chapter 120 st elevation myocardial … 120: st elevation myocardial infarction (stemi) contemporary...

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Chapter

119Brain Death and Management of the Potential Organ DonorDaviD S. GloSS ii, Kenneth e. WooD, and a. JoSeph layon

IntrODuctIOn

Management of the potential organ donor in the intensive care unit (ICU) represents a significant part of the solution to the ongoing crisis in organ donation. Ensuring maximal uti-lization and optimal management of the existing donor pool significantly increases the number of donors available for pro-curement and enables transplantation to save the lives—and enhance quality of life—of those with end-stage disease. As in other areas in medicine, standardization and the elimination of inappropriate variation in the management of the poten-tial organ donor leads to higher procurement rates, improved quality of organs procured, and improved recipient outcomes. The standardized approach to the management of the potential organ donor begins with surveillance to identify patients with severe neurologic injury that will likely progress to brain death, and identification of potential candidates for donation after cardiac death (DCD). The Organ Procurement Organization (OPO) notification process should, in addition, be standardized and utilize accepted clinical triggers such as the recognition of a nonsurvivable neurologic injury, initiation of end-of-life (EOL) discussions with a family, or the consideration of a formal brain death examination. The methodology to diagnose brain death should be standardized and followed by a uniform request for consent in all cases in which brain death occurs.

In the interval between the suspicion of brain death and its declaration, it is imperative that the patient be supported such that the brain death examination can be undertaken. Simi-larly, the brain-dead, potential organ donor should be fully supported in the interval between declaration and attempting to secure consent from the donor’s family. The Centers for Medicare and Medicaid Services (CMS) Conditions of Par-ticipation requires that potential organ donors be supported during this interval and that formal request for donation be made in all cases of brain death. While the patient is fully supported during this interval, formal donor management commences only after consent is obtained. Donor manage-ment necessitates an intensity of care that is, actually, indis-tinguishable from the management of any other critically ill patient in our ICU. However, the focus shifts away from the previously undertaken cerebral protective strategies to those resulting in optimization of transplantable donor organs. This is a crucial management period: (a) it facilitates donor somatic survivorship such that procurement may be under-taken; (b) it maintains the donor organs in the best possible condition; and (c) it mitigates ongoing ischemia–reperfusion (IR) injury. The latter has been linked to an inflammatory response, creating an immunologic continuum between the donor and recipient, which may jeopardize organ function in the recipient. Management of the potential organ donor

is effectively the simultaneous medical management of the seven potential recipients of the donor organs. The corner-stone of donor management is hemodynamic and cardiovas-cular maintenance, upon which we primarily focus.

BraIn Death PhysIOlOgy

Cushing’s landmark manuscript, published in 1902, described the “Experimental and Clinical Observations Concerning States of Increased Intracranial Tension” (1). Utilizing an ani-mal model and differentiating local compression from a general compression of the brain, Cushing examined the physiology of intracranial hypertension and its effect upon systemic hemody-namics, now known as Cushing triad—irregular respirations, decreased heart rate, and increased blood pressure. In contrast to Cushing model, where the experimentation is undertaken in a controlled setting, the physiology of human brain death remains challenging. For example, the time of actual brain death maybe significantly different from the certification time with significant physiologic changes occurring in the interval; treatment of the patient in the period antecedent to brain death and in the imme-diate postbrain death period may result in abnormalities inde-pendent of brain death; and lastly, there will never be a human model of brain death (2). Consequently, our understanding of brain death physiology is derived from animal models and infer-ential data from human case series.

Similarly, management of the potential organ donor requires an implicit understanding of the pathophysiology of brain death as well as an appreciation of the traumatic or physiologic events that contributed to, or precipitated, brain death, and which may act synergistically with brain death physiology to impair organ function during the management period. This is best exempli-fied in the cardiovascular system, in which hemodynamic insta-bility in the potential organ donor is likely reflective of a series of events conspiring to produce coincident cardiac dysfunction and vasodilatation. It is recognized that brain injury may lead to cardiac dysfunction, reflected in ECG abnormalities and cardiac enzymatic elevations (3). However, recent studies of survivors of severe brain injury have revealed significant cardiovascular dysfunction consequent to that injury, best exemplified in the subarachnoid hemorrhage (SAH) patient population. Recogniz-ing that the degree of injury in the brain-dead, potential organ donor is far greater than in survivors of severe neurologic injury, it is reasonable to assume that events predating brain death may precipitate cardiac dysfunction to which the brain death event is additive.

In patients with SAH, the initial event’s severity has been shown to predict the magnitude of cardiac dysfunction (4–6). Eighty percent of Hunt Hess Grade 5 SAH patients will exhibit a troponin release compared to less than 10% of those with a

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1560 SeCtion 12 neuroloGic DiSeaSe anD DySfunction

