/factor VIIa complex then activates factors X and IX. The TF/factor VIIa complex converts factor X to factor Xa directly. Factor Xa combines with its cofactor (factor Va) on the TF-bearing cell and generates small amounts of thrombin. This limited amount of thrombin is sufficient to activate platelets in the local area, as well as activating factor V, factor VIII, and factor XI, but it is insufficient to cleave fibrinogen. Factor VIII is cleaved off vWF and is then activated to factor VIIIa. Factor Xa produced in this manner cannot easily diffuse to the platelet surface because its two potent inhibitors, antithrombin III and TF pathway inhibitor, are present in sufficient concentrations. Therefore, its lifetime is limited to seconds.

Once activated by this small amount of thrombin, the platelet surface becomes coated with negatively charged phospholipid, an ideal catalytic surface for binding factor Va and factor VIIIa. Circulating platelets and adherent platelets can be activated in this manner. TF/FVIIa binds to factor IXa and then moves to the platelet surface as a complex. Factor IXa, in concert with factor VIIIa, produces factor Xa. This platelet, localized factor Xa, binds to factor Va on the platelet surface and catalyzes the conversion of prothrombin to thrombin at the rapid rate necessary for adequate hemostasis. The site at which factor Xa is produced is critical in this process ( Hoffman et al., 1998 ). Thrombin formation is accelerated, fibrinogen is cleaved, and the coagulation complex is further activated, further augmenting thrombin formation. The fibrin monomers undergo spontaneous polymerization to form the fibrin clot, which is then stabilized by cross-linking, mediated by factor XIIIa. The net result is a firm, platelet-fibrin clot that, over the course of time, decreases in size, mediated by platelets. The graphic representation of this new model of cell-based coagulation, which replaces the former intrinsic pathway, is shown in Figure 32-12 ( Gailani, 1991 ).


FIGURE 32-12  Hemostatic mechanism: cell-based coagulation model. BK, bradykinin; EC, endothelial cell; FSP, fibrin split products; GP, glycoprotein; K, kallikrein; PAI, plasminogen activator inhibitor; PK, prekallikrein; TF, tissue factor; TPA, tissue plasminogen activator; vWF, von Willebrand factor.  (Redrawn from Manco-Johnson M, Nuss R: Hemostasis in the neonate. Neoreviews 1:191, 2000.)




Modulators of Coagulation

Coagulation is modulated by a number of other plasma proteins, the most important of which are antithrombin III, thrombomodulin, TF pathway inhibitor, protein C, protein S, and factor V. Antithrombin III is a potent inhibitor of thrombin, factors IXa and Xa, and XIIIa. Inhibition of thrombin by antithrombin III is potentiated by heparin. Tissue factor pathway inhibitor (TFPI) limits factor Xa production to the IXa/VIIIa complex pathway. Activated protein C (APC), activated by the presence of thrombin, proteolytically inactivates FVIII/FVIIIa and FV/FVa, thereby downregulating production of factor Xa and thrombin. Protein S alone has little cofactor activity, but in the presence of factor V, its activity is dramatically increased. Factor V uniquely has procoagulant and anticoagulant activities. Genetic alterations in factor V (i.e., factor V Leiden) or deficiencies of protein C may result in excessive procoagulant activity, which may result in venous thromboembolism ( Tormene et al., 2002 ). When factor V is cleaved by thrombin, a number of intermediates are formed in addition to factor Va, the essential cofactor to factor Xa. These intermediates are cofactors for APC and act as anticoagulants. APC can cleave factor V directly, producing an anticoagulant and precluding factor V's transformation to factor Va ( Thorelli, 1999 ).


Fibrinolysis occurs simultaneously with the initiation of clot formation. Fibrinolysis limits thrombosis to the local area of injury and begins the process of clot revision, vascular damage repair, and ultimately vessel recanalization. During the initial phase of hemostasis, endothelial cells and platelets release plasminogen activator inhibitors (PAIs), which facilitate fibrin formation. In response to thrombin, endothelial cells begin to release tissue-type plasminogen activator (TPA), which along with prourokinase, converts plasminogen to plasmin. The plasminogen, which is bound to fibrin in the hemostatic plug is much more reactive to TPA than is circulating plasmin. After plasmin is produced locally at the site of the hemostatic plug, fibrinolysis or fibrin degradation can occur. Fibrinolysis at the hemostatic plug is opposed by ongoing coagulation and by antifibrinolysis mediated by α2-plasmin inhibitor, which also binds to fibrin.

The spectrum of endothelial cell and platelet interactions in the setting of clotting factors, adhesive proteins, fibrinolytic proteins, and the myriad inhibitors promotes an equilibrium which promotes fluidity of circulating blood and localization of hemostasis, and injury repair. Derangements in any portion of this precariously balanced mechanism can lead to a hemorrhagic or thrombotic complication. A defect in clot formation in the setting of physiologic fibrinolysis will lead to bleeding, as will normal clot formation in the setting of premature fibrinolysis. Thrombosis can occur in the setting of endothelial cell expression of TF, reduction in antithrombin function, and in excessive platelet aggregation and activation.

Laboratory Evaluation of Coagulation

The panel of tests routinely used to evaluate coagulation includes the platelet count, PT, aPTT, and the bleeding time.

The normal platelet count is between 150,000 and 500,000/mL, but increased bleeding due to thrombocytopenia rarely occurs at counts above 50,000/mL. Bleeding may also occur when platelets are relatively normal in number, but dysfunctional with regard to their role in coagulation.

The normal PT, which ranges from 11.5 to 14 seconds, reflects normal amounts of factors II, V, VII, and X, which are the vitamin K-dependent factors. Defects in the vitamin K-dependent clotting factors may be due to a deficiency of the vitamin, poor responsiveness to the vitamin because of liver disease, or to exposure to warfarin agents that impair vitamin K's transition to the reduced form. The international normalized ratio (INR) can be used to estimate the degree of factor deficiency. An INR in the range of 2 to 3 correlates with factor concentrations of 10%, between 3 and 4 correlates with concentrations of 5%, and more than 4 correlates with concentrations of 1% ( Boulis et al., 1999 ).

The normal aPTT is between 25 and 40 seconds. It requires normal levels of vWF and factors XII, XI, IX, and VIII.

The bleeding time assesses the integrity of the vascular and platelet aspects of coagulation. It is prolonged in patients with reduced numbers of platelets (<100,000/mL), in patients with defective platelet function (e.g., after aspirin, NSAID, or valproic acid administration), and in patients with von Willebrand's disease. The bleeding time is performed using a standardized template device to guide the incision with a tourniquet placed on the arm at 40 mm Hg for children, 30 mm Hg for newborns at term, and 20 mm Hg for premature infants. The bleeding time has suffered from a reputation of being difficult to perform and poorly reproducible, especially in newborns and infants. Results may be affected by skin thickness and device used to puncture the skin (surgical blade, manufactured bleeding time device), location of incision, and body temperature. A bleeding time device (Surgicutt, ITC, Edison, NJ) has been developed. It comes in three sizes for adults, children (5 months to 15 years), and newborns (up to 5 months). The blades are different lengths (and depth for newborns) and afford a standardized incision, rather than a puncture. This standardization should decrease the variability in bleeding times that result from different incision techniques and skin thickness related to age, but this has not been studied in a controlled fashion. The blood is blotted with filter paper every 30 seconds. Normal bleeding time is between 4 and 8 minutes in adults and may be as low as 2 minutes in newborns. The bleeding time in very-low-birth-weight infants is decreased after transfusion to a hematocrit of greater than 28% ( Sola et al., 2001 ). It is unknown whether the longer bleeding times at lower hematocrits are associated with an increased risk of clinical bleeding.


The hemostatic system in the newborn and young child is significantly different from that of the adult. Although considered immature, the hemostatic system is functional in that the young child is successfully protected from hemorrhagic and thrombotic complications. These differences are most exaggerated in the hemostatic mechanism of the newborn. As the coagulation and fibrinolytic factors do not cross the placenta, the proposed causes for the differences in the newborn's hemostatic system include decreased factor synthesis, enhanced clearance, general activation of the coagulation system with resulting factor consumption, and the synthesis of less active fetal forms of some proteins.

One of the most notable features of the coagulation system of the infant is that plasma clotting factors are inconsistently different from adult levels, as shown in Figure 32-13 . The most well known ontogenetic differences in the hemostatic system involve the vitamin K-dependent factors. These proteins are present at low levels at birth and coagulation is severely impaired in the absence of vitamin K supplementation, called hemorrhagic disease of the newborn. The levels of the four vitamin K-dependent coagulation factors (i.e., II, VII, IX, and X) and the contact factors (i.e., XI, XII, prekallikrein, and kininogen) are all lessthan 50% of adult values and slowly rise to within 20% of adult levels by 6 months of age ( Andrew et al., 1990a ). Factor VII levels increase rapidly after birth in premature and full-term infants. Factors II and VII remain less than adult values for most of childhood ( Andrew et al., 1992 ; Andrew, 1995 ). Factor IX activity can be as low as 15% of adult levels, and reach adult levels at 9 months of age. On the other hand, the levels of fibrinogen and factors V, VIII, and XIII are normal at birth; fibrinogen and factor VIII levels are at the high end of the normal range ( Andrew et al., 1987 ). VWF levels are increased during the first weeks of life and return to adult levels between 2 to 6 months of life ( Thomas et al., 1995 ). The net effect of these differences in the newborn's hemostatic system is delayed thrombin generation, similar to that seen in adults receiving anticoagulant medications, such as Coumadin or subcutaneous heparin ( Andrew et al., 1990b ). Thrombin generation in newborn plasma critically depends on the concentration of prothrombin, whereas the rate of thrombin production is proportional to the levels of the coagulation proteins. The plasma of children has a delayed and decreased (80% adult) capacity to generate thrombin. This has minimal hemostatic significance, but may contribute to a lower risk of thromboembolic phenomena ( Andrew et al., 1994 ).


FIGURE 32-13  Developmental hemostasis: changes in plasma concentration of coagulation proteins over the course of development.  (Redrawn from Andrew M: Developmental hemostasis: Relevance to thromboembolic complications in pediatric patients. Thromb Haemost 74(Suppl):415, 1995.)




In addition to these changes in thrombin, newborn concentrations of plasminogen are markedly reduced, and levels of TPA and PAI-1 are increased. Suppressed fibrinolysis appears to be associated with the development of intraventricular hemorrhages in preterm neonates ( Chen and Lorch, 1996 ). The concentration of coagulation factors in term and preterm infants relative to adult values is summarized inTable 32-20 .

TABLE 32-20   -- Concentration of coagulation factors in the term and preterm newborn


Level at Term (% of Adult)

Level at Preterm (% of Adult)




Factor VII



Factor IX



Factor X






Factor V



Factor VIII



Factor X



Factor XI



Factor XII



Factor XIII



Heparin cofactor II







150 to 200

150 to 200

Protein C



Protein S









Tissue plasminogen activator (TPA)



Plasminogen activator inhibitor





Laboratory Evaluation of Coagulation in the Newborn

Newborns with suspected coagulopathies are evaluated with PT, aPTT, platelet count, and levels of fibrinogen and fibrin degradation products. Patients suspected of having vitamin K deficiency should have evaluation of the proteins produced in vitamin K's absence. In newborns, as a result of the developmental differences in the coagulation protein levels, the PT and aPTT are prolonged compared with adult values. Because of the low plasma concentrations of many of the clotting factors in the newborn, the aPTT is markedly elevated. The developmental progression of the PT and aPTT in term and preterm infants is summarized in Table 32-21 .

TABLE 32-21   -- Developmental changes in the prothrombin time and activated partial thromboplastin time

Age of Infant

Day 1

Day 5

Day 30

Day 90




13 ± 1.4

12.4 ± 1.5

11.8 ± 1.3

11.9 ± 1.2

12.4 ± 0.8


42.9 ± 5.8

42.6 ± 8.6

40.4 ± 7.4

37.1 ± 6.5

33.5 ± 3.4

Preterm (30 to 36 Weeks)


13.0 ± 1.5

12.5 ± 1.3

11.8 ± 0.9

12.3 ± 1.2

12.4 ± 0.8


53.6 ± 13

50.5 ± 12

44.7 ± 9

50.5 ± 12

33.5 ± 3.4

Adapted from Andrew M and others, 1987; 1988.

aPTT, activated partial thromboplastin time; PT, prothrombin time.





Developmental Changes beyond the Neonatal Period

Many of the proteins that regulate coagulation and thrombin generation are also decreased in early infancy. Antithrombin IIIand heparin cofactor II are markedly decreased to levels that might predispose to spontaneous thromboembolic events. The α2-macroglobulin levels at birth are greater than those of adults and remain so until the third decade of life. By 6 months of life, antithrombin III levels exceed levels seen in adults. Protein C and protein S concentrations at birth are also substantially less than those seen in adults, and they remain low throughout childhood ( Andrew et al., 1992 ). Fibrinolysis is also suppressed throughout childhood. During childhood, plasminogen levels increase to adult levels, but the TPA/PAI-1 ratio is significantly lower than in adults, which explains the decrease in fibrinolysis in children ( Siegbahn and Ruusuvaara, 1988 ).

Developmental Aspects of Platelet Number and Function

Although normal in number, neonatal platelets are hyporeactive. This hyporeactivity is attributed to a defect in the signal transduction pathway ( Rao et al., 1993 ). Neonatal platelet aggregation is diminished in response to certain physiologic agonists, such as ADP, thromboxane, and epinephrine. Intracellular calcium transport is decreased as well, resulting in diminished granule release and slowed conformational change ( Kuhne and Imbach, 1998 ; Gelman et al., 1996 ). Increased vWF levels in the newborn period contribute to decreased bleeding times ( Andrew et al., 1997 ). Platelet function in the neonate is aided by a relatively high hematocrit. This causes an increased concentration of platelets directed to the wall by the dynamics of laminar flow. Platelet function improves over the first 48 hours of life (Rajasekhar et al., 1994, 1997 [410] [409]).

The most serious manifestation of thrombocytopenia in the newborn period is intraparenchymal brain hemorrhage. Of neonates with spontaneous intraparenchymal hemorrhage, one third will have an associated coagulopathy, such as vitamin K deficiency, hemophilia, or thrombocytopenia. Three studies in neonates with intraparenchymal hemorrhage identified a platelet count of less than 50,000 as a significant risk factor for hemorrhage, even in full term neonates ( Nanigan et al., 1995 ; Sandberg et al., 2001 ; Jhawar et al., 2003 ).


Hemostasis usually requires activity levels of coagulation factors at least 30% of normal. The aPTT may be normal with a factor level as low as 15% to 18% of normal. Past medical history and family history are invaluable tools in the evaluation of a bleeding patient. Substantial hemorrhage after oral cavity manipulation (whether by dentist or toothbrush) is frequently a sign of an underlying bleeding disorder, reflecting an imbalance between abnormal clot formation and normal salivary fibrinolysis. Patients with mild bleeding disorders who have never had trauma or surgery may present rather late in life and may have normal screening tests. Prenatal diagnosis of most congenital factor deficiencies can now be made from fetal DNA ( Andrew and Brooker, 1995 ).


Of the inherited deficiencies of coagulation factors, the most common are the X-linked recessive hemophilias; hemophilia A is factor VIII deficiency, and hemophilia B (i.e., Christmas disease) is factor IX deficiency. Thirty percent of cases arise from spontaneous mutation. Approximately 50% of mutations of factor VIII result from inversions of the DNA sequence within intron 22 ( Lakich et al., 1993 ). The incidence of hemophilia A is 1 in 5000 male live births, and that of hemophilia B is 1 in 30,000 ( Tuddenham and Cooper, 1994 ). Hemophilia B can result from spontaneous mutations, which cause decreased rates of activation of factor IX, altered binding of factor IX to phospholipid membranes, or reduced circulation times. Patients with factor IX Leyden, a single nucleotide substitution in the transcriptional promoter, have severe hemophilia until puberty, at which point factor IX spontaneously increases to 50% ( Briet et al., 1982 ; Stowell et al., 1993 ). This suggests that the transcription of factor IX gene is in part hormonally mediated. Factor IX is a smaller molecule than factor VIII and has a greater volume of distribution.

The clinical severity of hemophilia is usually dictated by the degree of clotting factor deficiency. Patients with severe hemophilia, less than 1% of normal plasma levels, have an annual average of 20 to 30 bleeds, bleeding events which may be spontaneous or marked by excessive bleeding after minor trauma, characteristically into joints or muscle. These patients are usually diagnosed within the first 2 years of life. Bleeding is less common in the newborn period than in later months, but when it occurs, it is most common after circumcision. Of newborns presenting with hemophilia, 30% bled from circumcision sites, 27% had intracranial hemorrhage, 16% had persistent bleeding from puncture sites, and 1% had subgaleal or cephalohematomas ( Girolami et al., 1985 ; Kulkarni and Lusher, 2001 ). Infants with severe hemophilia A or B have a 2% to 8% risk of spontaneous intracranial hemorrhage ( Bray and Luban, 1987 ). Patients with mild and moderate disease, corresponding to 6% to 30% and 1% to 5% of normal factor levels, respectively, usually bleed excessively only after trauma or surgery, and they are managed with on-demand factor replacement. These patients are often diagnosed later in life ( White et al., 2001 ).

Hemophilia A and hemophilia B are characterized by a prolonged aPTT with a normal PT. Because the neonate's aPTT is physiologically prolonged, it cannot be used to diagnose hemophilia in this age group. Instead, the factor VIII level must be directly measured. Factor IX levels are physiologically low at birth and do not reach adult levels until 6 months of age, making confirmation of the diagnosis of hemophilia B uncertain until later infancy, except in severe cases. The treatment of hemophilia has changed dramatically over the past 3 decades from the availability of plasma derived replacement factors in the 1970s to the engineering of recombinant factors in the 1990s to the recently begun trials of gene replacement therapy ( Mannucci and Tuddenham, 2001 ).

Preoperative Preparation of the Child with Hemophilia

Preparation of the child with hemophilia for surgery depends on the severity of the patient's disease and the proposed procedure. Patients with mild hemophilia A who have demonstrated an adequate response to DDAVP in the past can undergo minor procedures after intravenous DDAVP administration (0.3 mcg/kg) 30 minutes before surgery ( Mannucci, 1997 ).

Factor Replacement

Hemophilia A.

The type, timing, and dose of factor to be administered should be decided in advance in consultation with the patient's hematologist. In general, children with hemophilia A who require major procedures should have their factor VIII level maintained close to 100% of normal from 30 minutes before surgery through the first 2 to 7 days of the postoperative period. Factor VIII levels can then be weaned to 30% to 50% of normal for the next 3 to 7 days. Children undergoing minor procedures can be adequately covered with factor VIII levels of 50% after the second postoperative day ( Martlew, 2000 ; Kapural and Sprung, 1999 ). In determining factor replacement, it should be remembered that the plasma volume is 45 to 50 mL/kg. Because 1 mL of plasma contains one unit of factor VIII, 50 units per kg of factor VIII will increase the patient's level to 100% (rise of 2% per unit of factor VIII/kg). In the absence of inhibitors, the half-life of factor VIII in vivo is 8 to 12 hours; subsequent doses are timed to maintain the desired level of activity. The first dose has a somewhat shorter half-life than subsequent doses. Therefore, the second dose should be given after a somewhat shorter interval (6 hours).

Factor VIII may be administered as cryoprecipitate (0.2 bags/kg should raise factor VIII level to 50%), but the factor VIII level in cryoprecipitate is variable and plasma levels should be followed if bleeding is not well controlled. The use of heat- or detergent-treated factor concentrates (Monoclate, Hemofil-M) has been replaced with recombinant factor VIII preparations (Humate P). Although the treated factor concentrates had a lower risk of transmission of viruses (e.g., human immunodeficiency virus [HIV]; hepatitis A, B, or C) compared with cryoprecipitate, recombinant factor VIII carries no risk of viral transmission, but it is unknown whether the albumin in the recombinant preparations may have a risk of prion and parvovirus B19 transmission.

