Brain Death: Compliance, Consequences and Care of the Adult Donor

and Care of the Adult Donor

D.J. Powner

Introduction

Critical care physicians often certify brain death and may continue the care of those patients who become organ donors. This chapter will review recent publications and current practices in these topic areas with the intent of encouraging compliance with established policies for brain death determination and promoting investigations needed to establish evidence-based treatment guidelines for donor care.

Brain Death Certification Policies and Practices

Despite appropriate continuing discussion of the moral and ethical bases of the equivalence of brain death and patient death [1], its concept and certification pro- cesses have been widely accepted. Similarly, although not directly investigated, the irreversibility of brain death, as defined by current practice, has been indirectly vali- dated through publications in which patients with that diagnosis have been somati- cally supported without awakening for several months or longer. Diagnostic meth- ods were not always specified in these reports and some were related to maternal brain death wherein care was provided until delivery. However, over 70 such patients have been followed without a single neurological recovery recorded [1, 2].

Criteria for the declaration of death based upon absent neurological function have traditionally been set forth by policies and procedures. Internationally this process may be guided by national standards, individual physician practice or, as in the United States, by local hospital policy [3, 4]. Extensive variability in both policy requirements and physician compliance with those requirements has been documented [3 – 5].

Specific criteria have been recommended by authoritative groups [6, 7] and gen- erally include: warnings not to test in the presence of several confounding variables (e.g., certain drugs, severe hypothermia, shock), required documentation of unre- sponsiveness or cause of the coma, and specific testing methods, particularly for cranial nerve and medullary (apnea) function. ‘Confirmatory’ tests such as nuclide cerebral blood flow, electroencephalography, transcranial Doppler, or four-vessel angiography may be required or recommended when portions of the physical exam- ination might be compromised. Policies may reference ‘whole brain’ or ‘brainstem’

criteria and stipulate the number and qualifications of the examiner(s), if and when assessments should be repeated, and specific values for some tests (e.g. PaCO

dur- ing apnea testing).

Recent publications have highlighted: methodological variations in the assess-

ment of apnea [8], indicating equivalent results with T-piece, oxygen catheter, and

continuous positive airway pressure systems during testing; confirmatory testing with Doppler [9] wherein sensitivity for determining brain death was about 88 % but specificity was close to 100 %, radionuclide SPECT [10] showed a high degree of con- cordance with 4-vessel angiography, and the partial pressure of oxygen (PbtO

) in brain tissue [11] was diagnostic of brain death when the PbtO

became zero; and the occurrence of reflex or automatic movements after brain death from presumed spi- nal cord origins [12]. Thus, policies and procedures for certification of brain death may continue to change as newer techniques develop and interest in this area stimu- lates research. The critical care physician, therefore, is likely to be responsible for evaluating such technologies and providing leadership in the revision and enforce- ment of established policies/procedures.

Physiological Impact of Brain Death

Traumatic brain injury (TBI) and other catastrophic neuronal insults in humans release a large quantity of ‘stress hormones’ (e.g., epinephrine, dopamine, cortico- steroids) into the circulation. Superimposed upon this already hyper-adrenergic milieu, further catecholamine release/effects probably occur as anatomical brain death occurs. Animal studies have shown that the rapid induction of brain death stimulates the series of cardiovascular responses shown in Table 1. Hypertension, systemic and pulmonary arterial vasoconstriction and dysrhythmias occur early as the brainstem is compressed, but are soon followed by vasodilation and an abrupt decline in blood pressure. Histopathological contraction bands in the myocardium and pulmonary edema corroborate other physiological signs of acute heart failure.

Postulated mechanisms for these physiological changes during the evolution of clinical brain death include a ‘catecholamine storm’ of circulating hormone release, an accentuated sympathetic nervous system discharge, and the subsequent loss of autonomic vascular tone, described as ‘cerebro-spinal disconnection’ similar to changes after spinal cord injury. Pretreatment in animals with calcium channel and beta-receptor blockade before induction of brain death is protective, further impli- cating catecholamine-induced injury. Detailed recordings of these events in primates were published 18 years ago [13], but have not been duplicated in humans, although the sequence of clinical changes, histopathological findings and laboratory data in patients appear similar.

