Aditya K. Kaza and Max B. Mitchell
This chapter is relevant to all surgeons caring for victims of trauma because traumatic injury is a leading cause of brain death and subsequent organ donation. Because of the severe shortage of organ donors, it is critical that traumatologists recognize potential organ donors as early as possible and care for these patients assuming that organ donation may occur. It is important for physicians to understand the criteria for brain death and the local requirements for the pronunciation of brain death.
This chapter provides an overview of the procurement organization and how organs are allocated. The responsibilities of the local organ procurement organizations (OPOs) are underscored in this chapter (i.e., community education, evaluation and screening of potential donors, local hospital coordination, and family counseling). The trauma team’s role is to resuscitate the patient and maintain perfusion of the organs. Once a potential donor is identified the trauma team must coordinate its efforts with the OPO. Once a patient is declared brain dead the trauma team’s role does not end. Cooperation between the trauma team and representatives of the OPO will help to maximize donation of organs and is important for preserving the function of donated organs.
INTRODUCTION
The combined developments of effective immunosuppressant therapy and sophisticated surgical techniques have made organ transplantation very successful in treating the end-stage failure of most solid organs. Transplantation is now the treatment of choice for end-stage heart, lung, liver, and renal disease for patients who have no contraindications to transplantation. Pancreas transplantation has also proven successful in the treatment of diabetes mellitus. In addition, there is increasing demand for bone, skin, and other tissues used in the treatment of other disease processes. Despite advances in living-related solid organ transplantation,1 the majority of transplant recipients remain dependent on cadaveric organ donors.2 Improved supportive care for patients with advanced organ failure and expanded indications for transplantation have increased the numbers of patients waiting for organs. In contrast, efforts at increasing the pool of suitable organ donors have had comparatively little success in increasing the supply of organ donors; however, there is a slow increase in living donors as noted from 1988 to 2005 (Fig. 50-1). Consequently, the number of patients on the various transplant waiting lists continues to outpace the available donor pool. In the year 2000, an average of 114 patients were placed on waiting lists each day while an average of 63 patients per day received organ transplants.3 During the same year, an average of 16 patients per day died awaiting transplantation.3
FIGURE 50-1 Total patients in the United States who underwent organ transplantation from deceased and living donors from 1988 to 2005. (Reproduced with permission from United Network for Organ Sharing website. Accessed February 2005. http://www.unos.org/Data.)
Traumatic brain injury is the most common cause of death leading to cadaveric solid organ donation.4 Clinicians caring for severely injured patients necessarily play a key role in the initiation and implementation of the transplantation process. Early recognition of potential organ donors is critical to maximizing the available pool of donor organs and the number of transplantable organs per donor. It is essential for those caring for potential organ donors to be knowledgeable about the criteria and process for declaring brain death and the physiologic effects of brain death. Familiarity with local OPOs is important because of the vital role they play in counseling the families of potential organ donors and coordinating the transplant process. Lastly, following the declaration of brain death, treatment priorities aimed at minimizing brain injury require adjustment. Physiologic support directed at maintaining perfusion of potentially transplantable organs assumes priority, and timely initiation of this support is crucial to increasing the probability of successful transplantation.
ORGAN DONATION AND ALLOCATION
Under the National Organ Transplant Act (Pub. L. No. 98-507, Title I, 1984), the U.S. Congress established The Organ Procurement and Transplantation Network (OPTN). The OPTN is a unique public–private partnership linking professionals involved in the organ donation and transplantation system. Subsequent federal legislation mandated that all U.S. transplant centers and OPOs must be members of the OPTN to receive any funds through Medicare or Medicaid (H. Rep. No. 100-383, 1987, and Pub. L. No. 100-607, Title IV, 1988). Other members of the OPTN include independent histocompatibility laboratories involved in organ transplantation; relevant medical, scientific, and professional organizations; voluntary health and patient advocacy organizations; and members of the general public with a particular interest in organ transplantation.