Hemophilia B.

Children with hemophilia B should be given factor IX concentrate, maintaining similar levels to hemophilia A patients. The factor IX level is raised 1% for each unit of factor IX concentrate/kg. Only plasma-derived factor IX is available; there is currently no recombinant factor IX. Because the half-life of factor IX is 12 to 24 hours, it requires less frequent dosing to maintain adequate levels ( Shopnick and Brettler, 1996 ). As with factor VIII, the second dose should be give at a somewhat shorter interval than subsequent doses (6 to 8 hours).

Hemophilia C.

Hemophilia C is factor XI deficiency (i.e., Rosenthal's syndrome), an autosomally recessive disease that is most commonly reported in Ashkenazi Jews. The incidence in the Ashkenazic population is 3 in 1000, compared with a rate of 1 in 1,000,000 in the general population ( Weinstock and Schwartz, 1995 ). There is an increased incidence of hemophilia C among people with Noonan's syndrome ( Singer et al., 1997 ). Factor XI deficiency presents with a prolongation of the aPTT, with a normal PT. There is an incomplete correlation between the severity of factor deficiency and hemorrhagic symptoms, in that some patients with very low factor levels have no history of bleeding. Bleeding typically occurs after trauma or surgery, and it is commonly seen in sites that have a high fibrinolytic rate, such as the genitourinary tract, and after circumcision ( Andrew, 1997 ). Because factor XI levels are physiologically low in the neonatal period, the diagnosis is confirmed through levels obtained in later infancy. The perioperative management of these patients is dictated by their bleeding risk. Patients with factor XI levels of >15% without a previous history of bleeding, or patients with levels of 5% to 14% who have had previous surgery without significant bleeding without fresh frozen plasma (FFP) administration can be considered low risk. Patients with factor levels of less than 15%, a history of spontaneous bleeding, bleeding during previous surgeries, or those with a family history of such bleeding complications can be considered high risk. Depending on the surgical procedure, patients who are considered low risk can be managed with FFP immediately available. High-risk patients should receive FFP 2 hours before surgery ( Borud et al., 1999 ).

Von Willebrand's Disease


Von Willebrand's disease, the most common congenital bleeding disorder, is a deficiency or dysfunction of the adhesive glycoprotein vWF, which is produced in endothelial cells and megakaryocytes and is stored in Weibel-Palade bodies in endothelial cells and platelets. VWF is fundamental in platelet binding to damaged endothelial surfaces, promotes the secretion of factor VIII, and binds, carries, and protects factor VIII in plasma. von Willebrand's disease affects 1 in 1000 individuals and is inherited in an autosomal fashion (usually dominant), with males and females affected equally. It is characterized by impaired platelet adhesion to exposed subendothelium in high shear vessels. Because of the reduced or defective vWF, factor VIII is reduced to a mild and variable degree because of decreased secretion and enhanced clearance. Because von Willebrand's disease is a disorder of the protein responsible for the adherence of platelets to damaged endothelial surfaces, the clinical manifestations in affected individuals resemble those seen in patients with platelet disorders (i.e., mucocutaneous bleeding [nose, gingiva], menorrhagia, and increased bleeding with trauma or surgery).

There are three variants of von Willebrand's disease. Patients with the type 1 variant, the most common (80%), have a heterozygous quantitative deficiency of vWF (20% to 40% of normal) associated with diminished factor VIII levels. Type 1 patients frequently present with menorrhagia or mild to moderate bleeding from mucocutaneous sites. Medications that affect platelet function (e.g., NSAIDs) can cause hemorrhage in a previously asymptomatic patient with type 1 von Willebrand's disease. Type 2 von Willebrand's disease (17%) is characterized by the production of qualitatively abnormal vWF. Some of these patients have an associated thrombocytopenia, whereas others have a factor VIII deficiency that is out of proportion to the level of vWF. Type 3 von Willebrand's disease (3%) is marked by profound deficiencies of vWF and factor VIII. Homozygous patients may experience severe bleeding and spontaneous hemarthrosis. Because vWF levels are higher at birth and the proportion of the most functional high-molecular-weight multimeric units is increased, the incidence of bleeding in newborns is very low. When newborns with von Willebrand's disease bleed, it is the result of concomitantly low factor VIII levels. Acquired von Willebrand's disease has been associated with Wilms—tumor, systemic lupus erythematosus, congenital heart defects, and hemoglobin E-Thalassemia ( Jakway, 1992 ).

The laboratory diagnosis of von Willebrand's disease is based on a prolonged bleeding time and on decreased levels of vWF antigen and factor VIII in the face of normal PT, fibrinogen, and platelet count. The aPTT may be normal or mildly prolonged. Ristocetin cofactor assay, which measures vWF induced platelet agglutination, is used to identify type 2 von Willebrand's disease. It is recommended that screening be performed on three separate occasions before ruling out von Willebrand's disease because functional and antigenic vWF levels may overlap that of normal patients and vWF levels can fluctuate in unpredictable ways. The vWF levels rise during pregnancy. There is a significant linkage between ABO locus and the vWF antigen, such that patients with A and B blood types have marked higher levels (100% to 115%) of factor than those with type O (75%) ( Souto et al., 2000 ).

Preoperative Preparation

Most patients with type 1 disease respond to the intravenous administration of 0.3 mcg/kg of DDAVP 30 minutes before surgery. DDAVP induces the release of vWF from endothelial storage granules (Weibel-Palade bodies) into the circulation ( Mannucci, 1997 ) and results in a twofold to threefold increase in plasma von Willebrand antigen levels within 30 to 60 minutes, with the effect lasting more than 6 hours ( Mannucci, 1997 ). DDAVP may be administered two to three times each day, although tachyphylaxis may develop ( Mannucci et al., 1992 ). Because 10% of patients with type 1 von Willebrand's disease fail to respond to DDAVP ( Nolan et al., 2000 ), the response (increased factor VIII levels and normalization of bleeding time) should be documented before surgery to make sure it is adequate to prevent excessive perioperative bleeding. If it is effective, it may be used as the sole agent for the treatment of minor bleeding (e.g., epistaxis) or perioperatively for minor surgery, such as dental extraction.

Patients with type 2 and type 3 diseases usually require replacement of factor VIII and vWF to control bleeding. DDAVP is contraindicated in type 2b disease because it may exacerbate thrombocytopenia. Those who do respond to DDAVP may also need factor replacement before major surgical procedures or for major trauma. Plasma-derived, human factor VIII concentrate, which has a high concentration of vWF (Humate-P), is effective and is approved for replacement therapy in von Willebrand's disease ( Federici et al., 2002 ).

If the patient's response to DDAVP is adequate and bleeding is not a problem, liberal DDAVP administration may be substituted for factor concentrate in the postoperative period. Close monitoring of bleeding and communication with the hematologist should guide postoperative management of these patients.

Factor XIII Deficiency

The role of factor XIII in hemostasis is in stabilizing newly formed clot by cross-linking fibrin monomers. Plasma levels as low as 1% to 2% are usually adequate for hemostasis. Patients with factor XIII deficiency have bleeding despite a normal PT, aPTT, and platelet count. Factor XIII deficiency is a rare bleeding disorder that is inherited in an autosomal recessive manner and has an estimated incidence of 1 in 2 million ( Board et al., 1993 ). Typical symptoms are delayed hemorrhages after mild trauma. The most common manifestation is prolonged bleeding from the newborn's umbilical stump, which is virtually pathognomonic for this deficiency, or after circumcision. The major morbidity in factor XIII deficient children is a marked propensity for intracranial hemorrhages, up to 30% in some series (Anwar and Miloszewski, 1999 ). Seriously affected patients are treated with cryoprecipitate or purified factor concentrate. All traumatic brain or closed-head injuries are treated prophylactically.

Factor VII Deficiency

Factor VII has the shortest half-life of all the clotting factors, estimated to be 6 hours. Factor VII deficiency is a rare autosomal recessive disorder. The severity of the hemorrhagic diathesis does not correlate with factor VII levels. Many individuals have mutations of factor VII but are asymptomatic, and they come to medical attention as a result of an isolated PT prolongation. Much more common than an inherited factor VII deficiency is an acquired factor VII deficiency. Because the exquisitely short half-life of factor VII, liver failure, vitamin K deprivation, or oral anticoagulant toxicity first manifests as factor VII deficiency with an isolated increased PT value.

Platelet Abnormalities

Congenital Coagulopathies due to Platelet Abnormalities

Inherited coagulopathies include diseases associated with quantitative and qualitative platelet dysfunction. Wiskott-Aldrich syndrome is an X-linked disorder characterized by thrombocytopenia, immunodeficiency, and eczema. Newborns typically present with thrombocytopenia, due to underproduction. These platelets are abnormally small. The disease results from the mutation of the Wiskott-Aldrich syndrome Protein (WASP), a cytoskeletal regulatory protein found in megakaryocytes and lymphocytes ( Caron, 2002 ). Symptomatic bleeding is treated with platelet transfusions. Congenital bone marrow failure syndromes that result in congential thrombocytopenia include Diamond Blackfan syndrome anemia, Schwachman Diamond syndrome, and Fanconi anemia. These infants present with severe mucocutaneous bleeding or intracranial hemorrhage as a result of profound thrombocytopenia. These patients depend on platelet transfusions. Thrombocytopenia with absent radii (TAR) is another cause of neonatal thrombocytopenia that is associated with skeletal anomalies. The thrombocytopenia is most pronounced in the first year of life, when mucocutaneous bleeding commonly occurs, and platelet transfusions are required.

Thrombocytopenia of Immune Origin

Immune-mediated thrombocytopenias occur in the setting of isoimmunization, with transplacental transfer of maternal alloantibodies directed against paternally inherited antigens present on fetal platelets, or of maternal autoimmune diseases such as idiopathic thrombocytopenic purpura (ITP) and systemic lupus erythematosus (SLE). Thrombocytopenia is most severe in isoimmune disease. Isoimmune thrombocytopenia occurs in 1 of 1000 deliveries. The distinguishing characteristic is the maternal platelet count, which is normal in isoimmune disease and decreased in autoimmune disease. Infants are usually asymptomatic unless the platelet count is less than 10,000. Mucocutaneous, spinal cord, and intracranial hemorrhages are seen prenatally and postnatally in isoimmune disease ( Blanchette, 1988 ;Abel et al., 2003 ). The bleeding in autoimmune thrombocytopenia is usually not as severe, but the risk of intracranial hemorrhage increases when the platelet count is less than 40,000 in the newborn. Both diseases are treated with platelet transfusions, intravenous gamma globulin, and corticosteroids. The established treatment of alloimmune neonatal thrombocytopenia is the administration of washed, irradiated maternal platelets (10 mL/kg) ( Rothenberger, 2002 ), but donor platelets screened for the absence of human platelet antigen 1a (HPA-1a) have been shown to be effective ( Rayment et al., 2003 ).


Inherited qualitative platelet defects are uncommon conditions. They present with bleeding in the newborn period as well. Glanzmann thrombasthenia is an autosomal recessive deficiency of GPIIb/IIIa, impairing fibrinogen binding on platelets. Patients present with mucocutaneous bleeding in the neonatal period and have a life-long risk of bleeding. Platelet count and morphology are normal, but bleeding time, clot retraction, and platelet aggregation tests are all abnormal, and flow cytometry is required to confirm the GPIIb/IIIa deficiency. Bleeding is managed with platelet transfusions. Bernard Soulier syndrome is an autosomal recessive deficiency of the platelet vWF receptor. These patients have mild to moderate bleeding and have unusually large platelets. The diagnosis is confirmed by failure of agglutination in the presence of ristocetin.

Bleeding Diathesis Associated with Blood Vessel Abnormalities

Hereditary blood vessel disorders associated with a bleeding diathesis include uncommon connective tissue diseases such as Ehlers-Danlos and Marfan syndromes.


Vitamin K Deficiency

Hemorrhagic disease of the newborn is a bleeding disorder that is caused by a deficiency of vitamin K. Clinical bleeding occurs in 1 in 1000 to 1 in 10,000 babies who do not receive vitamin K supplementation. Vitamin K is poorly transferred across the placenta and is present in very low concentration in breast milk. Hemorrhagic disease of the newborn can be temporally divided into three types: early, classic, and late-onset. Bleeding within the first 24 hours of life is defined as early disease and is generally seen in infants born to mothers receiving oral anticoagulants or antiepileptic drugs. These infants often have serious bleeding, including intracranial hemorrhage. Bleeding within the first week of life is classic disease and usually involves cutaneous, gastrointestinal, or circumcision bleeding in infants who did not receive vitamin K supplementation at birth and who are usually breast-fed. Bleeding in the first 3 months of life is referred to as late-onset disease, and it is seen in exclusively breast-fed infants and in infants with disorders of fat absorption such as CF, biliary atresia, and celiac disease ( Lane and Hathaway, 1985 ; Sutor et al., 1999 ). The diagnosis is confirmed with a prolonged PT, increased levels of proteins produced in the absence of vitamin K, and a low vitamin K level. Administration of vitamin K subcutaneously or intravenously increases coagulation factors within 2 hours, with complete correction within 24 hours. Serious bleeding may be treated with FFP (10 to 20 mL/kg) or with a purified factor IX product.

Hepatic Dysfunction-Related Coagulopathy

Liver disease resulting in synthetic dysfunction has a major impact on hemostasis, because many of the coagulation factors are synthesized in the liver. Levels of these proteins are the first to decline with worsening liver disease, especially the very short-lived factor VII. Measurement of factor V, a hepatically synthesized, non-vitamin K-dependent protein, which is present in similar amounts in the newborn and the adult, is useful in differentiating vitamin K deficiency from hepatic dysfunction. Fibrin degradation products are increased as a result of their decreased clearance in the setting of hepatic dysfunction. The development of ascites results in further loss of coagulation proteins.

Perioperative management of these patients includes determination of the patient's exact deficiencies and correcting them with targeted management. Prolongation of the PT, resulting from depletion of vitamin K-dependent factors, can be treated with vitamin K or FFP. Vitamin K should normalize the PT in 6 to 8 hours. Hypofibrinogenemia should be treated with cryoprecipitate. Recombinant FVIIa has been successfully used to correct the coagulopathy associated with liver failure ( Bernstein et al., 1997 ). FVIIa has been used in very small numbers of patients to decrease transfusion requirements during liver transplantation, despite the fact that bleeding in that setting is multifactorial in nature ( Kalicinski et al., 1999 ; Hendriks et al., 2001 ).

Anticoagulant-Related Coagulopathy

Patients receiving therapeutic anticoagulation are at risk for devastating hemorrhagic complications. They have a 1% incidence of intracranial hemorrhage, either intracerebral or subdural, both associated with very high morbidity and mortality rates ( Wintzen et al., 1984 ). If surgery is contemplated or when procedural heparinization must be reversed, anticoagulation is reversed with protamine administered intravenously over 10 minutes. The dosage of protamine is based on the interval since the last dose of heparin, and it can be calculated using the following formula:

Low-molecular-weight heparin anticoagulation is also reversed with protamine, in a dose of 1 mg of protamine per 1 mg (100 Units) of low-molecular-weight heparin administered within the previous 3 to 4 hours ( Monagle et al., 2001 ). Protamine is given slowly, as rapid administration may cause profound hypotension.

Children receiving oral anticoagulation may be difficult to maintain in a therapeutic range because of variations in diet, concurrent medications, and underlying disease processes. Breast-fed infants are very sensitive to oral anticoagulants because of low concentrations of vitamin K in breast milk. Many of the common medications that are prescribed for children, including prednisone, amoxicillin, trimethoprim-sulfamethoxazole, and ranitidine, increase the INR of children on oral anticoagulants ( Michelson et al., 1995 ).

Acquired Thrombocytopathy

Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) are the most commonly used medications that affect the coagulation system. These medications inhibit platelet COX, blocking thromboxane synthesis and leading to a partial impairment of platelet function ( Clarke et al., 1991 ). Aspirin ingestion prolongs the bleeding time by 2 to 3 minutes. Two COX isoenzymes have been characterized: COX-1, which is always present on platelets and the gastric mucosa, and COX-2, which is upregulated during inflammation ( Cryer and Feldman, 1998 ). Nonspecific COX inhibitors increase perioperative bleeding complications after adenoidectomy. Preoperative administration of NSAIDs, such as ketorolac, increased blood loss by 70% to 80% in children undergoing tonsillectomy. In a meta-analysis of seven studies comprising 262 patients who received NSAIDs after tonsillectomy and 243 control patients, postoperative administration of NSAIDs resulted in a doubling of the number of children experiencing postoperative bleeding and a fivefold increase in reoperation for bleeding ( Marret et al., 2003 ).

Many anesthetic agents have been implicated in platelet dysfunction, as measured by platelet aggregometry; among them are inhaled anesthetics, such as propofol and ketamine ( Nakagawa et al., 2002 ). However, there are no data that demonstrate that these agents increase perioperative bleeding or transfusion requirements in the clinical setting ( Faraday, 2002 ).

Another class of drugs that may interfere with platelet function is the anticonvulsants, such as sodium valproate. Valproate has caused mild thrombocytopenia, neutropenia, and even red cell aplasia, and patients taking valproate should be evaluated before surgery with a complete blood count with platelet count. Bone marrow suppression usually occurs with levels higher than 100 mcg/mL and usually responds to a decrease in dose ( Acharya and Bussel, 2000 ). Bleeding time may be prolonged in patients taking valproic acid, but usually not to a clinically significant extent. Twenty percent of a small series of patients taking valproic acid were shown to have acquired von Willebrand's disease, with low ristocetin cofactor activity, although only two of six affected children were symptomatic (epistaxis) (Serdaroglu et al., 2002 ). One case report documented severe factor XIII deficiency resulting in severe intracranial bleeding after craniotomy for epilepsy surgery ( Pohlmann-Eden et al., 2003 ). This deficiency was reversible with cessation of valproic acid therapy. An extensive evaluation of the procoagulant and anticoagulant effects of valproate showed that the procoagulant effects might balance the anticoagulant effects and thereby reduce the risk of bleeding ( Banerjea et al., 2002 ). The blood loss during and after spinal surgery was evaluated in a small series of children with cerebral palsy, some of whom were taking valproic acid ( Chambers et al., 1999 ). There was a 30% increase in mean blood loss in the children taking valproic acid (38.6 versus 30 mL/kg), and increased postoperative blood product administration. These children also had a greater likelihood of having longer bleeding times. Therefore, the anesthesiologist should have a heightened awareness of the possibility of excessive surgical bleeding, especially during and after craniotomy, in patients taking valproic acid. Routinely performing a bleeding time in all children taking valproic acid is likely to have an extremely low yield and bleeding times are more difficult to perform, especially in young children. Nevertheless, some hematologists recommend a bleeding time for children scheduled for craniotomy, with further investigation including vWF and ristocetin cofactor and possible preoperative administration of DDAVP if indicated ( Acharya and Bussel, 2000 ).

Other Acquired Coagulopathies

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is the unregulated activation of the hemostatic system characterized by generation of activated clotting factors, fibrin, and accelerated fibrinolysis. Conditions associated with DIC are listed in Box 32-12 . Patients can present with bleeding, thrombosis, or only laboratory evidence of DIC. DIC is the result of the significant exposure of circulating blood to TF, commonly from endothelial disruption or from hypoxia, acidosis, and sepsis.

BOX 32-12 

Conditions Associated with Disseminated Intravascular Coagulation









Heat stroke












Head injury



Fat embolism



Crush injury



Burn injury



Toxin exposure†



Severe allergic reaction



Intravascular hemolysis



Liver disease






Myeloproliferative disease



Vascular anomalies



Kasabach-Merritt syndrome



Extracorporeal circulation



Obstetric complications



Amniotic fluid embolism



Placental abruption




*Antenatal hypoxia ( Hannam et al., 2003 ).

†Snake bite ( Gold et al., 2003 ).