Table 1. Physiological effects of brain death – Baboon model [13]

Initial: (minutes)

Bradycardia and other dysrhythmias

Increased systemic and pulmonary vascular resistances Hypertension

Elevated pulmonary artery occlusion (wedge) pressure Increased cardiac output and left ventricular contractility Secondary:

Decreased systemic and pulmonary vascular resistances by 15 minutes Decreased left ventricular contractility and blood pressure by 45 minutes Reduced right and left ventricular compliance

Decreased coronary artery perfusion

Cardiovascular collapse by 5 – 7 hours

Genetic induction causes production and release of pro-inflammatory cytokines, particularly tumor necrosis factor (TNF)- [ and interleukin (IL)-6 during the evolu- tion of brain death. The precise mechanism for this response remains unclear but appears related to reperfusion injury in donor organs/tissues [14, 15]. Cytokines are released locally in many organs, but increased circulating blood levels confirm a sys- temic distribution and effect. Tissue based cytokines not only produce alterations in donor organ function but also enhance subsequent graft rejection in the recipient [16].

Milieu for Donor Care

If organ procurement for transplantation is planned after brain death, the clinician is challenged to refocus care toward preservation and improvement of those organs [17]. Some data suggest that some outcome measures from living donors may be superior to those from cadaver sources, indicating that organs are compromised after brain death and during donor care. The etiology of such compromise may be a pre-existing condition (e.g., atherosclerotic cardiovascular disease), direct organ trauma, conditions resulting from the neurological catastrophe precipitating patient admission (e.g., myocardial stunning, coagulopathy), reperfusion injury, pro-inflam- matory/catecholamine production/release, or events related to organ removal/ trans- port/ implantation. However, clinical experience and many observational studies during donor care indicate that organ compromise, especially in the heart and car- diovascular system occurs before explantation.

Clinicians providing donor care, therefore, are often confronted with the several physiological challenges listed in Table 2 very soon after brain death. The traditional practice of rapid organ allocation so as to expedite removal of organs from the unfa- vorable milieu of the donor has recently evolved toward a more extended treatment time. The intention of continued donor treatment is to allow correction of physiologi- cal abnormalities, thus improving organ function so that marginal organs might become transplantable. Recovery of organ function, especially the heart, has been well documented using treatments titrated to targeted physiological parameters [19 – 21].

These studies demonstrate that although donor organs, especially the heart and lungs, may have been compromised, careful treatment may restore function and provide organs equivalent to those originally deemed ‘acceptable’ by standard criteria.

Organ Allocation versus Donor Care

Concurrent with the care of the donor is the allocation of his/her organs to recipient transplantation programs. This important selection process combines variables unique to the donor and recipient. Some allocation variables (e.g., age, sex, ABO blood type, body-mass index, cause of death, prior medial/surgical/medication his- tory, length of time after admission, smoking history) are important factors for allo- cation, but are not amenable to change during donor treatment. Other variables, however, are amenable to change and may affect the potential for transplantation of all organs or those specifically targeted. Those interventions amenable to change during donor treatment, therefore, will remain the focus of this chapter.

One of the most important investigational challenges within donor care is to

identify ranges of tolerance within physiological and laboratory variables that will

Table 2. Common physiological conditions present during donor care

Condition Cause/Comment Treatment

Hypothermia Loss of hypothalamic temperature regulation causing a poikilothermic state; infusion of fluids/blood products below normal body temperature

Passive/active rewarming via forced air/

water blankets; warm inspired gas from ventilator; warm intravenous fluids or gastric/colonic lavage

Hypotension Decreased left ventricular contractility ascribed to myocardial ischemia/stunning;

vasodilation after cerebro-spinal disconnec- tion; prior dehydration or hypovolemia