The OPTN is administered by the United Network for Organ Sharing (UNOS). UNOS is a private nonprofit charitable organization contracted by the Health Resources and Services Administration of the U.S. Department of Health and Human Services (DHHSS) to develop organ transplantation policy.5 Policy recommendations are then adopted and enforced by the DHHSS. UNOS facilitates organ transplantation by organizing the medical, scientific, public policy, and technologic resources required to maintain an efficient national transplantation system. UNOS is responsible for developing recipient priority policies and for managing the national transplant waiting lists. UNOS also sets professional standards for efficiency and patient care for transplant centers. UNOS maintains the national transplant database, plays a very important role in raising public awareness of the importance of organ donation, and helps to keep patients informed about transplant issues and policy.6
Organ donation, allocation, and procurement require a closely coordinated and complex series of efforts. In the United States, this process is coordinated by independent local OPOs. OPOs employ specially trained professionals who assist with the evaluation of potential organ donors, the declaration of brain death, counseling of donor family members, management of the donor, organ allocation, and the procurement process. When an organ donor is identified, the local OPO serves to ensure that brain death has been established and assists in obtaining consent for organ donation. Thereafter, coordination of organ placement and the procurement of the organs are facilitated by the OPO. There are currently 51 cooperating OPOs in the United States, distributed among 11 geographic regions. The regional system plays a pivotal role in the current process of allocating organs for transplantation. It was established to help reduce organ preservation time and improve organ quality and survival outcomes. In addition, it was intended to reduce the costs of organ transplantation and provide equal access to transplantation for patients regardless of where they live.
Donor organs are matched to individual patients according to waiting lists developed and coordinated by UNOS. Each organ waiting list incorporates specific criteria to establish individual patient ranking on the list. All lists incorporate patient waiting time and patient ABO blood grouping. For lung transplantation, these are the primary factors. The kidney waiting list also incorporates the degree of human lymphocyte antigen matching so that top priority is given to patients with a perfect human leukocyte antigens (HLA) match. This is not done for other organs. The heart and liver waiting lists differ by including organ-specific criteria to establish severity of illness prioritizing the sickest patients. All lists are patient specific so that organs are offered to an individual patient on a center’s list as opposed to the center. Organs are first offered locally within the boundaries of the involved OPO. If the organ is declined by all local centers, it is then offered regionally followed by national offers. There has been significant recent debate regarding the current allocation system with some parties advocating a nationally based system.7 Such a system would be predicated primarily on the severity of illness followed by waiting time while eliminating consideration of the region from which the organ originates. At this time, no changes in this system have been adopted.
DONOR SCREENING
The screening process for organ donors begins when a potential organ donor is identified. All patients who have suffered severe brain injuries and are either brain dead or likely to progress to brain death should be considered for organ donation regardless of their age, underlying cause of illness, and overall social history. Although perceived contraindications to donation may exist, they should be discussed with a representative of the local OPO before concluding that a given patient is not a candidate for organ donation (Table 50-1). The physician caring for the patient is responsible for notifying the local OPO of such patients. In many states physicians are legally required to notify the local OPO of each in-hospital death. All OPOs employ personnel who are responsible for advising health care providers on the suitability of an individual patient for organ donation. Communication with local forensic authorities is extremely important. The OPO will contact the medical examiner or coroner in order to obtain permission to proceed with organ donation. Once a donor is identified, the OPO is responsible for obtaining family consent for organ donation. Organ procurement specialists are trained in counseling families about the importance and process of organ donation, and it is advisable to refer families to these specialists when potential organ donation is discussed. These individuals also perform a careful review of the potential donor’s social and past medical history. The circumstances leading to brain death are very important, as is any history of the occurrence and duration of cardiopulmonary arrest. Screening also includes an extensive laboratory and serologic evaluation to exclude chronic disease and transmissible infections. A donor profile is then generated and includes current hemodynamics as well as an assessment of current organ function. The assessment of organ function is individualized to the donor based on the donor profile, the specific organs under consideration, and the level of medical support required to maintain the donor. The overall profile that is generated is crucial for transplant physicians who must evaluate the suitability of a given organ donor for the individual recipient.