No single laboratory test can establish or exclude the diagnosis of DIC. The most common laboratory abnormalities include thrombocytopenia or a rapidly falling platelet count and elevated D-dimer levels. Less commonly, microangiopathic hemolytic anemia, hypofibrinogenemia, PT and aPTT prolongation are seen ( Bick and Baker, 1986 ). D-dimers may be present in premature infants without DIC. Antithrombin III levels can be markedly depressed as well. The treatment of DIC is principally focused on eradicating the precipitating process; treating the consequences without treating the underlying cause is certain to fail. There is no evidence that prophylactic administration of platelets or plasma will improve the outcome of a nonbleeding patient. FFP, cryoprecipitate, and platelet transfusions are used only to treat bleeding symptoms in the older child. In the neonatal period, however, because of the risk of intracerebral hemorrhage, many aim to correct a platelet count of less than 50,000, fibrinogen level of less than 100 mg/dL, and an INR of more than 1.5. Sequential thromboelastograms (TEGs) are useful in monitoring the correction of DIC in the perioperative period ( Stammers et al., 2000 ). Activated protein C (i.e., drotrecogin alfa), a specific inhibitor of the TF/factor VIIa/factor Xa complex, is in clinical trials for the treatment of DIC ( Levi and ten Cate, 1999 ).

Acquired Hemophilia

Antibodies to coagulation factors develop in hemophiliacs treated with factor replacement and in nonhemophiliacs who have no prior exposure to hemostatic therapy. These acquired inhibitors to coagulation factors occur most commonly against factor VIII. Although many patients with acquired hemophilia are elderly, children can be affected in a devastating manner ( Stein and Ratnoff, 1993 ). Patients who develop inhibitors commonly have coexisting diseases, such as lupus or rheumatoid arthritis, or they have been recently treated for rheumatic fever ( Moraca and Ragni, 2002 ). Transplacental transfer of acquired inhibitors has been reported, resulting in hemorrhagic complications in the newborn period ( Ries et al., 1995 ). Patients with acquired inhibitors most frequently have bleeding into fascial planes and mucous membranes, rather than joints. The diagnosis is elusive due to inconsistent test results. There is no correlation between inhibitor titers and the severity or pattern of bleeding ( Yee et al., 2000 ).

In patients with inhibitors, even large amounts of cryoprecipitate or FFP may not promote satisfactory hemostasis. FFP administration leads to an anamnestic response. Factor VIII autoantibodies in acquired hemophilia are usually incompletely inhibitory so that factor VIII levels are usually detectable and may be as high as 10% to 20% of normal values. DDAVP is effective in many cases of inhibitor-associated hemorrhage ( Mudad and Kane, 1993 ). Porcine factor VIII is a viable therapeutic alternative in acquired hemophilia patients, because most autoantibodies are usually species specific, and therefore these patients have low or undetectable titers of anti-porcine factor VIII (Kobrinksy et al., 2002). Treatment is initiated with a dose of 50 to 100 IU/kg and titrated to maintain therapeutic levels. The development of neutralizing antibodies to the porcine factor takes 7 to 10 days to develop. Rarely, transfusion reactions and thrombocytopenia can develop. There are no reports of the transmission of a porcine virus to a human recipient ( Rubinger et al., 1997 ). Another therapeutic alternative is one of the commercially available activated prothrombin complex concentrates that, by bypassing factor VIII, stimulate fibrin clot formation in the presence of factor inhibitors. These agents are effective hemostatic agents in most bleeding patients with inhibitors ( Negrier et al., 1997 ). The risk of adverse effects such as thrombotic complications and disseminated intravascular coagulation are small but are increased in the settings of patients with extensive crush injuries, marked hepatic dysfunction, or with prolonged administration ( Teitel, 1999 ).

Recombinant Factor VIIa

In the presence of inhibitory antibodies, recombinant factor VIIa administered at a starting dose of 90 mcg/kg is effective at normalizing bleeding in more than 90% of surgical procedures, and in achieving adequate hemostasis in 78% of patients with life- or limb-threatening bleeding ( Scharrer, 1999 ; Arkin et al., 2000 ). The clinical response did not correlate with the degree of decrease of the PT after the recombinant factor VIIa infusion ( Hay et al., 1997 ). Immunomodulation therapy should be instituted concomitantly with hemostatic therapy. As there is no consensus on the optimal regimen, many have used multiple agents of demonstrable efficacy, such as intravenous immune globulin, corticosteroids and alkylating agents to reduce inhibitor levels.


Patients with no preoperative disorders of coagulation who have surgery may develop coagulopathy due to a combination of blood loss, fluid replacement, and other intraoperative circumstances. Conditions associated with the development of intraoperative coagulopathy are listed in Box 32-13 .

BOX 32-13 

Conditions Associated with Development of Intraoperative Coagulopathy



Neurologic conditions



Intracranial surgery



Traumatic brain injury



Cardiovascular conditions



Congenital heart disease






Kasabach-Merritt syndrome






Orthopedic conditions



Fat embolism



Scoliosis surgery



Osteogenesis imperfecta



Intramedullary nailing of long bone fractures



Miscellaneous conditions



Citrate-induced hypocalcemia



Factor V inhibition from exposure to bovine topical thrombin

Data from Iberrti et al., 1994 ; Hymel et al., 1997 ; Byrick RJ, 2001; Robinson et al., 2001 ; Vavilala et al., 2001 ; Keegan et al., 2002 ; Murshid et al., 2002; Neschis et al., 2002 .


Colloid-Induced von Willebrand's Syndrome

The administration of some synthetic colloids as volume expanders may be associated with the development of acquired von Willebrand's disease. Large amounts of dextran decrease vWF and factor VIII levels and enhance fibrinolysis ( Batlle et al., 1985 ). The increase in bleeding times after dextran infusion can be completely normalized by the administration of DDAVP. Dextran's anticoagulant properties have been used to prevent postoperative thromboembolic complications ( Clagett et al., 1998 ). Patients receiving dextran intraoperatively required more blood transfusions than did those receiving heparin prophylaxis ( De Jonge and Levi, 2001 ). Dextran also changes the structure of the thrombus formation and increases the clot's susceptibility to fibrinolysis.

High-molecular-weight hydroxyethyl starch (HES) is the only starch approved for use in the United States for plasma expansion, and is associated with decreases in plasma vWF and factor VIII levels, as well as increases in fibrinolysis and platelet dysfunction ( Egli et al., 1997 ). The aPTT is prolonged, the bleeding time is increased, and TEGs demonstrate prolonged clot formation and increased clot lysis (Mortier et al., 1997 ). Changing the molecular weight of the starch and modifying its in vivo degradation rate do not seem to decrease the risk of development of an induced von Willebrand syndrome ( De Jonge et al., 2001 ). Smaller volumes of HES seem to cause less hemostatic perturbation ( Treib et al., 1996 ).

Children are rarely given HES. They more commonly receive human serum albumin for volume expansion. Human serum albumin administration causes minimal changes in plasma factor VIII and vWF levels. However, albumin does prolong the bleeding time based on impairment of platelet aggregation ( Kim et al., 1999 ). In adult studies, when albumin is compared with dextran and high-molecular-weight HES, it is associated with less postoperative blood loss. Preliminary studies with middle-molecular-weight HES and albumin suggest that there is a minimal difference in postoperative blood loss. In patients with even mild forms of von Willebrand's disease, the administration of artificial colloid in patients can be associated with significant hemorrhagic complications; albumin or crystalloid should be used preferentially ( De Jonge and Levi, 2001 ).


There is substantial data that suggest that hypothermia is an independent and dramatic contributor to coagulopathy. Mild hypothermia of 35°C significantly prolongs the PT, aPTT, and bleeding time ( Valeri et al., 1987 ). A decrease of 1.6°C in a randomized study of normothermia compared with mild hypothermia in hip procedures resulted in a 30% increase in blood loss and transfusion requirements (Schmied et al., 1996 ). At a core temperature of 34°C, coagulation and platelet function are severely altered, despite normal fibrinolytic function ( Watts et al., 1998 ). The degree of hypothermia during cardiopulmonary bypass in infants undergoing correction of congenital heart disease has a high correlation with blood loss and transfusion requirements ( Williams et al., 1999a ). The transfusion of platelets and clotting factors does not correct the hypothermic coagulopathy completely in the absence of rewarming.

Both components of the hemostatic mechanism appear to be deleteriously affected by hypothermia. Platelet function is seriously impaired by mild hypothermia, due to a reduction in thromboxane A2 release ( Michelson et al., 1994 ). The clotting cascade involves a series of enzymatic reactions, all of which are slowed by hypothermia. The laboratory detection of hypothermic coagulopathy is often missed because most laboratories perform clotting tests at 37°C ( Eddy et al., 2000 ). The PT and aPTT performed at the patient's actual core temperature will be prolonged ( Rohrer and Natale, 1992 ). Some studies suggest that fibrinolysis is accelerated during hypothermia ( Yoshihara, 1985 ); TEG data suggest that hypothermia impairs clot formation rather than enhancing fibrinolysis ( Kettner et al., 1998 ). Thromboelastography can be adjusted to a patient's core body temperature to adequately evaluate the contribution hypothermia plays in a hypothermic coagulopathy.


Acute normovolemic hemodilution to minimize red cell transfusion requirements often results in alterations of hemostasis. Quantitative modeling of acute normovolemic hemodilution demonstrates that patients often attain inadequate fibrinogen levels (<100 mg/dL) before they would reach the hematocrit threshold for red cell transfusion, or the threshold for platelet transfusions ( Singbartl et al., 2003 ).

Massive Transfusion

Massive blood loss is defined as the loss of over one blood volume in a 24-hour period, the normal blood volume being 7% of ideal body weight in an adult and 8% to 9% in an infant. In the operating room, early recognition of major blood loss can be appreciated using the definitions of massive blood loss as occurring at the rate of 2 to 3 mL/kg per minute or 50% of blood volume in a 3-hour period ( Fakhry and Sheldon, 1994 ).

The progression from dilutional coagulopathy to dilutional thrombocytopenia is seen in massive transfusion and in extreme hemodilution. During the era of whole blood administration, thrombocytopenia was the initial coagulopathic event ( Counts et al., 1979 ). Currently, blood loss is most often replaced with plasma-poor RBC products, which are devoid of most coagulation factors. Under these conditions, dilution of coagulation factors is the initial coagulopathic event (marked by prolongation of the PT), and hypofibrinogenemia is the first factor deficiency that occurs, even while the platelet count is greater than 150,000/μL ( Hiippala et al., 1995 ; Murray et al., 1995 ). The PT becomes prolonged when less than one blood volume is lost, but a clinical coagulopathy does not occur until the PT and PTT exceed 1.5 to 1.8 times the control values ( Cote, 1991 ; Hirshberg et al., 2003 ). Fibrinogen concentrations fall below the hemostatically critical level of 100 mg/dL when blood loss is in excess of 150% of the patient's blood volume, and the remaining coagulation factors fall below 25%, after 200% blood loss. A platelet count of less than 50,000 should be anticipated when more than two blood volumes have been lost ( Hiippala et al., 1995 ; Stainsby et al., 2000 ).

Because patients with severe traumatic injury often lose almost 70% of their blood volume before transfusion therapy and operative intervention, FFP administration should be given early to patients with exsanguinating injuries ( Hirshberg et al., 2003 ). Simple dilution is the cause of these early coagulation abnormalities observed in patients with massive blood loss. Consumption, as a result of TF elaboration or excessive fibrinolysis, with production of fibrin degradation products, prolonged shock, or acidosis results in hemostatic failure at a much lower volume loss ( Drummond and Petrovich, 2001).

Treatment should be anticipated when blood loss approaches 150% of blood volume. In this setting, if rapid laboratory corroboration is possible, a complete coagulation profile should be obtained to determine the patient's specific replacement needs. In the absence of timely data or with continuing hemorrhage, empirical therapy with FFP is justified. FFP at a dose of 20 mL/kg will increase fibrinogen by about 60 mg/dL and increase clotting factors by 20%.

Traumatic Coagulopathy Independent of Blood Loss or Replacement

Traumatic coagulopathy manifests as a hypocoagulable state associated with hypothermia, acidosis, clotting factor dilution, and tissue destruction, which is directly proportional to the severity of the traumatic injury ( Kaufmann, 1997 ). Four risk factors have been identified as increasing the likelihood of the development of traumatic coagulopathy: pH less than 7.10, temperature less than 34°C, systolic blood pressure less than 70 mm Hg, and an injury severity score higher than 25 ( Cosgriff et al., 1997 ). Extensive tissue destruction releases tissue thromboplastins, which activate the clotting process and result in a consumptive coagulopathy. TPA and PAI-1 are released from the extensively damaged tissue bed. In the first few hours after traumatic injury, TPA increases out of proportion to PAI-1 and produces a systemic activation of fibrinolysis ( Enderson et al., 1991 ). This coagulopathy resembles that of DIC, but the diffuse microthrombi that are classically seen in DIC are not seen in traumatic coagulopathy.

The aggressive fluid management required by these patients produces a concomitant dilutional coagulopathy as well. Vigorous fluid resuscitation can result in a confluence of circumstances that in and of itself contributes to the traumatic coagulopathy. By increasing intravascular volume, blood pressure, and vasodilation, hemorrhage is further potentiated. These hemodynamic and rheologic perturbations increase the likelihood that hemostatic plug formation will not occur, and that blood will continue to leak around and through the hemostatic plug ( Riddez et al., 1998 ; Orlinsky et al., 2001 ).

Traumatic coagulopathy is diagnosed clinically by pathologic oozing from tissue. Early ACT values can be used to predict which traumatically injured patients are at risk for developing traumatic coagulopathy. However, because the ACT test is performed at 37°C, the contribution of hypothermia to the development of this coagulopathy will be underappreciated ( Aucar et al., 2003 ).

Intraoperative Evaluation of the Bleeding Patient

Activated clotting time (ACT) is a modification of a whole blood clotting test that uses kaolin or celite to accelerate coagulation by activating the contact pathway ( Box 32-14 ). A fixed volume of blood is placed into a tube with activator at 37°C for 60 seconds, after which the contents are stirred until a clot is formed. The normal ACT range is 80 to 120 seconds. This test can be performed easily at the bedside using commercially available equipment. ACT levels correlate well with anti-factor Xa heparin levels in the pre-cardiopulmonary bypass period, and are commonly used to monitor the adequacy of heparin anticoagulation levels during extracorporeal circulation ( Despotis et al., 1999 ). The relationship of ACT with heparin dosing is linear in the setting of normal antithrombin III concentrations and factor XII activity, normothermia, a platelet count of more than 50,000, intact platelet function, and a fibrinogen level greater than 100 mg/mL ( Spiess, 1998 ). However, in the absence of extracorporeal circulation, ACT has a much poorer correlation with plasma heparin concentrations than does the aPTT ( Koerber et al., 1999 ). ACT is insensitive to many coagulation abnormalities, such that clotting deficiencies and platelet abnormalities can be present with a normal ACT ( Girardi et al., 2000 ). Nevertheless, in the setting of major trauma, intraoperative ACT measurements were able to discriminate between patients who became coagulopathic and those who did not ( Aucar et al., 2003 ). ACT levels do not correlate well with low-molecular-weight heparin anti-Xa levels ( Henry et al., 2001 ).

BOX 32-14 

Evaluation of the Bleeding Child

Platelet Assessments



Abnormal number: thrombocytopenias, hemangiomas



Abnormal morphology: inherited platelet defects



Abnormal function: inherited or acquired

Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) Assessments



Abnormal PT, normal aPTT



Factor VII deficiency



Vitamin K deficiency, liver disease



Factor deficiencies: II, V, VII, X



Drug related: Coumadin



Normal PT, abnormal aPTT



Factor deficiencies: VIII, IX, XI, XII, kallikrein, prekallikrein, high-molecular-weight kininogen, von Willebrand's disease



Drug related: heparin



Abnormal PT, abnormal aPTT



Vitamin K deficiency, liver disease



Factor deficiencies: II, V, X






Drug related: heparin and Coumadin



Abnormal PT, abnormal aPTT, thrombocytopenia



Disseminated intravascular coagulation



Liver disease






Normal PT, normal aPTT, normal platelets



Factor XIII deficiency



α2-Antiplasmin deficiency

Thrombin Time*






Liver disease, vitamin K deficiency



Factor deficiencies: II, V, and X



Drug related: Coumadin






Liver disease



Disseminated intravascular coagulation






Drug related: heparin

*Useful in cases of abnormal PT and abnormal aPTT.

The thromboelastograph is a point-of-care evaluation of a patient's hemostatic balance, from initial clot formation to clot retraction or dissolution. Coagulation of blood has been compared with building a house: TEG profiling does not end when the foundation stone is laid, as do the other clinically employed clotting studies. The TEG also reflects the speed of the building process, whether the building will be sturdy, and whether it is likely to be damaged soon after it is built. Initially described in 1948, the TEG examines the elastic properties of blood as it clots. Placed into a rotating cup with an immersed pin, liquid blood begins to clot by forming fibers between the cup and the pin, transmitting motion to the pin. The TEG measures the elastic shear modulus of the clot, providing information about the rate of clot formation, clot strength, platelet function, and fibrinolytic activity, reflected in the characteristics of the tracing produced ( Samana, 2001 ; Srinivasa et al., 2001 ). The maximal elastic sheer modulus depends on platelet count, function, and the amount of fibrin deposited on the pin. The TEG is a global measure of hemostasis, useful when there are multiple hemostatic defects. The weakness of TEG is its inability to identify specific clotting abnormalities. The TEG is a sensitive indicator of hypocoagulable and hypercoagulable perturbations. The typical hypercoagulable TEG profile has the appearance of a cognac glass ( Fig. 32-14 ) ( Traverso et al., 1995 ).


FIGURE 32-14  Parameters of the thromboelastograph.



The TEG parameters are illustrated in Figure 32-15 :



R (i.e., reaction time): latency to initial clot formation; from onset of the tracing until a 2-mm amplitude on the tracing. This is similar to whole blood clotting time; it depends on an intact intrinsic pathway and an adequate generation of thrombin.



Prolonged: clotting deficiencies, heparin, thrombocytopenia



Correlated: aPTT



K (i.e., coagulation rate): rate of fibrin buildup and cross-linking, occurring from 2 to 20 mm



Prolonged: clotting deficiencies, platelet dysfunction, thrombocytopenia, hypofibrinogenemia



α angle: rate of increase in elastic shear modulus; the rate of fibrin buildup and cross-linking; slope of divergence of tracing from R



MA: maximal elastic shear modulus. Measured at maximal divergence of the graph, after the clot is entirely formed,this is the maximal clot strength. A typical clot has an MA of 50 mm, which is equivalent to 5000 dynes/cm2. MA is the best description of the competency of the clot. MA depends on platelet count and function and on the fibrinogen level, as defined by the equation (Chandler, 1995 ):



Decreased: thrombocytopenia, platelet dysfunction hypofibrinogenemia, deficiencies of factor VIII and factor XIII



Increased: prothrombotic state



A30, A60: represents the percentage of fibrinolysis or clot retraction at 30 and 60 minutes; percent relative to MA


FIGURE 32-15  Thromboelastographic tracings of common hemostatic abnormalities. 1, normal; 2, hemophilia; 3, thrombocytopenia; 4, fibrinolysis; 5, hypercoagulation.



A typical tracing and the parameters of the TEG are illustrated in Figure 32-14 . Figure 32-15 shows the tracings seen on the TEG for common disorders of hemostasis.

The R of patients receiving Coumadin increases with INR, but it may remain within a normal range ( Hepner et al., 2002 ). Patients with decreased clotting factors have decreased R and K values and a prolonged PT, or they have a decreased angle and a prolonged aPTT. Hypofibrinogenemia is associated with decreased R and K times, decreased angle, and decreased MA. Hyperfibrinolysis is characterized by reduced amplitude at 30 and 60 minutes.