Appropriate evaluation and treatment of abnormal preload, afterload, heart rate and contractility – see text

Polyuria Physiological mobilization of excess fluid;

hyperglycemic, osmotic, hypothermic or drug-related diuresis; diabetes insipidus;

serum sodium 8 155 mEq/l harms the donor liver [18]

Sequential assessment of urinary/serum electrolytes; hourly urine replacement with appropriate fluids; anti-diuretic hormone for diabetes insipidus

Infection Prior donor infection or nosocomial exposure (e.g., ventilator associated pneumonia, uri- nary/ intravascular catheters)

Continue antibiotics against known pathogens; obtain surveillance cultures;

prophylactic antibiotics not recom- mended

Nutrition Variable impact depending upon donor’s prior nutritional status and length of admis- sion

Continue nutritional support – enteral route preferred; caloric/carbohydrate loading is controversial; glycemic control is controversial – see text

Hypoxemia Usual causes in critically ill/injured patients;

prior goals of PaO

/FIO

ratio 8 300 chal- lenged by extended donor criteria – see text

Improvement in lung parameters due to donor care documented to ‘salvage’

lungs for transplantation – see text

still permit transplantation of an organ that will provide acceptable performance for the recipient. These ranges may extend beyond currently applied allocation stan- dards or the ‘normal values’ of laboratory or physiological testing and constitute

‘extended’ or ‘expanded’ criteria. Extended criteria have been supported in many small group series and expand the number of organs available. However, investiga- tions that provide reliable predictions of success from such extended criteria in larger recipient groups are lacking.

Similarly, tolerance ranges for parameters that can be influenced by the clinician must be integrated with those factors not amenable to change to create weighted sets of combined variables that may better anticipate the possibilities of success or com- plications after implantation. Creating these probability sets will require a large database of reliably obtained physiological and laboratory information and sophisti- cated statistical tabulations. However, this effort could provide evidence-based guid- ance to the allocation process that currently does not exist.

Finally, as others have expressed, an ‘acceptable’ outcome after transplantation may not be free of complications. An appropriately developed database, therefore, should assure with some recognized probability when more benefit than harm will likely occur from a given organ offering. Balancing the intensity of the recipient’s

‘need’ against such a ‘benefit/risk’ probability will ultimately always be somewhat

subjective but could be greatly assisted by a stronger data process.

Goals for Donor Treatment

In the absence of evidence-based data that address acceptable tolerances for those variables amenable to modification during donor care, many ‘authoritative’ recom- mendations have been published [22 – 26]. Guidelines for physiological parameters are shown in Table 3. The current goal for other laboratory variables is to maintain them within hospital “normal” values.

Table 3. Recommended cardiovascular and related parameters [22 – 26]

Central venous pressure: 4 – 12 mmHg

Pulmonary artery occlusion (wedge) pressure: 6 – 12 mmHg Cardiac index: 8 2.4 l/min/m

Cardiac output: 8 3.8 l/min

Left ventricular ejection fraction: 8 40 %

Systemic vascular resistance: 800 – 1200 dynes/s-cm

Mean arterial blood pressure: 8 60 mmHg Urine output: 1 – 3 ml/Kg/hr

Temperature: 8 36 °C (97°F) Hemoglobin: 8 10 g/dl Hematocrit: 8 30 %

Other laboratory parameters: within hospital normal values

Special Considerations

Several issues during donor care remain controversial and potentially conflict with other established critical care principles:

Glycemic Control

Rigorous treatment to avoid hyperglycemia is a widely promoted standard of critical care [27]. Hyperglycemia has been proposed to compromise the immune system in patients, but the harmful or possibly beneficial effects of such immunocompromise within the transplantation process soon to follow donor care are unknown.

The contribution to donor polyuria or other effects of serum hyperosmolality produced by hyperglycemia may complicate fluid/electrolyte treatment. Therefore, at least minimal therapy to avoid these effects may be necessary.