TABLE 50-1 Contraindications to Organ Donationa
DECLARATION OF BRAIN DEATH
Ethical standards in the United States mandate that all organ donors must be declared dead before organ donation can proceed. Brain death must therefore constitute a sufficient basis on which to declare a person legally dead. Despite continued interest in non-heart beating donors, the vast majority of cadaveric organs are procured from donors whose deaths are declared on the basis of brain death. Consequently, cadaveric solid organ donation is dependent on the ability to reliably determine that a patient is brain dead.8 Unfortunately, many clinicians remain poorly informed about brain death and how it is defined. The current concept of brain death used in the United States is based on guidelines published in 1981 by the President’s Commission for the Study of Ethical Problems and adopted under the Uniform Determination of Death Act (Table 50-2).9,10 This act states that death has occurred when there is irreversible cessation of all functions of the brain including the brain stem. Each state government has adopted these guidelines in legislating local criteria for the determination of brain death. The qualifications and number of physicians who must agree on the diagnosis of brain death in order to legally declare a patient brain dead vary considerably among the 50 states. Some states require two separate declaration procedures with a defined time interval between the two examinations. Some states require that the declaration be made by two separate physicians. In other states a single physician may declare a patient brain dead on the basis of one examination. In no case can the declaring physician take part in the recovery or transplantation of organs from the donor. Most hospitals have established policies within state guidelines for physician qualifications required to make the diagnosis of brain death. Physicians caring for these patients should be aware of local requirements and hospital guidelines in order to facilitate the declaration process and allow termination of care for brain dead patients who will not be organ donors.
TABLE 50-2 Defining Brain Death: Guidelines of the President’s Commission for the Study of Ethical Problems in Medicine (1981)
Symptoms that support the diagnosis of brain death are the absence of brain stem reflexes, absence of cortical activity, and the demonstration of the irreversibility of this state.8 Therefore, in order to declare brain death there must be proof of the cause of brain injury; otherwise, the irreversibility requirement cannot be met.11 A patient found unresponsive with no clear cause of brain death generally cannot be an organ donor. Secondly, all reversible causes of coma must be excluded. Causes of reversible coma include hypothermia, hypoxia, hypoglycemia, hyperglycemia, uremia, hepatic failure, Reye’s syndrome, hyponatremia, hypercalcemia, myxedema, adrenal failure, and central nervous system (CNS) depressants. The presence of CNS depressing agents such as narcotics, sedatives, anticonvulsants, anesthetics, and alcohol must be assessed. If any of these agents are present, confirmatory testing is usually required to declare brain death.12 In the brain dead patient, all cranial nerve function will be absent. The absence of brain stem reflexes must be confirmed by careful neurologic examination. Neuromuscular conduction must be intact in order to allow adequate examination; consequently, the presence of neuromuscular blocking agents must be excluded.
The most definitive finding supporting the diagnosis of brain death is the presence of apnea. The apnea test remains one of the most important parts of the neurologic evaluation of potential organ donors.13 To perform a reliable apnea test the PaCO2 is normalized to 40 mm Hg. The patient is preoxygenated with 100% O2 for at least 5 minutes. The patient is then disconnected from the ventilator and placed on 100% O2 delivered passively to the endotracheal tube via a T-piece at 8–12 L/min. The PaCO2 is allowed to rise to 60 mm Hg, confirmed by a blood gas drawn after approximately 10 minutes. If hemodynamic instability occurs, the patient should be immediately returned to mechanical ventilation and a blood gas should be drawn to assess the PaCO2. If there is any evidence of respiratory activity, the patient is not brain dead and should be immediately returned to the ventilator. If there is no evidence of spontaneous respiratory activity, the PaCO2 has reached 60 mm Hg, and the pH is acidotic, apnea is established and is strongly supportive of brain death.