The conditions under which a TEG is performed can be optimized to best define the clinical scenario. A TEG can be performed at the patient's core temperature to identify hemostatic perturbations due to modulation of body temperature. Additives have been employed to activate the coagulation process for TEG analysis, which shortens the study and reduces sample variability ( Yamakage et al., 1998 ).

The TEG has been used in the pediatric population. Miller looked at the effects of age on TEG variables in children younger than 24 months of age undergoing elective noncardiac procedures. He found that all of the TEG variables in children less than 1 year of age were different from that of an adult control group. The rates of clot initiation and clot buildup, as well as clot strength, were all greater in the infant groups. Despite ontogenetic differences in clotting factor concentrations, the investigators concluded that the hemostatic mechanism of the infant is balanced. The coagulation indices were not reported in his original paper. Using the reported data, all children had a coagulation index of more than 2.0, suggesting a hypercoagulable state ( Miller et al., 1997 ). The trend toward a hypercoagulable state in children was confirmed in a celite-activated TEG study as well ( Pivalizza et al., 2001 ). TEG has also been used to document the intraoperative development of a hypercoagulable state in children undergoing craniotomy and resection of brain tissue ( Goobie et al., 2001 ).

Copyright © 2008 Elsevier Inc. All rights reserved. -

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

Copyright © 2005 Mosby, An Imprint of Elsevier



Complications of life-threatening blood-borne virus transmission have been markedly reduced by the institution of multiple screening steps in the procurement of donor-derived plasma products. However, the risks of transfusion-associated transmission of thermostable viruses, such as hepatitis A and parvovirus B19, remain. Reports of transfusion associated-transmission of West Nile virus highlight the continued risks of using the blood supply as the principle source for hemostatic agents. Two nucleic acid-based tests for West Nile virus are in clinical trials and appear to be effective in detecting virus in asymptomatic donors. The list of potential blood-borne pathogens is long and continues to grow, although not all blood-borne viruses have been demonstrated to be pathogenic to humans ( Quirolo, 2002 ). Unfortunately, these concerns are not completely alleviated by the use of recombinant factor concentrates. With the outbreak of new-variant Creutzfeldt-Jakob disease in the United Kingdom, there is concern that prion proteins may be contained in and transmitted by the human albumin used in the manufacture and formulation of some recombinant factors ( Ludlam, 1997 ). Recombinant factor IX is unique because no human or animal protein is used in its preparation or formulation ( White et al., 1998 ).


The ASA Task Force on Blood Component therapy recommended that the triggers for treatment of the patient who is at risk for bleeding be multiple and not depend on a single factor. Often, the critically ill child may require an emergent invasive procedure before a complete hemostatic profile has been determined. In these circumstances, bleeding from puncture sites or general oozing in the surgical field may necessitate empirical treatment with FFP ( American Society of Anesthesiologists, 1996 ). Generally accepted treatment triggers for component therapy are listed in Box 32-15 .

BOX 32-15 

Recommendations for Blood Component Therapy

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


Patients who are experiencing severe bleeding should receive FFP in a dose of 20 mL/kg until vitamin K administration increases endogenous synthesis. Factor IX levels may be low in FFP ( Makris et al., 1997 ). Infusion of factor IX complex concentrate, which contains high concentrations of the activated vitamin K-dependent factors (II, VII, IX, X) can correct anticoagulation rapidly without the excessive fluid volume exposure of FFP. Factor IX complex, at a dose of 40 IU/kg in addition to an FFP infusion successfully corrected the INR in patients with intracranial hemorrhage in one third of the time with 9% of total fluid volume administered as compared with FFP alone ( Boulis et al., 1999 ). Recombinant factor VIIa is also able to correct oral anticoagulant-induced coagulopathy.

DDAVP is an analog of vasopressin that recruits factor VIII from storage sites within endothelial cells and may raise baseline factor VIII levels by 2-fold to 20-fold in normal patients and patients with mild hemophilia ( Mannucci, 1997 ). This increase in factor level is often sufficient to prevent or limit minor bleeding. DDAVP also increases the release of high-molecular-weight vWF multimers from the endothelium. DDAVP is the treatment of choice for children with type 1 von Willebrand's disease, mild hemophilia, or platelet dysfunction, including uremia and drug-induced bleeding diatheses. In one study, preoperative administration of DDAVP was efficacious in controlling perioperative bleeding in more than 94% of children with von Willebrand's disease undergoing adenotonsillectomy. Complications of DDAVP included hyponatremia and seizure, which occurred in three patients and one patient, respectively ( Allen et al., 1999 ). DDAVP is also effective in treating hemorrhage in patients with acquired inhibitors to factor VIII or factor IX ( McFarland, 1999 ). DDAVP has also been reported to improve the bleeding diathesis in osteogenesis imperfecta, which is due to abnormal collagen-induced platelet aggregation dysfunction ( Keegan et al., 2002 ).

DDAVP has been employed in a variety of procedures associated with risk of large volume blood loss in an attempt to decrease perioperative blood loss and transfusion requirements. Despite early studies to suggest that DDAVP reduced blood loss in cardiac surgery patients, most studies suggest that DDAVP is not efficacious in uncomplicated cardiac surgery ( Hedderich et al., 1990 ). Children undergoing complex congenital heart repair did not have any reduction in bleeding or transfusion requirements with the prophylactic use of DDAVP ( Oliver et al., 2000 ). Similarly, DDAVP does not appear to reduce blood loss in spinal fusion for patients with idiopathic scoliosis or for those with cerebral palsy-associated neuromuscular scoliosis ( Theroux et al., 1997 ; Alanay et al., 1999 ).

A test dose of DDAVP should be given in patients with von Willebrand's disease to predict the hemostatic effect before relying solely on this drug for treatment. The response can be measured by shortening of the bleeding time and the aPTT. Side effects include facial flushing, transient headache, tachycardia, and mild, transient decreases in systolic blood pressure. A dose of 0.3 mcg/kg administered intravenously over 20 to 30 minutes or intranasally (150 mcg for children weighing less than 50 kg and 300 mcg for those weighing more than 50 kg) increases factor VIII levels by 62%, and this dose may be repeated every 8 to 12 hours to control bleeding. Peak effects occur within 30 to 60 minutes after intravenous infusion and 60 to 90 minutes after intranasal administration ( Lethagen et al., 1987 ). Tachyphylaxis may occur after three or four doses ( Mannucci et al., 1992 ). Because severe hyponatremia-associated seizures have been reported with the use of DDAVP, close observation of fluid status and electrolyte balance is mandated ( Sutor, 1998 ; Allen et al., 1999 ; Francis et al., 1999 ). Arterial thrombosis has occurred in some patients treated with DDAVP (Desmopressin and arterial thrombosis, 1989).


Factor VIII

One unit of factor VIII per kilogram will increase the plasma factor VIII concentration by 2%. The half-life of infused factor VIII is shorter in hemophiliac patients with blood group O than in those with blood group A in the presence of active bleeding or after recent surgery. The half-life is increased with age and plasma concentration of vWF ( Bjorkman et al., 1994 ; Vlot et al., 2000 ). The goal is a peak post infusion factor VIII level of about 0.3 to 1 U/mL (30% to 100% of normal), depending on the severity of bleeding. This can be achieved with the administration of 15 to 50 U/kg of factor VIII concentrate. For perioperative prophylaxis, plasma concentrations should be followed. Most mild bleeding episodes respond to a single dose of factor VIII, but additional follow-up treatments at 12 and 24 hours may be needed. For severe bleeding or after major surgery or trauma, therapeutic factor VIII concentrations with a nadir of more than 0.5 U/mL should be maintained for 5 to 14 days. A continuous infusion of factor VIII at a rate of 1 to 4 U/kg per hour or administered by intermittent injection (6 to 24 U/kg every 6 to 12 hours), guided by close monitoring of the aPTT, should maintain therapeutic levels.

Von Willebrand Factor Concentrate

Patients with von Willebrand's disease who are unresponsive to DDAVP administration have been treated in the past with multiple units of cryoprecipitate, resulting in exposure to a large number of allogeneic donors, each with a finite infectious risk. Virally inactivated, pooled factor VIII concentrates with a high vWF content have become available; Humate P is one of these products that has been approved for use in treating von Willebrand's disease. The ristocetin cofactor assay of Humate P, a measure of vWF activity, is twice that of its factor VIII content ( Bolan et al., 2001 ).

Factor IX

The biologic half-life of factor IX is 24 hours, which is twice that of factor VIII. For severe bleeding in hemophilia B patients, an initial dose of 75 to 100 U/kg of factor can achieve the desired plasma level of greater than 0.75 U/mL, after which a continuous infusion or intermittent injections may be given. The levels of factor achieved after administration of recombinant factor IX are often markedly lower than with equivalent dosages of plasma-derived factor IX, mandating that serum levels be followed ( Roth et al., 2001 ).


Two classes of antifibrinolytics have been employed to optimize hemostasis in the setting of a bleeding diathesis and to reduce blood loss and transfusion requirements during major procedures: the synthetic lysine analogs, e-aminocaproic acid (EACA) and tranexamic acid, and the serine protease inhibitor, aprotinin. Antifibrinolytic drugs are commonly employed when bleeding occurs in sites that are rich in plasminogen activator and other fibrinolytic enzymes, such as the endometrium, the gastrointestinal tract, and the urinary tract ( Mannucci, 1998 ).

EACA binds to the lysine site on plasminogen and plasmin preventing plasmin binding to fibrin. Fibrinolysis is inhibited and clot stabilization is allowed to continue. EACA has been shown to be effective in decreasing blood loss in children undergoing cardiac surgery ( Williams et al., 1999b ). Children undergoing posterior lumbar fusion who received 100 mg/kg of EACA followed by an infusion of 10 mg/kg per hour had less blood loss and required less red cell transfusions than did a randomized control group ( Florentino-Pineda et al., 2001 ).

Aprotinin is a naturally occurring serine protease inhibitor that affects hemostasis through several mechanisms; it is an antifibrinolytic, inhibits kallikrein, plasmin, trypsin, and inhibits activated protein C. Aprotinin inhibits the initiation of fibrinolysis and the contact phase of coagulation. Aprotinin has no effects on platelet function. Aprotinin is inactive when given orally. Aprotinin was first shown to be effective in reducing blood loss in coronary artery bypass graft operations ( Lemmer et al., 1996 ). Aprotinin has been shown to be effective in reducing perioperative bleeding and transfusion requirements in cardiac surgery, liver transplantation, hip replacements, and in posterior spine fusion ( Urban et al., 2001 ; Samama et al., 2002 ).

Mouth bleeding is common in hemophilia patients, resulting in part from the potent fibrinolytic activity of saliva. For oral or gastrointestinal bleeding in hemophiliacs, EACA is often very effective and may dramatically reduce the need for additional coagulation factor infusions when given at a dose of 100 mg/kg orally every 6 hours for 5 to 10 days after a hemorrhagic episode. Antifibrinolytic mouthwashes allow for the performance of dental extractions on patients receiving long-term oral anticoagulant treatment without lowering the degree of anticoagulation ( Sindet-Pedersen et al., 1989 ).

Recombinant Factor VIIa

Recombinant factor VIIa (rFVIIa) is a synthetic clotting factor that was originally developed for use in patients with hemophilia who have developed inhibitors to factor VIII or factor IX. The rationale behind the development and clinical success of rFVIIa underscores the new paradigm of cell-based hemostasis presented earlier. Hemophiliacs are unable to generate the platelet-localized factor Xa necessary for explosive thrombin production because of deficiencies in factor VIII or factor IX. Hedner and Kisiel (1983) demonstrated that plasma-derived factor VIIa was effective in hemophilia A. Factor VIIa complexes with TF exposed at areas of vascular injury, acting as a local catalyst for coagulation. In sufficient quantities, factor VIIa binds to activated platelets and restores platelet-surface thrombin generation ( Monroe et al., 1997 ). Augmented thrombin production increases platelet activation and thrombin-activatable fibrinolysis inhibitor (TAFI), which decreases fibrinolysis. The FVIIa/TF/Xa complex can overcome a deficiency of factor VIII or factor IX, the foundation for rFVIIa's sole evidence-based indication. For hemophiliacs with high inhibitor titers, rFVIIa has been effective in randomized, controlled trials in adults and children to prevent or minimize spontaneous bleeding and to decrease intraoperative blood loss, and it has been approved for use in patients with inhibitors ( Leach et al., 1999 ; O—Connell et al., 2002).

The successful use of rFVIIa in mitigating uncontrollable bleeding in nonhemophiliac pediatric patients in a variety of clinical situations has been reported in numerous anecdotal accounts ( Tobias et al., 2003a , 2003b). Because factor VII is the first of the clotting factors to become deficient in liver failure, rFVIIa has been used in the setting of hepatic dysfunction and vitamin K antagonism. The enhanced platelet activation that results from increased thrombin production has led to the use of rFVIIa in treating quantitative and qualitative platelet dysfunction (D—Oiron et al., 2000; Patel et al., 2001 ). In thrombocytopenia patients rFVIIa resulted in a reduction in bleeding time in 50% of patients. The clot formed with rFVIIa use has a denser mesh of fibrin fibers, which is more resistant to plasmin degradation ( Hedner, 1998 ). Recombinant factor VIIa has been used in the massively transfused patient whose coagulopathy has been recalcitrant to conventional plasma component therapy.

The use of rFVIIa has many advantages. It is completely synthetic, decreasing the risks of infectious complications. The drug can be quickly reconstituted from powder, eliminating the time needed for thawing and procurement of products from the blood bank, and it is dissolved in a small volume, minimizing excessive volume load, electrolyte perturbations, and the latency between institution of treatment and correction of the hemostatic defect.

Recombinant factor VIIa has limitations as well. The efficacy of rFVIIa depends on the presence of the other clotting factors. In the setting of the massive transfusion, factor VIIa is not the only clotting factor that is deficient. Most of the anecdotal reports about the use of rFVIIa in massive transfusion-associated bleeding are in the context of earlier administration of FFP. RFVIIa has a short half-life, necessitating frequent dosing. In the context of liver failure or dilutional coagulopathy, dosing was required every 12 hours. In the presence of inhibitors to factor VIII or factor IX, doses must be given every 2 to 4 hours until hemostasis is maintained. Although no thrombotic complications have been reported in the limited anecdotal reports of the use of rFVIIa in the setting of noninhibitor coagulopathies, thrombotic events have been reported in patients with circulating inhibitors who have received rFVIIa. In an initial safety report, two episodes of DIC have been reported in a registry of 1947 uses of rFVIIa, an incidence of 0.1% ( Roberts, 1998 ). In another report of adverse events, there were four fatal thromboembolic events in more than 5500 patients treated with factor VIIa from 1996 to 2000 ( Martinowitz et al., 2001 ). Whether the difference in thrombotic complications is because of the limited experience with rFVIIa or is demonstrative of the differential prothrombotic tendency of rFVIIa under a variety of hemostatic conditions is unknown.

There is evidence that the interaction of TF and factor VIIa may have deleterious effects on the pulmonary vascular bed, with reports of the development of acute respiratory distress syndrome (ARDS) at the time of rFVIIa administration. TF-factor VIIa increases the expression of vascular endothelial growth factor, which is a key factor in the development of the capillary leak syndrome found in ARDS. Blockade of TF with site-inactivated factor VIIa, a competitive TF inhibitor, appeared to prevent the development of ARDS, renal insufficiency, and the systemic release of interleukin-6 and interluekin-8 in a baboon model of sepsis-induced organ dysfunction ( Welty-Wolf et al., 2001 ; Carraway et al., 2003 ). TF blockade appears to protect the lung from Escherichia coli lipopolysaccharide-induced lung injury as well ( Miller et al., 2002 ).

The recommended dose of rFVIIa is 90 mcg/kg administered over 2 to 5 minutes. Because of its short half-life, additional doses must be given every 2 to 4 hours until hemostasis is achieved. The dose for factor VII-deficient patients is 25 mcg/kg. In a series of 67 treatments of bleeding in patients with inhibitors to coagulation factors, there were three episodes of thrombophlebitis, and there was no evidence of disseminated intravascular coagulation or organ dysfunction caused by thrombotic complications ( Scharrer, 1999 ). No laboratory parameter is available to determine an adequate dose or whether a hemostatically relevant endpoint has been reached.

Although potentially promising, at this point, the role of rFVIIa in the treatment of the perioperative bleeding should be relegated to that of rescue therapy for the intractably bleeding patient in whom conventional transfusion treatment has been unsuccessful. Specifically, the use of rFVIIa in patients at risk for catastrophic thrombotic complications, such as children with small vessel anastomoses or palliative cardiac shunts should be approached with caution until further experience is garnered. After randomized, controlled trials have been completed to better define the thrombotic and pulmonary risks, rFVIIa may become a first-line agent for many of the coagulopathies that plague patients in the perioperative period.

Hemostatic Formulary

Table 32-22 summarizes the blood-based components available for treatment of the bleeding patient, including their constituents and indications for their use.

TABLE 32-22   -- Hemostatic formulary




Adult Dose


Whole blood

Hematocrit: 30% to 40%

Neonatal surgery




Most clotting factors

Massive transfusion




↓Factor V, factor VIII





No platelets




Fresh frozen

All clotting factors


10 to 15 mL/kg

↑15% in factors

plasma, 225 mL

2 mg/mL of fibrinogen

Liver failure

(2 units)↑40 mg/dL of fibrinogen




Factor XI deficiency

5 to 8 mL/kg




Disseminated intravascular coagulation





Warfarin toxicity



Platelets, 50 mL

>5.5 × 1010


5 to 10 mL/kg



50 mL of plasma

Platelet dysfunction

1 unit/10 kg (10 units)


Cryoprecipitate, 25 mL[*]

Fibrinogen >150 mg

↓ Fibrinogen

1 to 2 units/10 kg

↑60 to 100 mg/dL of fibrinogen


Factor VIII >80 units

Hemophilia A

(10 units)



von Willebrand factor

von Willebrand's disease




>80 units





Factor XIII >80 units




† Factor VIII dosing: desired FVIII-initial FVIII × plasma volume; about 1 unit/kg produces an increase of 2% factor activity.



Cryo units = (desired fibrinogen-initial fibrinogen) × Plasma Volume ÷ 100 mL/dL 150 mg fibrinogen/unit



Each unit of platelets contains 5.5 to 7.5 ×1010 platelets diluted in 50 mL of plasma. An apheresis platelet unit contains more than 3 ×1011 platelets in 250 to 300 mL of plasma. One third of all transfused platelets undergo splenic sequestration. In nonsurgical patients, spontaneous bleeding with a platelet count higher than 20,000 is uncommon. The ASA Task Force suggests that patients receive transfusions for platelet counts below 50,000/μL and that platelet transfusions be considered for patients with platelet counts between 50,000 and 100,000/μL, taking into consideration the risks and consequences of postoperative bleeding from the surgical site. If concurrent platelet dysfunction exists, the threshold for platelet transfusion should be raised. The ideal platelet dose is between 0.07 and 0.15 ×1011platelets/kg, which is approximately 10 mL/kg. A dose of 5 to 10 mL/kg or 1 unit/10 kg can increase the platelet count to 50,000.

Platelets are much more likely than RBCs to cause bacterial sepsis, because they are stored at room temperature for up to 5 days and potentially have a higher bacterial load. The reported incidence of bacterial contamination of platelet products is one case per 2000 units ( Snyder and Rinder, 2003 ). Storing the platelets in galactose-containing solution has been found to preserve platelet function despite chilling, and this approach may reduce the risk of bacterial contamination ( Hoffmeister et al., 2003 ). Platelet concentrates are more frequently contaminated but are diluted before administration. Single-donor platelets have a greater volume with higher numbers of bacteria per unit administered and are more frequently implicated in sepsis ( Busch, 2001 ). Platelet transfusions can also be associated with the development of pulmonary microvascular injury called transfusion-related acute lung injury (TRALI). TRALI is clinically similar to ARDS (discussed later). Within 6 hours of receiving a plasma-containing product, fever, tachypnea, dyspnea, progressive hypoxemia, radiographic evidence of pulmonary edema, and hypotension occur. The prevalence of TRALI in patients with platelet transfusions is estimated to be 3 per 1000 units of concentrate ( Silliman, 1999 ).