Liver glycogen content has been considered important in sustaining the explanted liver through cold storage and the possible reperfusion injury that may occur after implantation. Glycogen stores in the liver can be increased acutely at the time of liver removal using direct portal vein infusions of glucose [28] and may be possible as a function of donor nutrition [29], although a method of assuring glycogen ‘load- ing’ during donor care is not published. It seems unlikely that harmful liver steatosis could be induced during the short-term administration of extra carbohydrates, but this has not been investigated.

Islet cell stimulation by elevated serum glucose may be desirable prior to pancre-

atic organ or islet cell transplantation. However, potentially harmful effects have

been noted and the optimal serum glucose concentration to assure a desirable effect

is not established [30].

Therefore, several important considerations affect blood glucose tolerance during donor care. Without evidence-based data, the preferences of individual transplant programs/surgeons usually determine glycemic limits.

Hypertension/Hypotension

Hypertension is much less common than hypotension during donor care, but when present, potentially increases myocardial work and oxygen consumption. Goals include mean arterial pressure less than 90 mmHg [24] and systolic blood pressure

‹ 160 mmHg [26]. Only short-duration vasodilators, nitroprusside or nicardepine, or the beta-receptor blocker, esmolol, should be used to avoid possible pharmaco- logical suppression of contractility in the recipient.

Hypotension, due to the above noted mechanisms, is common. Resuscitation and maintenance of cardiovascular hemodynamics follow customary critical care prac- tices. A variety of tools has been used to assess measured or derived components of cardiac function, i.e., heart rate, preload, afterload and contractility. Diagnostic and monitoring methods include echocardiography, pulmonary artery catheterization, central venous pressure and esophageal Doppler [24, 26, 31, 32]. Appropriate assess- ment should direct selection of therapy, i.e., blood product/colloid/crystalloid fluid administration, inotropic drugs or vasopressor medications. Generally, of course, the minimum amounts of intravenous fluid or drugs needed to achieve the hemody- namic goals (Table 3) are preferred.

Mechanical Ventilation/Hypoxemia

No evidence-based data support mechanical ventilation methods different from those customarily practiced in critical care. The traditional allocation criterion of a PaO

/FiO

ratio 8 300 has been challenged by successful transplantation using expanded donor criteria at a lower ratio. Assertive pulmonary care also improves donor lungs and allows successful transplantation of these ‘marginal’ organs [33]. Ex vivo evaluation and treatment of compromised lungs prior to implantation [34]

remain investigational.

Hormonal Therapy

Replacement or supplemental administration of several hormones has been advo- cated, including glucocorticoids, thyroid, insulin, and vasopressin. A retrospective assessment of such use showed beneficial effects of some hormones in the number and function of some organs, but indications, dosages and concomitant information about donor condition or care were not given [35]. Donor treatment with methyl- prednisolone has become common practice as a method to increase oxygenation [36], but routine administration of thyroid and other hormones remains controver- sial [37]. If given, dosing recommendations have been published [23, 26].

Bacterial Contamination

Bacterial, viral, fungal, and protozoan infections may be transmitted from an

infected donor to the recipient(s) and may be associated with catastrophic conse-

quences in graft and patient survival [38], although recent case reviews have sug-

gested that certain Gram-positive donor infections may be tolerated after implanta-

tion [39]. Despite such reports, goals during donor care include continuing all pre- ventative measures to avoid nosocomial infections (e.g., established ventilator asso- ciated lower respiratory infection prevention protocols, blood stream infection pre- vention guidelines) and to treat recognized infection. The distinction between a ‘col- onized’ presence of infection and true tissue invasion is often difficult. Further, the latent incubation period before an infection present in the donor becomes manifest may contribute to findings of recipient contamination without evidence of donor infection. These factors have prompted some centers to initiate prophylactic antibi- otics during donor care, but recent consensus opinion recommends against such treatment [26].

Surveillance cultures and sampling of material or fluid that appears infected are justified, as is continued treatment of known infections. Best practice guidelines for culturing methods, interpretation of preliminary data, and selection of empiric anti- biotics recommend antibiotic selection based upon the sensitivities of organisms encountered in the local hospital followed by modifications when final cultures are known [40].