In many cases confirmatory testing must be performed in addition to a careful neurologic examination in order to firmly establish the diagnosis of brain death. Patients with cervical fractures above the level of C4 may not have intact diaphragmatic function precluding a reliable apnea test. Apnea testing is also unreliable in cases involving overdoses of substances that depress respiratory drive such as alcohol, antiseizure medications, and sedatives. Hemodynamic instability during apnea testing will also preclude the establishment of the diagnosis of brain death on the basis of apnea. In other cases local requirements and or hospital policy may dictate the use of additional confirmatory testing. Confirmatory tests may also be useful in demonstrating a clear etiology for brain death or severe anatomic damage and can decrease the observation period required to establish the diagnosis of brain death.12
Confirmatory tests of brain death include electroencephalogram (EEG), testing of brain stem auditory-evoked response (BAER), and methods of demonstrating the absence of cerebral blood flow. EEGs are not entirely reliable and are now rarely used for this purpose with the exception of brain death determination in young infants. BAER testing involves measuring electrical waveforms generated in the brain stem in response to an auditory stimulus transmitted by headphones. In the brain dead patient no waveform will be detectable. BAER testing is rarely used at this time. Demonstration of the absence of cerebral blood flow is the most common confirmatory test currently in use. Methods used to make this determination include cerebral angiography, cerebral blood flow Doppler ultrasound scanning, and radionucleide cerebral blood flow scanning. The latter two methods are noninvasive, low risk, relatively inexpensive, and are more readily available than cerebral angiography. These tests are highly accurate in verifying the absence of cerebral blood flow and are useful in reducing the time required to establish the diagnosis of brain death. Conversely, an examination that indicates continued cerebral blood flow does not necessarily exclude the diagnosis of brain death. Uncommonly, cerebral blood flow may persist despite brain death due to testing before increasing intracranial pressure completely shuts down flow, skull pliability in infancy or in the presence of decompressing fractures, ventricular shunts, ineffective deep brain flow, reperfusion, brain herniation, jugular reflux, the presence of emissary veins, and pressure injection artifacts.14
Appropriate documentation of brain death is very important in facilitating organ donation for a brain dead patient. The diagnosis of brain death must be documented in writing and it must be unequivocal. The circumstances leading to brain injury, the specific findings of the neurologic examination, and the results of any confirmatory tests should be clearly recorded. Lastly, the date and time of the declaration of brain death must be noted before OPO personnel may obtain the permission of local authorities and the consent of the potential donor’s family. Despite the presence of evidence indicating a person’s desire to be an organ donor, family consent for donation must be obtained. Family refusal is the most common reason that otherwise suitable donors do not become organ donors. If consent for donation is declined, appropriate testing and documentation of brain death is necessary in order to initiate the withdrawal of care.
PHYSIOLOGIC CONSEQUENCES OF BRAIN DEATH
Brain death has profound effects on virtually all organ systems either directly or secondarily as a consequence of the accompanying effects on the cardiovascular and respiratory systems.15 Disruption of normal autonomic innervation may lead to profound vasodilation and hypotension. In turn decreased organ perfusion is injurious to potentially transplantable organs. Direct myocardial depression may occur and is largely due to increased sympathetic outflow as a response to sudden increases in intracranial pressure.15 This may lead to arrhythmias, myocardial ischemia, and in some cases myocardial infarction. Circulatory instability impairs distal organ perfusion leading to significant injury that may preclude organ donation. Respiratory dysfunction associated with brain death will have profound effects on all other organ systems. Impaired gas exchange is common in brain dead patients who have required mechanical ventilation for any length of time. Pulmonary infection and or aspiration injury frequently occur in potential organ donors either prior to or early after the time of endotracheal intubation. Neurogenic pulmonary edema is another cause of impaired gas exchange that may accompany brain death.16 Myocardial dysfunction may also contribute to lung dysfunction due to increases in left atrial pressure thereby potentiating pulmonary edema. Similarly, hypoxemia will further impair myocardial function leading to a precarious hemodynamic state. Endocrine dysfunction is also common. The absence of hypothalamic function leads to the loss of thermoregulation and is manifested by the development of hypothermia. Impaired thyroid regulation contributes to hypothermia, and circulatory instability. Diabetes insipidus is common because antidiuretic hormone is no longer released from the posterior pituitary. If not managed appropriately diabetes insipidus will have a profound effect on fluid and electrolyte balance. The systemic release of substances from necrotic brain tissue may lead to disseminated intravascular coagulation producing a consumptive coagulopathy that is often exacerbated by hypothermia. Without appropriate intervention brain death is followed by severe injury to all other organs, and circulatory collapse will usually occur within 48 hours.