Fresh Frozen Plasma

FFP contains 250 mL of plasma and 500 mg of fibrinogen in a citrate anticoagulant. One unit of FFP has a concentration of coagulation factors similar to that of 4 to 5 units of platelet concentrates, 1 apheresis unit of platelets, and 1 unit of fresh whole blood; 1 mL/kg of FFP raises most factor levels by approximately 1%. After a dose of 10 to 15 mL/kg of FFP, plasma clotting factors rise about 15%, and the fibrinogen level rises by 40 mg/dL. However, FFP contains only 0.6% of factor VIII.

FFP use is indicated for treatment of microvascular bleeding in massively transfused patients, for documented coagulopathy (PT > 1.5 times) in the massively transfused patient, for urgent reversal of anticoagulant therapy, and for active bleeding with a history or course suggesting an inherited or acquired coagulopathy, for which specific factor concentrates are not available.


Cryoprecipitate is the most practical source for fibrinogen replacement. Each unit contains approximately 200 mg of fibrinogen and more than 80 units of factor VIII, vWF, fibronectin, and factor XIII. Achieving fibrinogen plasma levels of 80 to 100 mg/dL and maintaining this level above 50 to 60 mg/dL usually controls hemorrhagic symptoms. To raise the fibrinogen level 100 mg/dL, 0.17 unit of cryoprecipitate per 1 kg of body weight should be infused. Fibrinogen has a long half-life, and replacement therapy, therefore, can be given at intervals of 3 to 4 days.

Cryoprecipitate is indicated for several uses:



Prophylactic use in patients with congenital fibrinogen deficiencies, von Willebrand's disease unresponsive to DDAVP, and factor VIII deficiency when factor VIII concentrate is not available



Bleeding patients with von Willebrand's disease or factor VIII deficiency when factor VIII concentrate is not available



Consumptive coagulopathies when the fibrinogen level is less than 80 to 100 mg/dL



Microvascular bleeding in the massively transfused patient when hypofibrinogenemia cannot be immediately documented

Factors V, X, XI, and XIII

The only source of factor V is FFP. Normal hemostasis is achieved with levels above 25 U/dL. This can be achieved with a loading dose of 20 mL/kg of FFP, followed by infusions of 6 mL/kg every 12 hours. Factor V is very labile in FFP, and recently donated FFP should be used. FFP (1 mL/kg) increases the plasma level of factor X by 1 U/dL. FFP (1 mL/kg) increases circulating factor XI by 1.5 U/dL. Hemostatic levels of factor XIII are 2 to 3 U/dL. FFP (5 to 10 mL/kg) is adequate to achieve therapeutic levels. Cryoprecipitate may also be used. One bag of cryoprecipitate contains 75 U of factor XIII.


Citrate Intoxication

Citrate, when infused rapidly as the storage solution of blood products, can cause a temporary reduction in ionized calcium levels. FFP has considerably more citrate than does packed RBCs in CPDA-1. The signs of citrate intoxication include hypotension, narrow pulse pressure, flattening of the instantaneous slope of the arterial catheter tracing, elevated end diastolic pressures, prolongation of the QT interval, widening of the QRS complexes, and flattening of the T waves. Hypocalcemia is directly related to the rate of citrate administration, and it is unlikely to occur unless transfusions exceed 1 mL/kg per minute. Impaired perfusion or liver dysfunction lowers this threshold for potential hypocalcemia. Slow calcium administration during rapid blood product administration can avert this induced hypocalcemia ( Cote et al., 1988 ).

Transfusion-Related Acute Lung Injury

TRALI usually manifests as bilateral pulmonary infiltrates within 4 hours of transfusion. The clinical picture is that of ARDS. There are two proposed mechanisms for TRALI. Granulocytes from transfused blood products interact with antibodies in the pulmonary microvasculature leading to endothelial injury and alveolar exudation. Anti-leukocyte antibodies are found in this group of patients. The other proposed mechanism involves clinical settings such as trauma, sepsis, or massive transfusion, in which cytokine production partially activates endogenous neutrophils. These neutrophils become adherent to the pulmonary microvascular endothelium. On exposure to the lipids contained in transfused blood products, neutrophil activation becomes complete and endothelial damage results in the clinical picture of TRALI ( Silliman et al., 1998 ; Silliman, 1999 ).

Transfusion-Associated Graft-versus-Host Disease

Transfusion associated graft-versus-host disease (TA-GVHD) results when immunocompetent lymphocytes are transfused into a patient who is unable to reject allogeneic cells. The pathogenesis of TA-GVHD appears to require recipient secretion of tumor necrosis factor and interleukin-1 in response to preexisting injury or infection to enhance antigen recognition by donor T cells ( Ferrara and Krenger, 1998 ). These transfused lymphocytes react with host antigens producing fever, skin rash, pancytopenia, diarrhea, and abnormal liver function test results. TA-GVHD can occur 10 to 28 days after transfusion. The pancytopenia is profound and mortality approaches 100%. Median survival is only 21 days after transfusion. Patients who are at high risk for developing TA-GVHD include neonates, patients with congenital immunodeficiency, leukemia, or lymphoma and those who have received intensive chemotherapy and bone marrow or solid organ transplants. Infants and children with severe combined immunodeficiency syndrome (SCIDS) are of most concern, in part because SCIDS is often unrecognized at birth or in early infancy. Although many children with SCIDS are diagnosed by 6 months of age, children have been diagnosed with SCIDS up until 2 years of age. Children with the DiGeorge anomaly and those with conotruncal defects or Tetralogy of Fallot in whom immunodeficiency has not been excluded should be considered at risk for TA-GVHD as well ( Neill and Zuckerberg, 1995 ). Patients with HIV do not appear to be at increased risk for TA-GVHD, as only one case has been reported despite significant transfusion support ( Kruskall et al., 2001 ). The lack of TA-GVHD in HIV patients may underscore the key role the recipient's CD4 cells, which are depleted early in the course of HIV infection, plays in the pathogenesis of TA-GVHD ( Ammann, 1993 ).

TA-GVHD can occur in patients without an immunodeficiency. Patients who receive products from a donor who is homozygous for a shared haplotype are also at risk for TA-GVHD. The chance of receiving haplotype homozygous blood from an unrelated donor varies in different countries, ranging from 1 in 874 in Japan, 1 in 7147 whites in the United States, and 1 in 16,835 in France. Trauma patients with no known risk factors for TA-GVHD had evidence of microchimerism for as long as 1.5 years after transfusion ( Lee et al., 1999 ). The spectrum of patients who are at potential risk for TA-GVHD is likely to increase with the use of immunosuppressive regimens in the treatment of autoimmune and inflammatory bowel diseases.

The prevention of TA-GVHD lies in attenuation of donor lymphocyte reactivity. The only method approved by the U.S. Food and Drug Administration (FDA) is irradiation (Williamson et al., 1995). Irradiation damages the DNA in donated T cells, which precludes their proliferation and prevents TA-GVHD development (Shlomchik, 1999). Most blood centers rely on a nominal dose of 25Gy. Patients at risk for TA-GVHD should receive only irradiated RBCs, platelets, and granulocytes. A summary of situations in which irradiated blood products should be administered is presented in Box 32-16 .

BOX 32-16 

Indications for Irradiated Blood Products



Intrauterine transfusions



Patients < 2 years old






Bone marrow transplantation



Organ transplantation



Oncologic conditions


















Congenital immunodeficiency



Wiskott-Aldrich syndrome



Conotruncal abnormalities



Acquired immunodeficiency



Human immunodeficiency virus infection



Patients receiving immunosuppressive drugs



Recipients of blood products from first-degree relatives

To avoid the risk of TA-GVHD in patients with late-presenting severe combined immunodeficiency syndrome (SCIDS), all children younger than 2 years should receive only irradiated products. Blood components donated from first- or second-degree relatives should be irradiated, because there is usually homozygosity for an HLA haplotype ( Kanter, 1992 ). FFP and cryoprecipitate do not need to be irradiated, because most authorities feel that the freezing and thawing process destroys any donor T cells ( Luban, 2002 ). Nevertheless, there are reports of some progenitor cells that have survived the freezing and thawing process, suggesting that even FFP and cryoprecipitate be irradiated as well ( Anderson, 1995 ; Wieding et al., 1994 ).


Acute hemodynamic decompensation after red cell transfusions should be considered hyperkalemia, until proved otherwise. Large volumes (>25 mL/kg) of stored red cells given rapidly to infants have been associated with hyperkalemic arrests ( Hall et al., 1993 ). The combination of perturbations of calcium and potassium concentrations in the context of central venous blood administration may be sufficient to produce a hyperkalemic dysrhythmia ( Eder, 2002 ).

Copyright © 2008 Elsevier Inc. All rights reserved. -

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

Copyright © 2005 Mosby, An Imprint of Elsevier



Clinical Presentation

The acquired immunodeficiency syndrome (AIDS) epidemic has had an enormous deleterious impact on worldwide health and this effect has not spared children. In 1997, the World Health Organization (WHO) estimated that there were more than 30 million people worldwide who were infected with HIV ( Kahn and Walker, 1998 ). Of this number, 1.1 million were younger than 15 years. Most people infected with HIV live outside the United States. HIV/AIDS incidence varies by both ethnicity and geography. In the United States, AIDS is seen more frequently in Hispanic and African-American children than in Caucasians. In 1996, the CDC National HIV/AIDS surveillance system reported that 58% of the children with AIDS in the United States were African American, 23% were Hispanic, and 18% were white. Most U.S. cases have been reported in the Northeast (44%) and the South (36%), primarily in larger metropolitan areas. Although adolescents comprise a small percentage of cases of HIV/AIDS, the number of adolescents with HIV/AIDS is growing rapidly.

Transmission of HIV can occur through parenteral exposure to blood, sexual contact, or through vertical transmission from mother to child. In the United States, most HIV infections in children younger than 13 years have resulted from vertical transmission. Approximately 6000 to 7000 children are born to HIV-positive mothers annually in the United States. Women of childbearing are one of the fastest growing groups of individuals with AIDS in the United States, accounting for greater than 20% of adult AIDS cases reported (CDC, 1996). Transmission of HIV from mother to child can occur before, during, or after delivery. The highest percentage of HIV-infected children acquire the virus during delivery, most likely through exposure to infected blood and secretion during delivery. Chance of transmission is increased with preterm births, low birth weight, low maternal CD4 counts, and intravenous drug use during pregnancy. Transmission has been decreased by cesarean section and with prenatal, intrapartum, and postnatal zidovudine (AZT) treatment ( CDC, 1997 ).

In the United States, postpartum transmission by breast-feeding is the least common mode of perinatal transmission; however, it is quite important in developing countries. Transmission of HIV through contaminated blood or blood products accounts for approximately 3% of AIDS cases in the United States. Blood product screening for HIV began in the United States in 1985, and since then, the risk of transmission has decreased dramatically. Sexual transmission of HIV is rare in pediatric patients, but a small number of cases have been reported ( American Academy of Pediatrics, 2001a ). The age at which AIDS is diagnosed in children varies with the mode of transmission. Children who were infected by transfusion of contaminated blood or blood products, primarily between the years of 1978 and 1985, are now teens or young adults. Children who acquired the disease during birth can be diagnosed as infants with detection of virus as early as 1 week of age. The viral load increases with time, and by 4 months of age, almost all infected infants have virus detectable in the peripheral blood ( American Academy of Pediatrics, 1997 ). There are three patterns of progression of HIV in infected infants and children. Some newborns, those who were infected during gestation, develop symptoms within the first few months of life. Without treatment, these infants often die before their first birthday. These infants have detectable virus very early in life. Most newborns acquire the infection during birth, and these infants have a much slower progression of disease. The viral load increases in the first few months of life then declines over the subsequent 2 years. A small percentage of infants with perinatal infection survive for extended periods with minimal progression of the disease.

Children infected with HIV have generally the same immunologic effects as adults. Because infants and children have a lymphocytosis, true lymphopenia is relatively rare. However, there is progressive depletion of CD4 lymphocytes with development of opportunistic infections. The CDC classification system for HIV in young children includes the presence of signs and symptoms, the state of immunodeficiency, and the immunologic category of the disease (CDC, 1994). The recommendations for initiation of antiretroviral therapy in infants, children, and adolescents are summarized in Tables 32-23 and 32-24 [23] [24] (CDC, 1998). In the perioperative environment, caring for children with HIV/AIDS centers on two major considerations: the effects of this systemic infection and its treatment on the child's readiness for anesthesia and surgery and the protection of health care workers from infection from these children. Infants and children with HIV/AIDS have many opportunistic infections, which may involve all organ systems. The most common serious infections are pneumonia, bacteremia, and sepsis; nearly every organ system may be affected by opportunistic infections.

TABLE 32-23   -- Indications for initiation of antiretroviral therapy in children younger than 12 months with human immunodeficiency virus infection

Clinical Category[*]


CD4+ Cell Percentage

Plasma HIV RNA Copy Number[†]


Symptomatic (clinical category A, B, or C)


<25% (immune category 2 or 3)[*]

Any value


Asymptomatic (clinical category N)


≥25% (immune category 1)

Any value

Consider treatment[‡]

Adapted from


Clinical and immune category parameters and specific treatment guidelines with recommended drugs can be found at

Plasma human immunodeficiency virus (HIV) RNA levels are higher in HIV-infected infants than in older infected children and adults, and they may be difficult to interpret in infants younger than 12 months because overall HIV RNA levels are high, and there is an overlap in HIV RNA levels between infants who have and those who do not have rapid disease progression.

Because HIV infection progresses more rapidly in infants than on older children or adults, some experts treat all HIV-infected infants younger than 6 months or younger than 12 months, regardless of clinical, immunologic, or virologic parameters.


TABLE 32-24   -- Indications for initiation of antiretroviral therapy in children 1 year old or older with human immunodeficiency virus infection

Clinical Category[*]


CD4+ Percentage


Plasma HIV RNA Copy Number


Acquired immunodeficiency syndrome (AIDS) (clinical category C)


<15% (immune category 3)


Any value


Mild to moderate symptoms (clinical category A or B)


15% to 25%[†] (immune category 2)


≥100,000 copies/mL[‡]

Consider treatment

Asymptomatic (clinical category N)


>25% (immune category 1)


<100,000 copies/mL[‡]

Many experts defer therapy and closely monitor clinical and viral parameters

Adapted from


Clinical and immune category parameters and specific treatment guidelines with recommended drugs can be found at

Many experts initiate therapy if the CD4+ cell percentage is between 15% and 20%, and they defer therapy and increase monitoring frequency for children with CD4+ cell percentages between 21% and 25%.

There is controversy among pediatric human immunodeficiency virus (HIV) experts regarding the plasma HIV RNA threshold warranting consideration of therapy in children in the absence of clinical or immune abnormalities; some experts consider initiation of therapy in asymptomatic children if the plasma HIV RNA levels are between 50,000 and 100,000 copies/mL.


Anesthetic Considerations

As many as 80% of children with HIV develop lung disease ( McSherry, 1996 ). Pulmonary function is compromised by bacterial and viral infections, but many children with AIDS also develop lipoid interstitial pneumonia (LIP) ( Rubinstein et al., 1986 ). The incidence of LIP in HIV-infected children is approximately 20% to 30%. Clinical characteristics of this condition include tachypnea, wheezing, cough, hypoxemia, and even clubbing. This condition presents with bilateral infiltrates. Severely affected children may have bronchiectasis and lung cysts. The most common opportunistic infection in children with AIDS is probably Pneumocystis carinii pneumonia. Most people are infected with this very common organism in childhood, but disease is caused only in immunocompromised individuals. The peak incidence of this infection is in children younger than 1 year. Pneumocystis carinii pneumonia is often characterized by the acute onset of fever, hypoxemia, and respiratory distress, but a more slowly progressing disease also occurs ( Simonds and Orejas, 1999 ). Infection with respiratory viruses in children with HIV are common and often more severe in these patients. In children with AIDS, infections with RSV, parainfluenza viruses, and influenza viruses are more likely to be symptomatic, and infections with adenovirus or measles may lead to serious morbidity ( Englund and King, 1998 ).

Children with LIP and/or infectious pneumonia may present to the operating room for bronchoscopy with bronchoalveolar lavage for diagnosis. These children are often hypoxemic and in respiratory distress before the procedure. These cases are often quite challenging because establishing a diagnosis is important in prescribing therapy; the procedure cannot be delayed until the child's condition improves. Children who are infected in the perinatal period with HIV often have involvement of the CNS, although opportunistic infections of the CNS are uncommon. In toddlers, the presentation is that of a progressive encephalopathy with loss of developmental milestones or arrest of development. CNS pathology includes low brain weight, acquired microcephaly, inflammatory infiltrates, and calcific vasculopathy of the basal ganglia vessels. As the encephalopathy progresses, there may be loss of fine and gross motor skills, loss of language skills, and development of behavioral problems. In older children, the clinical picture often becomes one of a static encephalopathy ( Browers et al., 1998 ). Seizures and focal neurologic signs are unusual, and their presence should prompt a search for other causes such as infection, stroke, or a tumor.

Approximately 10% to 20% of children with HIV infections have clinically significant cardiovascular involvement. Careful echocardiographic and electrocardiographic evaluations of children with AIDS may uncover subtle abnormalities in a much higher percentage of patients ( Lipshultz et al., 1989 ). Common abnormalities include resting sinus tachycardia, sinus arrhythmias, and ventricular hypertrophy. Echocardiographic studies of children with HIV infection have demonstrated both LV diastolic and systolic dysfunction. One center reported that 10% of children with HIV required temporary treatment for congestive heart failure, generally during an intercurrent illness ( Luginbuhl et al., 1993 ).

Hepatosplenomegaly and a gallop are indications of congestive heart failure in these patients. Medical therapy has been generally effective in reversing the symptoms of congestive heart failure. In children with advanced AIDS, hemodynamic instability may occur ( Evenhouse et al., 1987 ; Stewart et al., 1989 ).

Children with AIDS often have lowered counts of all the formed elements of the blood. Poor bone marrow function in these patients may be due to the disease itself, poor nutrition, or the side effect of the medications used to treat the disease. As with many chronic conditions, the anemia seen in AIDS patients is often normochromic or normocytic, with low reticulocyte counts. In the preoperative evaluation of these children, other causes for anemia, such as occult bleeding, should be ruled out ( Morse, 2002 ). Treatment of anemia in HIV-infected children should address the cause but also often includes administration of erythropoietin (rh-EPO). Perioperative transfusion of RBCs should be undertaken only to provide a minimally acceptable level of oxygen delivery and after careful consideration of the possible deleterious effects in patients with HIV/AIDS ( Hillyer et al., 1999 ; Jacobson et al., 1990 ). Only cytomegalovirus-negative, leukocyte-depleted RBCs should be used. Thrombo-cytopenia has a high prevalence in patents with HIV. The cause is sometimes difficult to determine, but both impaired production and increased destruction have been found in AIDS patients. Complicating thrombocytopenia, a lupus-type anticoagulant was found in 20% of AIDS patients undergoing routine coagulation testing ( Cohen et al., 1986 ).

Gastrointestinal and nutritional problems can be very common and very difficult to treat in children with AIDS. Infections of the gastrointestinal tract cause major morbidity and can be quite severe in these patients ( Doyle and Pickering, 1990 ). Oral infections with candida or ulcerative gingivitis are seen in HIV-infected children. Bacterial, viral, or fungal infections may cause diarrhea. With recurrent or chronic diarrhea, children develop malnutrition and failure to thrive. Although linear growth may correlate with the severity of viremia, growth failure in these children can result from malabsorption, poor nutrient intake, and altered energy use. Hepatosplenomegaly is seen in up to 80% to 90% of children infected with HIV, and it is associated elevated levels of serum aminotransferase. Coinfection with hepatitis B or C virus is common in HIV-infected children. Pancreatitis can occur, usually as a complication of the drug therapy for HIV or one of the opportunistic infections. Other clinical manifestations of HIV infection include various rashes such as eczema or seborrhea and manifestation of renal dysfunction such as proteinuria, hematuria, hypoalbuminemia, and edema.