Coagulopathy

Abnormal coagulation leading to serious hemorrhage during donor care may result from previous medications prior to or during the current hospitalization that affected platelet function or production of coagulation proteins, consumption or dilution of normal coagulation factors, or development of disseminated intravascu- lar coagulation (DIC). Factor replacement therapy or treatment of thrombocytope- nia or dysfunctional platelets follows standard critical care practice as titrated against appropriate laboratory measurements. The presence of donor DIC is not considered an absolute contraindication to organ use [41].

Off-label administration of recombinant factor VIIa has been widely reported in patients who may evolve brain death and following transplantation, especially in liver recipients. Its use during donor care, however, has not been evaluated and must be considered investigational. Severe thromboembolic complications in patients are well known [42] although their incidence in a general population of bleeding patients [43] and among donors is not.

Reperfusion Injury and Preconditioning

Cellular injury to an organ after its removal, storage and re-implantation is well doc-

umented and considered likely due to production of oxygen radicals or other pro-

inflammatory mediators. It is also hypothesized that the accumulation of pro-

inflammatory cytokines during the evolution of brain death may similarly stimulate

a form of reperfusion injury due to the cardiovascular and hormonal changes previ-

ously discussed [14, 44]. Preconditioning interventions during donor care have been

proposed as possibly beneficial in preparing organs for such injury and perhaps

favorably modifying their response to reperfusion stress [45]. Induced liver ischemia

just prior to liver removal in the operating room [46], and an association between

donor cardiopulmonary arrest and better liver function in the recipient have sug-

gested a benefit from preconditioning ischemia [47]. Dopamine-induced production

of heme oxygenase and other immunologic properties may be protective especially

during renal transplantation [48, 49], but routine use of dopamine for this purpose

has not yet been recommended.

Anemia

No evidence-based data are available to guide therapy to optimal hemoglobin con- centrations. Harmful effects of both anemia and blood transfusion are well recog- nized within critical care [50]. Donor organ tolerance for anemia after cessation of cerebral oxygen consumption and the effect of immunomodulation induced by transfusion upon subsequent recipient care, however, are unknown. Recommenda- tions for hemoglobin include 9 – 10 g/dl [23, 26] or hematocrit 8 30 % [24].

Future Challenges

A potentially positive impact of donor care upon subsequent graft and recipient sur- vival has been accepted. However, the range of donor organ tolerance among vari- ables that can be altered during donor care remains largely unknown. Because many of these variables are inter-related the relative weighted importance of each must be investigated. Similarly, the interaction of variables amenable to change and those that cannot be altered and their relative importance must become known. Existing local, national and international databases should be expanded to include more detailed physiological data from donor care so as to create the data platform from which statistical correlation with outcomes may be derived. This complex statistical process may provide quantifiable risk information during organ selection and allo- cation, and provide better definitions of donor characteristics that are associated with acceptable recipient outcomes. These parameters would allow donor care in the future to be directed toward broader tolerance ranges for physiological parameters and thereby expand the pool of useable organs.

Conclusion

Brain death certification and donor care are commonly the responsibility of the crit- ical care physician. Adherence to applicable policies/procedures and providing lead- ership in modifying those policies as evidence-based data indicate are important parts of that responsibility.

Physiological changes that evolve during brain death challenge the clinician to recover or maintain organ function that will provide the best possible organ to the recipient. Many factors causing the profound abnormalities in cardiovascular/pul- monary function, fluid-electrolyte/acid-base balance, and hormonal dysregulation are unknown. Treatment is, therefore, often directed toward symptom management rather than pathophysiological mechanism.

Further investigation is required into the extended limits of those variables ame-

nable to change during donor care that will produce an acceptable organ. Integra-

tion of these limits with similar expanded criteria for those fixed variables not ame-

nable to change may provide better predictions of outcome during allocation and

better goals during donor care.

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