DONOR MANAGEMENT
Prior to the declaration of brain death, the treatment of patients with severe brain injury is directed at controlling intracranial pressure and preserving cerebral perfusion pressure in order to limit secondary brain injury. Once the diagnosis of brain death is established and a patient is recognized as a potential organ donor, treatment priorities must shift in favor of preserving the function of potentially transplantable organs. Preservation of organ function requires maintenance of adequate organ perfusion. Therefore, the goal of donor management should be to normalize hemodynamics and maintain biochemical parameters of organ function in as normal a condition as possible. Because of the profound effects on the cardiovascular system, invasive hemodynamic monitoring is essential to guide the appropriate resuscitation of brain dead patients. Central venous access should be obtained to allow measurement of volume status and to provide a reliable means of administering vasoactive drugs. Arterial access is required to facilitate continuous monitoring of blood pressure and frequent measurements of acid–base status, gas exchange, and serum biochemical parameters.
Hypovolemia is common in brain dead patients due to vasodilation and in some cases blood loss as a result of trauma or fluid loss due to diabetes insipidus. In general, patients should be resuscitated with crystalloid and appropriate blood products based on measurements of hematocrit and coagulation status. Resuscitation should be guided by frequent monitoring of central venous pressure or pulmonary capillary wedge pressure. Body temperature must be monitored and should be maintained above 36°C using passive warming as needed. Urine output should be maintained at 2 mL/kg/h. Renal dose dopamine (3–5 μg/kg/min) is recommended for nearly all donors unless higher doses are required to maintain perfusion. Vasopressin should be infused to treat diabetes insipidus when present, and fluids should be adjusted on the basis of electrolyte measurements.17 This will usually require the administration of 5% dextrose solution. Serum sodium and osmolarity should be kept as normal as possible. Replacement fluids should be based on measurements of serum electrolytes and urine output. Frequent serum glucose measurements are required to facilitate treatment of hyperglycemia. Excess fluid administration may lead to pulmonary edema causing the lungs to become unsuitable for transplantation. Therefore, judicious fluid resuscitation is important in order to maximize the number of transplantable organs.
Inotropic support should be introduced to support blood pressure if initial volume resuscitation fails to restore adequate perfusion pressure.18 Dopamine is usually the first agent of choice. Pure vasoconstrictors such as norepinephrine should be avoided whenever possible due to deleterious effects on myocardial, and splancnic perfusion. Dobutamine is frequently added to increase cardiac output. If these agents are not effective at restoring hemodynamic stability, an epinephrine infusion should be initiated and titrated to the lowest dose required to achieve adequate support. Thyroxine (T4) or triiodothyronine (T3) infusions are commonly used due to their inotropic effects and potentiation of myocardial catecholamine sensitivity.19 However, there is continuing controversy regarding whether or not the use of thyroid hormone infusions have a beneficial effect on organ function following transplantation. Consequently, thyroid infusions should be used primarily at the discretion of OPO representatives in consultation with their medical directors and the involved transplant physicians.