Anesthesia and Procedures

The procedures that children with HIV/AIDS commonly undergo are diagnostic bronchoscopies with bronchoalveolar lavage, diagnostic upper and lower endoscopies, placement of gastrostomy tubes for nutritional support, and placement of central venous catheters. In addition to procedures specific to this systemic infection, these children can require anesthesia for any other surgical or diagnostic procedure such as myringotomy, herniorrhaphy, and others. In the evaluation of these children before anesthesia, the effects of the infection on the organ systems should be evaluated as outlined previously. The anesthesiologist should be aware of medications taken and of their effects and side effects. In addition to medications specific for the treatment of AIDS, these children are often being treated with antibiotics and with corticosteroids. Pulmonary insufficiency is often seen in patients with AIDS, and despite meticulous care during the procedure, clinical deterioration commonly occurs after the procedure. During the preanesthetic visit, the anesthesiologist should, when indicated, discuss the possibility of postoperative intubation and ventilation. In advanced cases for which there is a do not resuscitate (DNR) or other advance directive in place, the anesthesiologist should discuss these plans thoroughly with the child and family ( Truog et al., 1999 ). It may be that the person caring for the child is not a biologic parent, necessitating additional administrative steps in the informed consent process.

Although the specific agents and techniques chosen for a case will depend on the particular child and situation, there are several points to keep in mind when making those choices. CNS involvement is relatively common, and CNS depressants such as barbiturates, benzodiazepines, and opioids should be carefully titrated. If liver or renal dysfunction occurs, drug metabolism and elimination will be impaired. Attention to sterile technique, often not a priority among anesthesiologists, is important in these children who have severe immunocompromise.

Pain Management

There are many causes for pain and suffering in infected children in addition to postoperative pain. The anesthesiologist/pediatric pain specialist should be prepared to participate in management of both the acute and chronic pain that afflicts these children. The clinical presentations of pain and suffering in children with AIDS are varied and the pharmacologic and nonpharmacologic treatments that may be employed are very broad. Assessment is often very difficult because of the nature of the discomfort and to the difficulty of communication with children afflicted with encephalopathy.

Health Care Providers and Exposure to Human Immunodeficiency Virus

Those caring for a child with AIDS must take prudent steps to prevent transmission. Although HIV has been isolated from saliva, the titer is generally low. Studies of hundreds of household contacts have confirmed that the risk of transmission from casual contact is nearly zero. It is, therefore, very unlikely that operating room personnel would contract AIDS from passive contact with an HIV-positive child. By far the greatest risk of contracting AIDS for health care workers is by a needlestick with a contaminated needle. Seroconversion is not a common occurrence after accidental needlestick in health care workers. An earlier report found that seroconversion occurred in 0.4% of all health care workers and that all the conversions occurred after needlesticks or lacerations.

Hollow-bore needles, those used to administer medications, give a much larger inoculum of blood and infectious agent than solid needles. After parenteral exposure to HIV, three steps should be taken: postexposure prophylaxis, postexposure treatment, and follow-up. A health care worker who has a parenteral exposure to blood or body fluids from a child known or suspected to have AIDS should have the wound thoroughly washed and then irrigated with saline. Exposed mucous membranes should be thoroughly irrigated with saline. The exposure should be immediately reported to the institutional employee health service or the “stick team.” As prophylaxis is begun, the employee should be tested to document HIV status. Subsequent testing should occur at 6 and 12 weeks. Postexposure prophylaxis should be undertaken immediately after the parenteral exposure to the blood or body fluid from a child suspected or known to have HIV infection.

A retrospective study done by the CDC was undertaken to determine the rate of seroconversion of health care workers. The study involved health care workers in England, France, and the United States. There were three conclusions: exposure to a large quantity of blood was associated with a higher rate of seroconversion; seroconversion was more likely when the exposure was from a patient in the terminal stages of AIDS; and there was a 79% decrease in seroconversion when zidovudine was begun after exposure. Guidelines for treatment of exposed health care workers recommend initiation of zidovudine with the possible addition of lamivudine or indinavir. Anesthesiologists should be familiar with the needlestick policy of their institution and be prepared to follow it and advise others of the policy in the event of an exposure. Following universal precautions, as recommended by the CDC ( Michna and Mason, 2002 ), should be the practice for all health care workers who have direct patient contact or exposure to patients—bodily fluids.


The first published report in an American medical journal of allergy to rubber gloves appeared in 1933 ( Downing, 1933 ). Subsequently, there were sporadic reports until the late 1980s and early 1990s, after which there was a sharp increase in the reporting of allergic reactions to latex. This increase is thought to reflect the increased exposure of health care workers and patients after the CDC's publication of the Universal Precautions Guidelines (CDC, 1987). The annual use of surgical gloves in the United States increased by a factor of 25, from 800 million to 20 billion. Allergic reactions to latex were first reported by pediatric anesthesiologists in 1991, before the Medical Alert circulated in 1991 by the FDA warning health care workers of this emerging problem ( Holzman et al., 1990 ).

Latex allergy is a significant problem in health care. As of 1997, the FDA had received through its mandatory reporting database reports of more than 2300 allergic reactions involving latex-containing medical products, with 225 cases of anaphylaxis, 53 cardiac arrests, and 17 deaths. Patient populations at increased risk for latex allergy have been identified ( Hochleitner et al., 2001 ; Randolph, 2001 ;Hourihane et al., 2002 ):



Patients who have undergone multiple surgical procedures



Patients with spina bifida (Myelomeningocele)



Patients with bladder exstrophy



Health care personnel



Individuals with a history of atopy



Individuals with a history of allergy to tropical fruits

Many children who have experienced allergic reactions to latex in the operating room have had spina bifida or urinary tract anomalies. These two groups undergo multiple surgical procedures, making it difficult to ascertain whether the high prevalence of latex allergy is caused by frequent exposure or an immunologic response associated with specific conditions. Reactions to latex have been divided into three types: irritant contact dermatitis; type IV hypersensitivity (i.e., skin reactions similar to poison ivy); and type I, or IgE-mediated, hypersensitivity. Type I hypersensitivity is by far the more severe reaction. All the deaths reported to the FDA were caused by type I hypersensitivity. This type of response to latex has been reported in many clinical settings, including intraabdominal surgery, genitourinary surgery, dental procedures, and even while putting on latex-containing gloves. Manifestations of type I, IgE-mediated hypersensitivity include the following:



Hives, urticaria, red eyes, angioedema of the eyelids



Nasal congestion



Gastrointestinal cramping, nausea, diarrhea



Headache, anxiety



Shortness of breath, tachycardia, hypotension, anaphylaxis

Intraoperative type I hypersensitivity generally does not occur immediately at the beginning of the surgical procedure but after exposure of the peritoneum or other mucous membrane to latex. The presentation includes bronchospasm, hypoxemia, hypotension, and tachycardia. There may also be skin manifestations such as urticaria or flushing. The bronchospasm and hypotension are difficult to treat, even with IV epinephrine, and the syndrome persists until the exposure is stopped. In a series of patients reported by Holzman, the mean SpO2 fell from 100% to 92% ( Holzman, 1993 ).

Treatment of Intraoperative Anaphylaxis

As more and more medical equipment is manufactured free of latex, it is important to maintain vigilance to the possibility of inadvertent exposure of an at-risk patient with resultant reaction. Delay in diagnosis of an episode of latex anaphylaxis will only make treatment more difficult due to continued exposure to the offending allergen. The mainstays of treatment are stopping the latex exposure andresuscitation.

All latex must be removed from the surgical field and the procedure ended as rapidly as possible. Materials whose latex content is unknown should also be removed. If blood and/or antibiotics are being administered, this administration should be stopped. Consideration should be given to evaluating the patient for a transfusion reaction if the symptoms and signs of anaphylaxis began during blood administration. Resuscitation efforts are directed toward stabilization of the vital signs and reversal of the pathophysiology of anaphylaxis. Because these reactions often occur during intraabdominal surgery, the patients are usually already intubated when the reaction occurs. If the patient is not intubated, strong consideration should be given to intubation. Based on the progress of the surgery and the patient's vital signs, administration of anesthetic agents should be stopped. Intravenous fluid and epinephrine doses should be given to maintain blood pressure, a Foley catheter placed, invasive hemodynamic monitoring should be instituted, and inhaled bronchodilators should be given through the endotracheal tube. If repeated doses of epinephrine are needed, as often occurs, an infusion of 0.05 to 0.1 mcg/kg per minute should be started. The patient may require treatment as outlined previously for several hours and intensive care admission should be arranged. A Latex Alert sign should be placed outside the patient's operating room and in the intensive care unit, and the condition should be noted prominently in the medical record. After the vital signs are stable, secondary treatments can begin. These include administration of diphenhydramine, ranitidine, and hydrocortisone. Further therapy depends on the patient's condition as the resuscitation progresses.

Diagnosis of Latex Anaphylaxis

After the patient is stabilized, tests to document the diagnosis of latex allergy can be performed. Although there are many tests available to confirm the diagnosis, there is not a universally accepted serum test for the diagnosis of a type I hypersensitivity reaction. An elevated level of serum tryptase occurs in the first four hours in patients who have experienced anaphylaxis with mast-cell degranulation, regardless of the cause. The latex radioallergosorbent (RAST) or enzyme allergosorbent (EAST) tests are available for specific proteins. Blood should be sent for testing, even if an individual may or may not be reacting to that particular protein. Nevertheless, a skin prick test using antigen extracted from latex similar to that used in medical products is used to determine type I hypersensitivity to latex. However, testing materials and methods have only recently begun to be standardized ( Hamilton et al., 2002 ). The patient should be referred to a specialist in allergy and immunology for complete evaluation. The performance of skin testing should be delayed until 4 to 6 weeks after the anaphylactic event to allow time for cellular inflammatory mediators released as a consequence of the reaction to be reconstituted ( Dakin and Yentis, 1998 ). Performance of testing before allowing time for reconstitution increases the risk of false-negative results. This testing must be done carefully and in the proper setting because severe reactions have been seen in sensitive individuals even with the exposure due to this test ( Kelly et al., 1993 ). After the diagnosis is confirmed, the patients should be offered the opportunity to wear a MedicAlert bracelet.


Avoidance of latex exposure is by far the best approach to this problem ( Holzman, 1997 ). Many operating rooms are working toward becoming completely latex free, but this goal has not yet been achieved. Avoidance, therefore, depends on recognizing those at risk for latex sensitivity. Specific at-risk groups are known, such as children with spina bifida and urinary tract anomalies. The preanesthetic assessment should include questions about atopy and allergy to foods, especially tropical fruits. Children thought to be at risk based on the history simply should not be exposed to latex. If a child is thought to be at risk for latex sensitivity but, when questioned, denies (or the parents deny) facial redness after touching balloons or after dental care and has not undergone latex-sensitivity testing, it seems prudent to avoid latex-containing products, especially because more and more products are manufactured to be latex free. The operating room should have Latex Alert warning signs that can be placed outside the door for these patients to help avoid inadvertent exposure to latex. Clinicians must keep themselves informed about the progress in this area. Products formerly unsafe may become safe with a change in manufacturing, but given the high morbidity of an anaphylactic reaction, it is essential that caregivers be certain of the safety of the medical products used in children at risk for latex sensitivity. All equipment used by anesthesiologists is available free of latex. Intravenous sets and tubing, breathing circuits and breathing bags, and sterile and nonsterile gloves are available latex free. Most multidose vials are made with latex-free stoppers. Unfortunately, not all medical equipment and products are latex free, and it is important to check each new product for possible latex content.

Prophylaxis and Desensitization

Although it is difficult to create a completely latex-free environment, the consensus opinion seems to be that prophylaxis of patients with known or suspected latex sensitivity need not be undertaken. There are case reports of patients who developed anaphylaxis after exposure to latex despite preoperative administration of the recommended prophylactic medication ( Kwittken et al., 1992 ; Setlock et al., 1993). Those who endorse prophylaxis propose administration of diphenhydramine, ranitidine, and corticosteroids from the preoperative through the postoperative period. There have been interesting reports of efforts to desensitize latex-sensitive patients. Children with spina bifida or urologic anomalies, or both, were not included in the reports. Many of the participants in these efforts were actually health care workers, and none of them had suffered anaphylaxis after exposure to latex. Although most patients were adults, one report included subjects as young as 8 years of age. The techniques used were cutaneous exposure over a 12-month period and rush, 4-day, desensitization by means of sublingual exposure ( Patriarca et al., 2002a , 200b). At this point, however, desensitization does not appear to be an option for children with type I hypersensitivity to latex.

Occupational Latex Allergy

In 1998, a report of latex sensitivity among the staff of the anesthesiology department at the Johns Hopkins Department of Anesthesiology ( Brown et al., 1998 ) documented a 24% incidence of irritant or contact dermatitis and nearly13% incidence of latex-specific IgE positivity, although pediatric anesthesiologists may have a somewhat lower incidence ( Ben-David and Gaitini, 1997 ; Greenberg et al., 1999). A large meta-analysis of all health care workers showed a 0% to 30% prevalence of type I latex allergy in the group. The investigators did not have data that elucidated the reasons for the large variation in prevalence ( Garabrant and Schweitzer, 2002 ). In other reports, there has been a suggestion that avoidance of latex reverses the sensitivity, at least in health care workers ( Zeldin et al., 1996 ). The creation of a latex-free operating room environment will benefit the patients and those who care for them.


The term epidermolysis bullosa encompasses a heterogeneous group of congenital, hereditary blistering disorders. The disease is subdivided into three major subtypes: epidermolysis bullosa simplex, junctional epidermolysis bullosa, and dystrophic epidermolysis bullosa. These types differ in histology, clinical severity, and mode of inheritance, but all are characterized by the easy development of blisters after minor trauma or friction. The review by Smith (1993) remains an important source of information regarding the anesthetic management of children with one of these rare conditions. Junctional epidermolysis bullosa is often clinically apparent early in life and heal with scarring. A discriminating feature of this variant is the relative sparing of the hands and feet. Involvement of the mucous membranes may be severe, however, and ulceration of the respiratory epithelium has been documented. The recessive variant of dystrophic epidermolysis bullosa may be the most severe form of the condition. Mucous membranes lesions are common in this variant. Treatment of children with this condition is supportive. Infections are frequent and should be promptly treated. Adequate nutrition is paramount but often difficult to provide in cases with esophageal blisters. Children with the more severe forms may come to the operating room for a variety of procedures, such as scar revisions, corrections of digital fusions, placement of gastrostomy tubes, and colonic interpositions.

Anesthetic Management

The preanesthetic evaluation of a child with epidermolysis bullosa should involve the dermatologist and pediatrician who care for the patient. These physicians can advise the anesthesiologist about the child's general course with regard to blistering, skin infections, and nutritional status, as well as the possible utility of additional steroid administration. In addition to assessing the child's general condition and health, the physical examination should focus on the airway, which may be compromised by scarring around the mouth, intravenous access sites, and the location and condition of existing and recent blisters.

Friction and secondary pressure must be avoided in caring for children with this condition in the perioperative period. Monitoring must adhere to the ASA standards but the application of the monitors should be modified. The precordial stethoscope is placed onto the chest, the temperature is monitored with an axillary probe, and soft padding is placed between the skin and blood pressure cuffs. Electrocardiographic leads should be nonadhesive, and intravenous and arterial catheters are sutured and covered with a gauze bandage that is lightly applied. The eyes should be lubricated but not held closed with adhesive tape. Endotracheal tubes are secured with umbilical tape lubricated with steroid cream rather than taped to facial skin.

A variety of anesthetic techniques have been used for procedures performed on these challenging patients ( Holzman et al., 1987 ; Smith, 1993 ). An oral premedication may be useful in children with epidermolysis bullosa coming to the operating room because a struggling child who is restrained may develop blisters where he or she is held by the operating room team. Alternatively, intramuscular ketamine has been used to induce and maintain anesthesia in these patients ( Idvall, 1987 ; LoVerme and Oropollo, 1977 ). The induction technique chosen depends on the preoperative assessment and the planned procedure. Induction of general anesthesia can be achieved with an inhalational technique, but contact with the child's face must be very gentle. Oropharyngeal airways should be avoided. Laryngoscopy with a straight blade without contact with the epiglottis is preferred, and intubation with a smaller than predicted, lubricated endotracheal tube after muscle relaxation can minimize trauma to the tracheal mucosa. If there are no contraindications, a deep extubation will decrease tracheal trauma due to coughing. Cases of postoperative bullae in the pharynx, some of which caused airway obstruction, have been reported but predisposing factors are difficult to identify ( James and Wark, 1982 ). Laryngeal mask airways should not be used due to the large area of contact/pressure of the “cuff” with the pharyngeal wall. The decision to admit these children after the procedure must be made on an individual basis. However, these patients warrant careful observation in a well-monitored environment after surgery and anesthesia. Although general anesthesia is used very frequently in these patients, reports of successful regional techniques have been published ( Kaplan and Strauch, 1987 ).


The incidence of trisomy 21 is 1 in 600 to 800 live births. More than one half of trisomy conceptions spontaneously abort early in pregnancy. The syndrome has many clinical manifestations, some of which are of particular note to the anesthesiologist.

Approximately 40% of children with trisomy 21 have anomalies of the cardiovascular system. The three most common anomalies seen in these children are complete atrioventricular canal (comprising approximately 40% of the total), ventricular septal defect (25%), and atrial septal defect (10% to 15%). Children with Down syndrome who undergo repair of complete atrioventricular canal have significantly higher perioperative mortality than those without trisomy 21. The outcome after surgery is not different for other cardiac anomalies, however. These defects have in common the propensity for increased pulmonary blood flow, which the anesthetic plan should attempt to minimize. Repair or palliation of a cardiac defect does not eliminate the need for particular attention to the cardiovascular system in the evaluation of these patients preoperatively.

Children with Down syndrome have various degrees of mental retardation, and it is important to be aware of the degree of intellectual impairment when meeting and talking with these patients. Hypotonia is one the most common clinical features seen in these children, and it may affect the adequacy of the upper airway. Partial airway obstruction while awake and during sleep is often seen in children with trisomy 21. This situation is exacerbated by the administration of sedatives and during inhalation inductions. The incidence of hearing loss and of hypothyroidism is increased in these children ( Tuysuz and Beker, 2001 ). There is an increased incidence of subglottic stenosis in trisomy 21 children, and often, the proper-sized endotracheal tube for a given child is smaller than would have been predicted. The relatively large tongue, short neck, and crowded midface and laryngomalacia contribute to the upper airway obstruction ( Clark et al., 1980 ; Kanamori et al., 2000 ; Mitchell et al., 2003 ). The orthopedic anomaly of great concern in these children is ligamentous laxity of the atlantoaxial joint that may predispose affected individuals to C1-C2 subluxation and possible spinal cord damage. The incidence of this anomaly is 12% to 32%, depending on the ages of the children studied and the exact definition of laxity used. Other associated findings in patients with Down syndrome are included in Box 32-17 .

BOX 32-17 

Associated Findings in Patients with Down Syndrome



General findings



Low birth weight



Short stature



Cardiovascular findings



Congenital heart disease



Increased susceptibility to pulmonary hypertension



Atropine sensitivity



Respiratory findings



High-arched, narrow palate









Increased susceptibility to respiratory infections



Subglottic stenosis



Postextubation stridor



Upper airway obstruction, sleep apnea



Gastrointestinal findings



Dental abnormalities



Duodenal obstruction



Gastroesophageal reflux



Hirschsprung's syndrome



Nervous system findings



Mental retardation









Musculoskeletal findings






Hyperextensibility or flexibility



Dysplastic pelvis



Atlantoaxial subluxation



Immune system findings






Leukemia (acute lymphoblastic, acute myeloid forms)



Hematologic findings



Neonatal polycythemia



Endocrine findings



Low circulating level of catecholamine




Perioperative Management

The preoperative evaluation of a child with Down syndrome should focus particular attention on the organ systems commonly affected in this condition. The history of prior surgeries should be reviewed. These children often have undergone cardiac procedures, removal of the tonsils and adenoids, myringotomy and tube placement, and other common pediatric procedures. Records from other doctors may have helpful information about associated conditions such as obstructive sleep apnea syndrome, atlantoaxial laxity, or subluxation. Management of these children regarding possible C1-C2 subluxation is a difficult matter. The American Academy of Pediatrics (AAP) has published statements by the committee on Genetics and the Committee on Sports Medicine and Fitness that include discussion of this clinical problem. The Committee on Genetics policy statement on health care supervision of children with Down syndrome recommends radiographs looking for evidence of atlantoaxial instability or subluxation be performed between 3 and 5 years of age ( American Academy of Pediatrics, 2001b ). The Committee on Sports Medicine and Fitness reviewed the topic of atlantoaxial instability in Down Syndrome in a 1995 publication and tentatively concluded that lateral plain films are of potential but unproved value in detecting patients at risk for developing spinal cord injury during participation in sports (1995). The Special Olympics does not plan to remove its requirement that all athletes with Down syndrome receive lateral spine radiographs (Special Olympics Bulletin, 1983). In 1984, the Committee on Sports Medicine and Fitness published a paper recommending that all children with Down syndrome have cervical spine radiographs, a much stronger endorsement of the practice ( American Academy of Pediatrics, 1984 ). Some conclusions can be drawn for the published case reports summarized in the AAP Committee on Sports Medicine Subject Review and the recommendations cited earlier ( American Academy of Pediatrics, 1995 ).

The preoperative history and physical examination should include a careful search for evidence of cervical instability. The parent should be questioned about past cervical radiographs, if they were taken. The family and patient should be questioned about the occurrence of any type of neck pain, limitation of neck mobility, torticollis, head tilt, abnormalities of gait, bowel or bladder dysfunction, or other signs of upper motor neuron dysfunction. The examination similarly should look for spasticity, hyperreflexia, extensor-plantar reflex, or clonus. If the history and physical examination reveal problems or the cervical radiographs show an atlantodens interval of more than 5 mm, the child's elective surgery is delayed, and neurosurgical consultation is sought. If previous radiographs were negative and the history and physical examination findings did not suggest a problem, it is not certain whether the x-ray films should be repeated. Although there is a very low incidence of worsening of the atlantodens interval over time ( Pueschel et al., 1992 ; Pueschel, 1998 ), some patients did show progression. Even in asymptomatic patients, there is the possibility that a postoperative neurologic disability may occur (Williams et al., 1987 ). Whatever the result of the evaluations, if surgery and anesthesia are undertaken, there is general agreement that these patients should be kept in the neutral position throughout the perioperative period. A reassuring study of children with Down syndrome with cervical radiographs who underwent tonsillectomy and adenoidectomy in the usual position showed no changes in the latency or amplitude of the somatosensory potentials ( Abramson et al., 1995 ). It should be noted that atlantoaxial instability occurs in conditions other than Down syndrome and at much higher frequency ( Box 32-18 ).

BOX 32-18 

Conditions Associated with Atlantoaxial Dislocation



Congenital abnormalities



Trisomy 21



Klippel-Feil syndrome



Larsen's syndrome






Spondyloepiphyseal dysplasia



Metatropic dwarfism



Kniest syndrome



Chondrodysplasia punctata



Chondrodystrophia calcificans congenita















Trauma (especially in young children)



Postoperative complication (especially after airway surgery)









Ankylosing spondylitis


Characteristics and Classification

Genetic studies during the past several years have led to a clearer understanding of the molecular causes of genetic-based muscle diseases. In most cases, the identification of the proteins altered in the disease states has added to our understanding of the function of muscle and the neuromuscular junction. However, the anesthetic management suggested for these diseases and syndromes has not changed as a result of the knowledge. The purpose of this section will be to review what is presently known concerning the generation of muscle contraction in a normal cell ( Fig. 32-16 ), molecular nature of diseases of the neuromuscular system, the clinical presentations of these diseases and their anesthetic implications.


FIGURE 32-16  A schematic diagram of the muscle cell and motor neuron. An action potential travels down the motor neuron causing the release of acetylcholine and the neuromuscular junction (NMJ). An action potential is generated in the muscle, travels down the transverse tubules, and causes the influx of calcium at the base of the tubules. The small calcium currents trigger release of larger amounts of calcium from the calcium stores in the sarcoplasmic reticulum into the matrix of the muscle cell. This activates the actin-myosin filaments to contract. The filaments attach (not shown) to the surface of the cell and the extracellular matrix to cause effective mechanical contraction.



The genetic muscle diseases can be divided into four broad categories: muscular dystrophies, myotonic syndromes, mitochondrial myopathies, and myasthenic syndromes. Though there is some overlap between malignant hyperthermia and the other genetic muscle diseases, malignant hyperthermia is included in this section where overlap exists between malignant hyperthermia and other muscle diseases. For further discussion of malignant hyperthermia, see Chapter 32 (Malignant Hyperthermia). The general location in the muscle cell of the molecular changes leading to these classes of genetic muscle diseases are shown in Figure 32-17 . Generally, the syndromes are caused by the following changes:



Myasthenic syndromes affect transmission of the action potential from the motor neuron to the muscle cell. This generally involves a disruption of the signal carried by the neurotransmitter, acetylcholine, across the synaptic cleft (see Fig. 32-17A ). The molecular changes may affect release of the neurotransmitter, acetylcholine, or its action at the postsynaptic receptor.



Myotonic syndromes affect transmission of the action potential along the muscle membrane and are generally caused by abnormalities in sodium, chloride, or potassium channels (see Fig. 32-17B ). These changes cause a prolonged depolarization of the muscle membrane, which leads to prolonged contraction of the muscle. A subgroup of these syndromes causes muscle degeneration and is called myotonic dystrophy.



Mitochondrial myopathies are caused by abnormalities in mitochondrial function. Because mitochondria are important for supplying ATP in most tissues (most importantly nerve and muscle), the symptoms of mitochondrial myopathies often involve the nervous system and muscle (see Fig. 32-17C ). The lack of ATP in muscle leads primarily to weakness and wasting of muscle. Mitochondrial myopathies are a complex and diverse group of diseases with a wide range of clinical implications.



Muscular dystrophies result from the dissociation of contractile force from the muscle to the surrounding connective tissue. The actin-myosin filaments in the muscle cell contract but they are no longer adequately connected to the cell membrane or the surrounding tissue. As a result, there is the equivalent of electromechanical dissociation (see Fig. 32-17D ), which is the electrical signal from the muscle cell membrane that is not translated into effective mechanical force.


FIGURE 32-17  The diagram in Figure 32-16 is expanded to show the main areas of defects leading to muscular disease. A, Disruption of the signal across the neuromuscular junction (NMJ) leads to myasthenic syndromes. B, Defects in the calcium, potassium, and sodium channels in the muscle cell membrane give rise to myotonias. The membranes remain depolarized too long, causing the inability to relax. C, Mitochondrial dysfunction leads to decreased intracellular levels of ATP. The decreased ATP concentration is responsible for the inability to contract strongly and defects in the reuptake of calcium into the sarcoplasmic reticulum. D, Defects in the attachment of the actin-myosin filaments to the cell surface and extracellular matrix produce muscular dystrophies. These attachments are important for mechanical force and for organizing and stabilizing the membrane.



Skeletal muscle contraction is accomplished by the generation of a neuronal action potential that terminates at the neuromuscular synapse (see Fig. 32-16 ). The neuronal action potential (AP) stimulates sodium channels in the neuronal axon that propagates the signal along the axon. As the AP reaches the end of the axon, voltage-gated calcium channels are activated, allowing the influx of calcium into the neuron. This influx of calcium stimulates the release of a neurotransmitter, acetylcholine, from the nerve terminal into the synapse. Acetylcholine binds to acetylcholine receptors on the cell surface of the postsynaptic cell, in this case the muscle. Binding of acetylcholine to its receptors allows influx of sodium into the muscle, generating a new AP, which propagates a transmembrane signal that spreads along the membrane of the muscle cell.

The AP is carried from the cell surface into the interior of the cell by a series of invaginations of the cell membrane known as transverse-tubules. These structures allow transmembrane electrical depolarizations to be carried deeply within the cell, where they would otherwise not be generated. At the ends of the T-tubules the sodium currents are replaced by calcium currents, resulting from the activation of a voltage-gated calcium channel known as the dihydropyridine receptor ( Fig. 32-18 ). These calcium currents stimulate a greater release of calcium from the large stores of calcium in the sarcoplasmic reticulum through acalcium-sensitive calcium channel, the ryanodine receptor. These larger fluxes of calcium stimulate movement of the actin-myosin filaments, an ATP-requiring step (and therefore dependent on functioning mitochondria). The filaments are attached to the surface of the muscle and the surrounding matrix through a variety of proteins, most notably dystrophin. Movement of the filaments is transduced into shortening of the cell (i.e., muscle contraction) by the connection to the cell surface and surrounding matrix. Relaxation is accomplished by reuptake of the intracellular calcium primarily back into the sarcoplasmic reticulum. This reuptake is energy requiring ATP-dependent calcium pumps. Because reuptake of calcium requires energy, it also depends on mitochondrial function and ATP generation.


FIGURE 32-18  An expansion of the region of the transverse tubules (T-tubules). Sodium, potassium, and calcium channels on the cell surface are responsible for propagation of the action potential (AP) along the cell membrane and into the T-tubules. When the AP reaches the terminus of the T-tubule, the sodium currents are replaced by calcium currents through the voltage-gated dihydropyridine receptor. These calcium currents trigger release of calcium through the ryanodine receptor from the large calcium stores in the sarcoplasmic reticulum.



This normal flow of electrical signal transduced to mechanical force can be disrupted at many places. As anesthesiologists, we often inhibit the transmission of the signal across the neuromuscular junction with the use of neuromuscular blockers such as vecuronium. Such an effect is similar to a myasthenic syndrome. The use of local anesthetics directly on muscle blocks voltage-gated sodium channels in the muscle membrane and acts oppositely to the changes seen in myotonic syndromes. Volatile anesthetics are also inhibitors of the voltage-gated membrane channels (sodium, potassium, and calcium) and act oppositely of myotonia. However, these drugs also inhibit mitochondria, and are capable of causing a relaxation effect in a manner similar to a mitochondrial myopathy. These examples are given only to further acquaint the anesthetist with the underlying causes of the myopathies; the drugs certainly do not cause these diseases. However, these similar effects largely predict the interactions of the drugs with the disease states.

Myasthenic Syndromes

Myasthenic syndromes are the result of the failure of transmission of the signal from the terminal of a motor neuron to the muscle innervated by the neuron. Most myasthenic syndromes are the result of immune responses against components of the neuromuscular junction (primarily the post-synaptic acetylcholine receptors) and are not truly genetic diseases. The symptoms result from decreased neurotransmission across the neuromuscular junction, and task-specific fatigue is the hallmark of these diseases (see Fig. 32-17A ).

The classic disease of myasthenia gravis is an example of such a disorder, though it is primarily a disease of adulthood. Myasthenia gravis can occur neonatally due to placental transfer of maternal antibodies. Rarely, inherited disorders of neuromuscular transmission, known as congenital myasthenic syndromes, can result from acetylcholine receptor mutations or other mutations involving the release of acetylcholine. Included in this group are familial infantile myasthenia, familial limb-girdle myasthenia, end-plate acetylcholinesterase deficiency, and syndromes with altered or deficient acetylcholine receptors ( Vincent et al., 1997 ; Menold et al., 1998 ). As an example, Maselli and others describe a form of congenital myasthenia gravis that results from a deficiency in the calcium-induced release of neurotransmitter or impaired recycling of synaptic vesicles ( Maselli et al., 2001 ). These genetic diseases can mimic myasthenia gravis in their presentation and implications for anesthesia and can manifest in children ( Dalal et al., 1972 ). Juvenile-onset myasthenia gravis is also associated with thymoma ( Kiran et al., 2000 ). Because these syndromes are not well described, their management is determined by analogy to that for adult-onset myasthenia gravis.

Anesthetic Considerations

The primary concern during the perioperative period for patients with myasthenic syndromes is to avoid respiratory compromise from weakened respiratory muscles or upper airway muscles ( Abel and Eisenkraft, 2002 ; Brown et al., 1990 ). For this reason nondepolarizing muscle relaxants are used sparingly, if at all, in these patients. Patients with myasthenia gravis or myasthenic syndromes are often resistant to succinylcholine ( Baraka, 2001 ). It is important to remember that patients can appear strong on awakening only to become fatigued later in the recovery period. Itoh and others (2002) showed that seronegativity for the anti-acetylcholine receptor antibody (seen in myasthenia gravis) did not predict a normal response to muscle relaxants. Myasthenia gravis patients “cured” by thymectomy may also retain a high sensitivity to muscle relaxants ( Itoh et al., 2002 ). The conclusion of these reports is that the anesthesiologist must presume a high sensitivity to muscle relaxants in all patients with myasthenic syndromes, even if they are functioning well after medical or surgical treatment. When muscle relaxants are needed, short-acting agents are favored.

Techniques using short-acting anesthetics without the addition of muscle relaxants have been very successful ( McBeth and Watkins, 1996 ; Della Rocca et al., 2003 ). It should be remembered that the volatile anesthetics are also muscle relaxants and may accentuate the compromised strength in myasthenic patients. Short-acting inhaled anesthetics (sevoflurane or desflurane) would seem to have a useful role with these patients. Opioids must also be used sparingly, when possible, to avoid adding to inhibition of respiratory effort. It is advisable to monitor the ventilatory status of myasthenic patients for a longer time than that done normally.


Myotonia is a temporary, involuntary contraction of muscle fibers due to transient hyperexcitability of the surface membrane ( Miller, 1989 ). In general, the myotonias may be thought of as a family of channelopathies mostly affecting muscle ( Jurkat-Rott et al., 2002 ; Rosenbaum and Miller, 2002 ). The abnormalities in the channels leads to prolonged depolarization in the membrane once an action potential is generated (see Fig. 32-18 ) and leads to prolonged or increased release of calcium into the cell. This leads to prolonged stimulation of the actin-myosin contractile apparatus of the muscle cell (Fig. 32-19 ). The persistent contracture of the skeletal muscle generally occurs after muscle stimulation but may be triggered by other stimuli such as cold, pain, or stress. A classic finding in patients with myotonia is the inability to easily relax after a firm handshake.


FIGURE 32-19  Calcium is released from the sarcoplasmic reticulum and causes contraction of the actin-myosin filaments. Calcium reuptake is achieved by ATP-dependent calcium pumps. Contraction and reuptake depend on the function of mitochondria.



Two forms of myotonia (myotonia congenita and Becker's disease) result from defects in the same skeletal muscle chloride channel (ClC-1) ( Pusch, 2002 ; Renner and Ptacek, 2002 ; Jurkat-Rott et al., 2002). Myotonia congenita (i.e., Thomsen's disease) is an autosomal dominant disease, presenting in childhood associated with a normal life expectancy and minimal symptoms ( Grunnet et al., 2003 ). Becker's disease, not to be confused with Becker muscular dystrophy, is an autosomal recessive form of this channelopathy, appearing in childhood also ( Pusch, 2002 ). Some mutations in this chloride channel cause a variant of dominant myotonia with a milder phenotype, myotonia levior ( Ryan et al., 2002 ; Farbu et al., 2003 ). These myotonic diseases are nonprogressive and do not have a dystrophic component (i.e., there is no deterioration of the muscle over time). Other, milder myotonias result from abnormalities in sodium or potassium channels on the muscle cell membrane. These include paramyotonia congenital (sodium channel), hyperkalemic periodic paralysis (sodium channel) and hypokalemic periodic paralysis (calcium, sodium, or potassium channels) ( Jurkat-Rott et al., 2002 ).

Anesthetic Considerations

Myotonic contractions may be precipitated by stress, cold, and pain. These triggering factors must be carefully avoided during the perioperative period for these patients. Regional anesthesia and neuromuscular blockade do not reverse the contractions because they act upstream from the molecular causes of the syndrome (compare Figs. 32-17A and 32-17B ). Succinylcholine has been noted to precipitate contractions, as have neuromuscular blocking reversal agents. These contractions have been most notable in the occurrence of masseter spasm after the use of succinylcholine, but they can also involve other muscles and lead to extreme difficulty with positive pressure ventilation and intubation ( Farbu et al., 2003 ). For these reasons, the use of succinylcholine is discouraged in patients with myotonia. If an episode of myotonia occurs during anesthesia, volatile anesthetics, quinine, or procainamide can be used for relaxation. Because the myotonias occur as the result of abnormal ion channels, great care must be taken to keep electrolytes normal at all times. Although myotonic syndromes may have symptoms in common with malignant hyperthermia (especially muscle contracture after the administration of succinylcholine), they are not associated with true malignant hyperthermia.

Myotonic Dystrophy

Myotonic dystrophy (i.e., Steinert muscular dystrophy) is the most common form of myotonia ( Anderson and Brown, 1989 ). This disease is a form of muscular dystrophy and includes congenital myotonic dystrophy. Myotonic dystrophy is discussed here instead of with other muscular dystrophies because its presentation is different, more resembling the myotonias than the dystrophies.

It has been shown that myotonic dystrophy actually includes two different molecular diseases ( Ranum and Day, 2002 ). Myotonic dystrophy type 1 results from alterations in the human dystrophica myotonica-protein kinase gene (DMPK) ( Amack and Mahadevan, 2004 ). The precise mechanism by which this mutation causes the disease is not clear but the dystrophy results from abnormal development of the muscle cells ( Wansink and Wieringa, 2003 ; Martorell et al., 2004 ). However, the myotonia probably is the result of abnormal phosphorylation of sodium channels resulting in delayed inactivation after channel opening ( Lee et al., 2003 ). The prolonged channel activation causes prolonged muscle contraction. The changes in the protein kinase gene are in the promoter or starting region of the gene and are the result of duplications in short repetitive sequences (i.e., CTG triplets). The number of repetitive sequences is often increased in the offspring compared with an affected parent. As a result, each successive generation tends to exhibit a more severe form of the disease. Myotonic dystrophy type 2 has a clinically diverse presentation, including myotonia, proximal muscle wasting, and endocrine, cardiac, and cerebral abnormalities. Myotonic dystrophy 2 also results from expansion of a sequence in the promotor of a gene, but the gene is separate from that causing myotonic dystrophy type 1 and codes for a probable transcription factor, ZNF9 ( Finsterer, 2002 ; Liquori et al., 2003 ). The precise physiologic changes leading to myotonic or dystrophic changes are not known. In both disease states, the abnormalities result from abnormal RNA species that disrupt normal development of the cells ( Mankodi and Thornton, 2002 ).

Anesthetic Considerations

Production of muscle relaxation can be very difficult in these patients. As with the other forms of myotonia, cold, stress, pain, and succinylcholine can precipitate myotonia. Because this is a dystrophy with muscle wasting, succinylcholine can elicit a hyperkalemic response and should be avoided. Unlike the other myotonias, myotonic dystrophy leads to deterioration of the muscle fibers, affects tissue other than skeletal muscle, and is associated with weakness and hypotonia in infants and children. Paradoxically, however, the patients can trigger a myotonic episode as well. These patients can have profound respiratory depression, severe cardiac conduction abnormalities, cardiomyopathy, developmental delay, dysphagia, and decreased gastric motility. Muscle relaxants must be used with great care, if at all, in these patients. Smaller doses are probably necessary and a neuromuscular blockade monitor is advised. As with other myotonias, reversal agents may induce myotonia. Because respiratory depression is notable in these patients, the respiratory status is potentially fragile when any narcotic or general anesthetic is used. Their care presents challenges involving several physiologic systems. Myotonic dystrophy and their anesthetic implications have been reported ( White and Bass, 2003 ). Although myotonic dystrophy is also commonly thought to be associated with malignant hyperthermia and shares similar features with malignant hyperthermia, nonetheless, myotonic dystrophy is not associated with true malignant hyperthermia.