Ventilator management in potential organ donors is dependent on the respiratory function of the donor. Pulmonary injury is common in brain dead patients, and all attempts should be made to preserve the possibility of lung donation. As mentioned previously, fluids must be managed carefully and should be guided by measurements of central venous pressure. Chest radiographs should be obtained to assess pulmonary expansion, guide appropriate intervention to counteract atalectasis, and assess the suitability for transplantation. A nasogastric tube should be placed and kept on suction in order to minimize gastric distension and the risk of aspiration. An endotracheal tube with an internal diameter of 7.5 mm or larger should be inserted whenever possible in order to accommodate a therapeutic size fiberoptic bronchoscope. This will assist in the evaluation of potential lung donation and will facilitate clearing secretions to optimize lung expansion. Excessive mean airway pressures should be avoided. Tidal volumes and physiologic levels of positive end-expiratory pressures (PEEP) should be maintained to provide adequate lung expansion and minimize atalectasis. High concentrations of inspired oxygen are injurious to the lungs and should be avoided. The inspired oxygen concentration should be titrated to maintain an oxygen saturation of 95%. In patients with significant pulmonary injury, lung donation is unlikely; therefore, increased levels of PEEP and higher inspired oxygen concentrations may be required.
ORGAN PROCUREMENT
The actual process of multiorgan procurement occurs in the operating room environment under the usual sterile conditions.20 Representatives of the local OPO will coordinate the use of the operating room with the arrival of the various transplant procurement teams involved with a particular donor. Frequently, this procedure may involve several teams whose members are operating together for the first time. In addition, the initial phases of the transplant operations for heart and lung recipients are commonly carried out simultaneously with the donor procurement procedure in order to minimize graft ischemia time.
An anesthesiologist is required to provide physiologic support of the donor during the procurement procedure. The donor patient is prepped and draped to allow an incision from the sternal notch to the pubis. In this manner, the thoracic and abdominal organs can be evaluated and procured simultaneously. In all cases, the final determination of organ suitability for transplantation is made after visual inspection and manual palpation of the organ. Biopsy of any suspicious lesions should be performed, and pathologic evaluation of frozen sections must be confirmed before the recipient transplant operation is initiated. Similarly, a liver biopsy may be required to evaluate the degree of fatty infiltration present in some donors. Following inspection the thoracic and abdominal organs are dissected to allow rapid removal after flushing with the appropriate preservation solution. There are numerous preservation solutions in use and vary according to the organ being procured and the preference of the procuring institution. All preservation solutions are kept at approximately 4°C because hypothermia is a key element of organ preservation. After all intended organs are dissected, the patient is systemically anticoagulated with heparin. Appropriate vascular cannulas are inserted in the abdominal and thoracic vessels to allow rapid flushing of the organs being procured. When all members of the procuring teams are prepared the superior vena cava, ascending aorta, and the supraceliac aorta are clamped. The inferior vena cava is transected at the cavoatrial junction and blood is suctioned from the open inferior vena cava exsanguinating the patient. The left atrium is vented in order to prevent left ventricular distension and back pressure on the pulmonary vascular bed. Preservation fluids are infused through the previously placed cannulas flushing the procured organs of blood and rapidly lowering their temperature. Topical ice is applied augmenting rapid cooling. Thereafter, the heart and lungs are usually removed first. Donor hepatectomy is then carried out followed by removal of the kidneys. Variations in this sequence are required when the pancreas and or small bowel are also procured. The iliac vessels and occasionally segments of the descending thoracic aorta are then removed to provide additional vascular conduits that are sometimes necessary for complex vascular reconstructions at the time of organ implantation. All organs are inspected on the back table to ensure that no surgical damage has occurred. Finally, the organs are placed in sterile containers containing cold preservation solution or saline. The containers are then packed in ice in preparation for transport to the location where transplantation will occur. Once all solid organs are removed any additional tissues approved for donation are removed.