Mitochondrial Myopathies

An increasingly large list of disease syndromes is associated with mitochondrial dysfunction. The more commonly seen mitochondrial syndromes are Leigh disease, Kearns-Sayre syndrome, and Leber hereditary optic neuropathy. However, mitochondrial dysfunction is also associated with unnamed myopathies and encephalopathies and with symptoms of failure to thrive. Mitochondrial abnormalities have been involved in some forms of autism and Parkinson's disease. The presentation of mitochondrial disease may be quite varied.

Mitochondria are the principal source of energy metab-olism within cells, especially those of nerve and muscle (see Fig. 32-17C ). Within mitochondria reside the enzymes responsible for the Krebs cycle, fatty acid β-oxidation, and, most importantly, oxidative phosphorylation ( Fig. 32-20 ). Mitochondria contain the enzymes that metabolize glucose, fatty acids, and amino acids to generate NADH and succinate, which are used as electron donors for the electron transport chain. By passing electrons down the electron transport chain (complexes I to IV), a proton gradient is generated across the mitochondrial inner membrane, and electrons are donated to oxygen to generate water. The proton gradient is then used to drive an ATP synthase (complex V). The coupling of electron transfer to phosphorylation is known as oxidative phosphorylation, and it is overwhelmingly the major source of ATP and other high-energy phosphate bonds supplying energy to the cell. ATP is necessary for actin-myosin filament contraction and for reuptake of calcium by ATP-dependent calcium pumps into the sarcoplasmic reticulum (see Fig. 32-19 ).


FIGURE 32-20  A representation of the electron transport chain (ETC) of mitochondria. Substrates for the ETC are generated from the Krebs cycle and enter the ETC at complex I or complex II. Protons are pumped into the intermembrane space (arrows) and return through complex V to drive the production of ATP. The figure demonstrates the complexity of the ETC and surrounding matrix.



Mitochondrial complexes are composed of groups of proteins ranging from just a few (complex II) to over 40 (complex I). The dehydrogenases, membrane transporters, and structural proteins raise the number of functional proteins in the mitochondria into the hundreds. Some of the proteins are encoded for by genes in the cell's chromosomes, whereas some are encoded by the mitochondria's own DNA. The genetics of mitochondrial disease is complicated by the fact that mitochondria are inherited from the mother. However, different populations of mitochondria may be passed to different offspring, so that the inheritance pattern can be quite varied. Mitochondrial dysfunction has effects other than energy depletion. Increased free radical damage to other cellular components and alterations in protein phosphorylation may be seen with mitochondrial disease. Each of these effects can give rise to mixed, but wide-ranging, functional changes in affected individuals.

It is a common mistake to group all mitochondrial diseases together as similar entities. Because a mutation can occur in any of the mitochondrial proteins, the resulting functional protein changes can manifest differently. Mitochondria in different tissues can be quite varied in their activity. The differences among tissues with regard to mitochondrial function, coupled with the varied inheritance pattern discussed previously, give rise to different clinical symptoms even among members of a family carrying identical mutations. It is dangerous to assume that, because an anesthetic technique was successful in a few patients with mitochondrial disease, the same technique would be safe for all patients with mitochondrial dysfunction.

Muscle and nerve cells uniquely depend on the energy delivered by these mitochondria. Mutations in mitochondrial proteins are responsible for the clinical features, including myopathy, cardiomyopathy, encephalopathy, seizures, and cerebellar ataxia. Because motor neurons may be affected, a hyperkalemic response to succinylcholine may occur. Malignant hyperthermia is thought to be associated with some forms of mitochondrial myopathies, but the nature of this relationship is unclear ( Fricker et al., 2002 ; Keyes et al., 1996 ).

Anesthetic Considerations

The perioperative period is a time during which a patient may be exposed to periods of stress. Conditions of stress may lead to inadequate ATP levels relative to energy demands. Shivering due to hypothermia probably represents the greatest threat to these patients. However, hyperthermia and stress from untreated pain also represent serious risks. The failure for ATP production to meet metabolic demands inevitably leads to a lactic acidosis, often of profound significance. To avoid such problems great care must be taken to keep patients normothermic during surgical procedures and to adequately treat postoperative pain. Postoperative pain represents a particularly troublesome problem because narcotics can further compromise the patient's respiratory status.

Patients with mitochondrial disorders may become acidemic due to high levels of lactate as a result of hypovolemia. Prolonged preoperative fasting should be avoided in these patients. If fasting is necessary, intravenous fluids containing glucose must be administered to avoid anaerobic metabolism. As cyanide inhibits the respiratory chain, sodium nitroprusside should be avoided. For similar reasons, tourniquets should be avoided if possible. It is not clear what hematocrit is adequate in these patients, but it is probably prudent to maintain a near normal level. Although mild levels of hypotension are commonly used in many patients to avoid blood loss, such an approach is less desirable in patients with mitochondrial disease. These patients are probably less able to compensate for decreased oxygen delivery.

Unfortunately, essentially every general anesthetic studied has been shown to depress mitochondrial function. The most notable of these are the inhaled anesthetics and propofol. It is reported that these agents significantly depress mitochondrial function at doses higher than their clinical concentrations. However, studies have also shown that even at doses commonly used in the operating room, anesthetics cause a significant depression of mitochondrial function from normal patients ( Miro et al., 1999 ). Studies in animals have shown that when complex I is abnormal, sensitivity to volatile anesthetics is markedly increased ( Kayser et al., 1999 ). Case reports have also indicated that some children exhibit an increased sensitivity to sevoflurane ( Morgan et al., 2002 ). Wolf and others (2001) have shown that the propofol infusion syndrome probably occurs by means of mitochondrial inhibition. This has been interpreted to indicate that propofol also should be used with caution and increased monitoring in patients with mitochondrial disease. Because propofol and inhaled anesthetics primarily inhibit complex I function (see Fig. 32-20 ), patients with complex I-specific defects may have increased susceptibility to these drugs.

There is a strong clinical impression that children with mitochondrial myopathies have an increased risk during surgery ( Bolton et al., 2003 ; Morgan et al., 2002 ). Because metabolism is altered in patients with mitochondrial disease, the abilities of the cell to generate ATP and to effectively use oxygen are diminished; consequently, exposure to anesthetics probably represents an increased risk compared with other patients ( Bolton et al., 2003 ). The use of regional anesthetics should be considered if appropriate for the patient. However, it has also been noted that mitochondria are the probable target for the cardiac complications of bupivacaine ( Weinberg et al., 2000 ); patients with mitochondrial myopathies may be at increased risk with this drug as well. Lastly, these patients (as with all patients with myopathies) must not be stressed with respect to their respiratory status. Caution must be used in weaning them from mechanical ventilation to ensure adequate spontaneous ventilation with minimal increases in the work of breathing.

The primary complications of mitochondrial myopathies include respiratory failure, cardiac depression, cardiac conduction defects, and dysphagia. Each of the volatile anesthetics depresses respiration, although to different degrees. However, because volatile anesthetics do not require metabolism for excretion, this route of elimination may present an advantage over intravenous anesthetics, which depend on energy-requiring mechanisms for their metabolism.

During the past decade, the intravenous anesthetic propofol has become increasingly popular as a maintenance anesthetic. However, it has many of the same side effects as volatile anesthetics. One notable exception is that it is not known to cause much muscle relaxation. Although propofol is viewed as a very-short-acting drug, its ultimate excretion is metabolism dependent, and patients with mitochondrial myopathy may have an increased risk for developing propofol infusion syndrome during prolonged exposure ( Wolf et al., 2001 ).

Although all of the general anesthetic agents are known to directly inhibit mitochondrial function, all of these agents have been successfully used in patients with mitochondrial disease. It may be that as the different types of mitochondrial disease are better defined, preferences for an anesthetic in certain cases may become clear. It is imperative that patients with mitochondrial diseases are monitored closely, and the effects of the anesthetics have dissipated before assuming that the patient can ventilate adequately.

Patients with mitochondrial myopathies respond well to the nondepolarizing relaxants, though they probably have an increased sensitivity. These drugs should be titrated to the desired effect, monitored by nerve stimulation, and reversed fully beforediscontinuing ventilatory support. Because motor neurons may be affected, a hyperkalemic response to succinylcholine may be seen. Succinylcholine should be used only when absolutely necessary in these patients. Succinylcholine and volatile anesthetics are also known as triggers for malignant hyperthermia. Malignant hyperthermia is thought to be associated with some forms of mitochondrial myopathies, but the nature of this relationship is unclear. It may be that a group of mitochondrial myopathies mimics malignant hyperthermia by having inadequate ATP for reuptake of calcium from the cytoplasm of muscle cells into the sarcoplasmic reticulum. Such a failure could cause prolonged muscle contraction and lead to increased metabolism, and this represents a complicated problem in these patients. Whether they will increase their temperature or become acidemic will depend on the quality and severity of their disease.

There is no perfect anesthetic for patients with mitochondrial myopathies. When possible, consideration should be given to the use of local anesthetics in small amounts. When a general anesthetic is necessary, probably each of the general anesthetics in use has its place. At present it is not possible to eliminate one group as less safe than others. What is clear is that these patients must be monitored closely.

Muscular Dystrophy

At least five forms of muscular dystrophy are clinically relevant for anesthesiologists ( Farrell, 1994 ). These include Becker's, Duchenne's, facioscapulohumeral, Emery-Dreifuss, and limb-girdle muscular dystrophies. These entities vary greatly in severity of presentation ( Kerr et al., 2001 ; Schmidt et al., 2003 ). Duchenne's muscular dystrophy is an X-linked disorder resulting from deletion mutations in the dystrophin gene resulting in a complete lack of dystrophin in skeletal muscles (see Fig. 32-17D ). The defect is present in about 1/3500 live births with the onset of disease often before school age and progressing to wheelchair dependence by the second decade of life. Dystrophin is a large protein which helps anchor the contractile components (the actin-myosin filaments) to the cell membrane and indirectly to the surrounding extracellular matrix ( Fig. 32-21 ). Loss of this protein leads to profound muscle weakness and eventual respiratory insufficiency ( Muntoni et al., 2003 ; Finsterer and Stollberger, 2003 ). Other, less global changes in this same gene cause Becker's muscular dystrophy and the related disease, X-linked dilated cardiomyopathy. Cardiomyopathy is occasionally seen in female heterozygote carriers of the mutation.


FIGURE 32-21  Representation of attachments of the actin filaments to the cell membrane and extracellular matrix. Disruption of these attachments alters protein distribution in the membrane and membrane stability. Some of the specific proteins that cause dystrophies are listed.



Dystrophin is also found in cells other than skeletal muscle and has an apparent role in organizing protein complexes in the membrane and stabilizing the membrane. Absence of the protein leads to membrane instability which causes eventual muscle cell deterioration. Associated defects seen in patients with Duchenne's muscular dystrophy and Becker's muscular dystrophy include cardiomyopathy, cardiac conduction defects, and occasionally, mild mental retardation. The presence of the protein in other cell types provides an explanation for the involvement of the nervous system in affected patients.

Dystrophin also is important in organizing the postsynaptic acetylcholine receptors ( Muntoni et al., 2003 ). In its absence, abnormalities occur both in the types of receptors and in their number and location. In the absence of dystrophin, there is an increase in expression of acetylcholine receptor subunits and changes in interacting proteins ( Chen et al., 2000 ). The membrane instability coupled with changes in acetylcholine receptors may explain the sensitivity of the muscle to succinylcholine and volatile anesthetics.

Anesthetic Considerations

The main anesthetic implications of Duchenne's muscular dystrophy and Becker's muscular dystrophy are related to the profound myopathies. As would be expected in patients with muscle weakness, significant postoperative respiratory insufficiency can result from either disease. Cardiac muscle and conduction are also involved and drugs that further depress cardiac function, or which increase the likelihood of arrhythmias, should be avoided. All patients with Duchenne's muscular dystrophy or Becker's muscular dystrophy should receive a full cardiology evaluation and pulmonary function tests before any surgery. Dysphagia is common and gastric motility may be decreased requiring expedient control of the airway. The association of malignant hyperthermia with Duchenne's muscular dystrophy and Becker's muscular dystrophy appears to be coincidental only.

Both Duchenne's muscular dystrophy and Becker's muscular dystrophy patients can have rhabdomyolysis and hyperkalemia in response to succinylcholine; succinylcholine, therefore, is contraindicated in these patients. It is unclear whether volatile anesthetics alone can cause rhabdomyolysis in these patients.

Other Dystropies

Other forms of congenital muscular dystrophy exist that also involve other proteins necessary for attaching the contractile machinery to the extracellular matrix (see Fig. 32-21 ). Although this is a heterogeneous group of mutations, it is probably best to treat these patients as if they had Duchenne Muscular Dystrophy.

More than 30 different forms of congenital muscular dystrophy are now known, and are caused by defects in a wide array of components of the basement cell membrane and extracellular matrix ( Engvall and Wewer, 2003 ). These are not discussed in detail as their clinical implications are similar to each other. Examples are the absence of laminin, or a related protein merosin, which give rise to similar forms of congenital dystrophies. These often have profound effects both on skeletal muscle and the nervous system.

The most common remaining dystrophies—facioscapulohumeral, Emery-Dreifuss, and limb-girdle muscular dystrophy—are much milder in their presentations ( Emery, 2002 ). Facioscapulohumeral is one of the most common muscular dystrophies, but the molecular basis of facioscapulohumeral is unknown. Facioscapulohumeral is the most benign muscular dystrophy usually with little respiratory involvement ( Fitzsimons, 1999 ). However, the neck, face, and scapular stabilizing muscles are often weak, and the ability to raise the head (at the end of anesthesia) may be of little use in determining respiratory muscle strength. Of clinical importance is that these patients may lose the ability to swallow well and therefore be unable to protect their airway during emergence from anesthesia.

Emery-Dreifuss dystrophy may result from multiple causes. The most common form has its onset in the teenage years and results from mutations in emerin, an inner nuclear membrane protein that interacts with laminin (part of the nuclear matrix) and transcription regulators (see Fig. 32-21 ). These patients have cardiac conduction defects, cardiomyopathy, contractures (positioning problems) and often a fusion of C3-C5, resulting in a less mobile neck (difficulty during intubation) ( Aldwinckle and Carr, 2002 ; Shende and Agarwal, 2002 ).

Limb-girdle dystrophy results from mutations in several proteins (at least 11 are known), such as α-sarcoglycan, which associate with dystrophin. Limb-girdle disease is associated with some respiratory muscle weakness and significant cardiac conduction abnormalities. At least some cases of Limb-girdle disease result from a defect in a protein which interacts with muscle cell membrane and is implicated in membrane repair ( Capanni et al., 2003 ).

Anesthetic Considerations

There is little experience in the literature on the interaction of anesthetics with LG dystrophy ( Pash et al., 1996 ). In all three forms of muscular dystrophy, succinylcholine should be avoided because hyperkalemia can result. Malignant hyperthermia is not reported in these three milder forms of muscular dystrophy. Although not universal, the recurring themes with muscular dystrophy are to avoid succinylcholine, to watch for respiratory depression, and to avoid cardiac depressants and arrhythmogenic drugs. Anesthetic complications have been reported for most of these forms of muscular dystrophy ( Farrell, 1994 ). These episodes most commonly result from a hyperkalemic episode and sudden cardiac arrest may occur. Such events can occur in patients who are still in a subclinical stage of their disease and in whom the crisis may be the first manifestation. For this reason, many clinicians limit their use of succinylcholine in children.


Several other genetic diseases of muscle exist which are of interest to anesthesiologists. These include primary diseases of metabolism which lead to chronically weak muscles or muscles that are prone to damage when exposed to high metabolic stress. McArdle disease, an inherited disorder of muscle phosphorylase activity which downregulates a Na+-K+ membrane pump, is a prototypic disorder of this type ( Clausen, 2003 ). Muscle from patients with McArdle disease can function normally until stressed by exercise or ischemia, at which time severely painful electrically silent contracture develops, which can be followed by rhabdomyolysis, myoglobinuria, renal failure, and death. This sequence is similar to anesthesia-induced malignant hyperthermia. Several patients with anesthesia complications suggestive of malignant hyperthermia have had features of metabolic dysfunction on muscle biopsy, raising the possibility that disorders of intracellular energy production may underlie the malignant hyperthermia phenotype in some patients ( Isaacs et al., 1989 ).

Patients with other less common diseases, such as Schwartz-Jampel syndrome, King-Denborough syndrome, and Lambert-Brody disease, are also prone to anesthetic complications. In each case, malignant hyperthermia-like responses have been reported, but their exact relationship to malignant hyperthermia is not clear. King-Denborough syndrome is a progressive myopathy, and affected patients have short stature, severe scoliosis, pectus deformities, ptosis, low-set ears, and cryptorchism ( Heiman-Patterson et al., 1986 ). Anesthesia-related deaths, fulminant episodes of malignant hyperthermia, and positive in vitro contracture test results have been commonly associated with this disorder ( Isaacs and Badenhorst, 1992 ). Because this disease is rare, genetic information about it is still lacking.

Patients with Brody's disease (i.e., Lambert-Brody disease) elicit a decreased ability to relax on repeated activation of their muscle that results from an identified defect of the sarcoplasmic reticulum Ca2+-ATPase ( Odermatt et al., 2000 ). An in vitro contracture test performed on muscle from such a patient was abnormal, which may indicate that such patients may be at risk for malignant hyperthermia-like syndrome ( Froemming and Ohlendieck, 2001 ). Severe myotonia or neuromyotonia is a common feature of Schwartz-Jampel syndrome, in which hyperexcitability can be exacerbated by anesthetic agents and muscle relaxants considered as triggering agents for malignant hyperthermia ( Seay and Ziter, 1978 ; Ray and Rubin, 1994 ). It is unclear whether true malignant hyperthermia is associated with this syndrome. Abnormal neck and laryngeal structure leading to difficulty with intubation has been reported ( Stephen and Beighton, 2002 ).

Unfortunately, the molecular and genetic studies of these diseases raise nearly as many questions as they answer. Recommendations for the anesthetic care of these patients remain rather general. Physicians probably should avoid the use of succinylcholine and volatile anesthetics. The use of nontriggering anesthetics seems to be safe for these patients, although any muscle relaxant must be used with the utmost caution.

Most myopathies have been shown to be unrelated to malignant hyperthermia, though some overlap in their response to drugs may exist. However, the use of succinylcholine should be avoided. Other muscle relaxants can be used as necessary, but the anesthesiologist must carefully monitor their effects. Volatile anesthetics alone may present a risk of rhabdomyolysis in some muscular dystrophies. Mitochondrial disease represents a wide array of molecular changes and clinical presentations. The response of patients with mitochondrial disorders to anesthetic agents does not appear to be consistent.

Copyright © 2008 Elsevier Inc. All rights reserved. -

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

Copyright © 2005 Mosby, An Imprint of Elsevier


The anesthetic care of the pediatric patient with a systemic disorder provides myriad challenges for the anesthesiologist. A thorough understanding of the patient's disease and the effect that the anesthetic will have on the disease process are the two most important issues the anesthesiologist must address. For some of these patients, appropriate consultation with the surgeon, pediatrician, and pediatric subspecialist is essential to the proper management of these potentially difficult and challenging anesthetics.

Copyright © 2008 Elsevier Inc. All rights reserved. -

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

Copyright © 2005 Mosby, An Imprint of Elsevier


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