CONCLUSION
Organ transplantation benefits thousands of people every year in the United States alone. However, donor organs remain a precious resource as evidenced by increasing recipient waiting times and the increasing number of patients who die waiting for donor organs. Efforts at expanding the available donor pool have not kept up with the need for organs. More recent efforts include the use of non-heart beating donation strategies,21 the relaxation of donor organ criteria for recipients who would otherwise not be candidates for transplantation,22 and other strategies. In general, these measures have not been widely adopted and the donor to recipient disparity will undoubtedly continue. Advances in the development of artificial organs and xenotransplantation hold great promise in relieving this situation. Nevertheless, health care providers who care for traumatically injured patients will continue to play an important role in the identification and critical care management of potential organ donors for the foreseeable future.
REFERENCES
1. Bak T, Wachs M, Trotter J, et al. Adult-to-adult living donor liver transplantation using right-lobe grafts: results and lessons learned from a single-center experience. Liver Transpl. 2001;7:680.
2. UNOS Website. 2000 Annual report of the U.S. Scientific Registry for transplant recipients and the Organ Procurement and Transplant Network transplant data: 1990–1999. http://www.unos.org/Data/anrpt00/ar00_data_fig_01.htm. Accessed January 6, 2002.
3. UNOS Website. http://www.unos.org/Newsroon/archive_newsrelease_20011220_statquote.htm. Accessed January 12, 2002.
4. UNOS Website. 2000 Annual report of the U.S. Scientific Registry for transplant recipients and the Organ Procurement and Transplant Network transplant data: 1990–1999. http://www.unos.org/Data/anrpt00/ar00_table12_05_alld.htm. Accessed January 6, 2002.
5. UNOS Website. http://www.unos.org/About/who_main.htm. Accessed January 12, 2002.
6. UNOS Website. http://www.unos.org/About/what_main.htm. Accessed January 12, 2002.
7. Fung J. Survival of the sickest. Organ allocation should be based on patients’ medical need, not location. Mod Healthc. 1998;28:29.
8. Beresford HR. Brain death. Neurol Clin. 1999;17:295.
9. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical Behavioral Research: Defining Death. A Report on the Medical, Legal, and Ethical Issues in Determination of Death. Washington, DC: U.S. Government Printing Office; 1981:1.
10. Beecher HK, Adams RD, Banger AC. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA. 1968;205:337.
11. Lazar NM, Shemie S, Webster GC, et al. Bioethics for clinicians: 24. Brain death. CMAJ. 2001;164:833.
12. Lopez-Navidad A, Caballero F, Domingo P, et al. Early diagnosis of brain death in patients treated with central nervous system depressant drugs. Transplantation. 2000;70:131.
13. Lessard M, Mallais R, Turmel A. Apnea test in the diagnosis of brain death. Can J Neurol Sci. 2000;27:353.
14. Flowers WM Jr, Patel BR. Persistence of cerebral blood flow after brain death. South Med J. 2000;93:364.
15. Power BM, Van Heerden PV. The physiological changes associated with brain death–current concepts and implications for treatment of the brain dead organ donor. Anaesth Intensive Care. 1995;23:26.
16. Rogers FB, Shackford SR, Trevisani GT, et al. Neurogenic pulmonary edema in fatal and nonfatal head injuries. J Trauma. 1995;39:860.
17. Powner DJ, Kellum JA, Darby JM. Abnormalities in fluids, electrolytes, and metabolism of organ donors. Prog Transplant. 2000;10:88.
18. Powner DJ, Darby JM. Management of variations in blood pressure during care of organ donors. Prog Transplant. 2000;10:25.
19. Roels L, Pirenne J, Delooz H, et al. Effect of triiodothyronine replacement therapy on maintenance characteristics and organ availability in hemodynamically unstable donors. Transplant Proc. 2000;32:1564.
20. Van Buren CT, Barakat O. Organ donation and retrieval. Surg Clin North Am. 1994;74:1055.
21. Fung JJ. Use of non-heart-beating donors. Transplant Proc. 2000; 32:1510.
22. Laks H, Marelli D. The alternate recipient list for heart transplantation: a model for expansion of the donor pool. Adv Card Surg. 1999;11:233.