Hunt Hess Grade 1 SAH. Temporally, this release occurs in the early days after the bleed. In this population, left ventricular systolic dysfunction is reported to occur in 10% to 28%, and diastolic dysfunction in 70% of patients. Diastolic impairment and the associated distortion in the pressure volume relation-ship of the left ventricle will assume an important role in the volume resuscitation of organ donors and potentially contrib-ute to increased extravascular lung water. The pattern of wall motion abnormalities reported differs appreciably from those related to coronary artery disease, with a pattern of unique apical sparing and frequent involvement of the basal and mid-ventricular portions of the anteroseptal and anterior walls and the mid-ventricular portions for the inferoseptal and antero-lateral walls; this myocardial dysfunction is reversible over time which may have implications for the echocardiographic assessment of potential organ donors. In a study compar-ing sympathetic innervation evaluated with MIBG scanning (meta{123} iodobenzylguanidine) to myocardial vascular per-fusion assessed with MIBI scanning (technetium sestamibi) in SAH patients with cardiac dysfunction, an association between regions of contractile dysfunction and abnormalities in sympa-thetic innervation with normal perfusion was noted. Patients with evidence of global cardiac denervation manifested the lowest cardiac ejection fraction (EF) and worst regional wall motion scores compared to patient’s without evidence of car-diac denervation, whose EF and wall motion scores were pre-served (7). The preceding is at least partially explained by a catecholamine release hypothesis related to severe brain injury with the resultant effect upon cardiac function. Although not well studied, it appears that similar neurocardiac associations occur in other forms of severe brain injury such as traumatic brain injury (TBI). Insofar as severely brain-injured patients that ultimately die undoubtedly have a more severe form of

brain injury than those surviving, it would be reasonable to conclude that the antecedent brain injury, in conjunction with the brain death process described below, will significantly impact upon cardiac function.

Similar to the above recognition of a neurocardiac axis, there is evidence of endocrine dysfunction in patients with severe brain injury. Given the controversial use of hormone resuscitation therapy (HRT) in the management of potential organ donors, it is important to appreciate that antecedent endocrine dysfunction may be present in advance of brain death and contribute to the instability of potential organ donors. Prebrain death endocrine dysfunction may be precipitated by direct injury to the hypothalamic pituitary axis, neuroendo-crine effects from catecholamines and cytokines, disruption of the vascular supply, or from systemic infection or inflamma-tion. In a review of endocrine failure after TBI in adults, the estimated incidence of hormonal reduction was adrenal 15%, thyroid 5% to 15%, growth hormone 18%, vasopressin 3% to 37%, and gonadal 25% to 80%; hyperprolactinemia was present in more than 50% of patients. The authors concluded that severe TBI, when accompanied by basilar skull fracture, hypothalamic edema, prolonged unresponsiveness, hyponatre-mia, and/or hypotension, was associated with a high incidence of endocrinopathy (8,9). As with antecedent cardiac dysfunc-tion, it would seem reasonable that prebrain death endocrine dysfunction, in conjunction with the brain death process, may contribute to instability during the donor management period.

In concert with the previously described prebrain death physiology associated with severe brain injury, the process of brain death results in significant pathophysiologic changes in all organ systems with the cardiovascular system being most impacted. The rostrocaudal progression of ischemia, con-temporarily known as coning is illustrated in Figure 119.1.

Heart rate

Physiologic CorrelationIschemic Distribution

Normal Brain

Herniation and Brain Death

Progressive Cerebral—Spinal Ischemia “Coning”

Heart rate

Irregular breathing

Endocrine dysfunction?

Thermoregulatory impairment

Cardiac output

Blood pressure

Cerebrum................ Vagal Activation

Spinal Cord............. Sympathetic Deactivation

Hypothalamus Destruction

Pituitary Destruction

MedullaOblongata...............

Sympathetic Stimulation Only(Autonomic Storm)

Pons........................ Mixed Vagal and SympatheticStimulation (Cushing Respone)

Heart rate

Cardiac output

Blood pressure

Blood pressure

Blood pressure

Heart rate

FIgure 119.1 the rostrocaudal progression of ischemia contemporarily known as coning.

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Chapter 119 Brain Death and Management of the potential organ Donor 1561

Ischemia at the cerebral level produces vagal activation asso-ciated with a decreased heart rate, decreased cardiac output (CO), and decreased blood pressure. Although underappreci-ated, the first signs of incipient central herniation may simply be bradycardia in a severely brain-injured patient. Ischemia at the pons level produces the mixed vagal and sympathetic stimulation known as the Cushing response characterized by bradycardia and hypertension associated with irregu-lar breathing. Further progression of the coning process to involve ischemia of the medulla oblongata is associated with a sympathetic stimulation termed the autonomic storm; Table 119.1 details the progression of central herniation. During this period, dramatic increases in catecholamines are reported with significant tachycardia and elevations in blood pressure. This represents the severely brain-injured patient’s attempt to main-tain cerebral perfusion pressure (CPP) gradients in the face of elevated increased intracranial pressure (ICP) and evolving herniation. During this period, there is ischemic destruction of the hypothalamic pituitary axis resulting in thermoregulatory impairment and purported endocrine dysfunction. Further progression of ischemia results in spinal cord destruction with herniation and sympathetic deactivation characterized by bra-dycardia, vasodilatation, and a low CO state. Somatic death after clinical brain death will inevitably occur in the absence of aggressive support. In an era when brain death was not accepted, prolonged survivorship, with a mean duration of 23 days, was noted in a study that aggressively maintained brain-dead patients (10). Autopsy studies of patients that were declared brain dead revealed histopathologic evidence of necrosis and liquefaction (11).

The catecholamine surge or autonomic storm produces multiple ECG and hemodynamic abnormalities along with biochemical and histologic changes in the cardiac system. In a series of sentinel observations and experiments, Novitzky (13–18) initially defined the cardiovascular pathophysiology associated with brain death. Catecholamines induce a sudden increase in cytosolic calcium, which jeopardizes ATP production and activates lipases, proteases, and endonucleases. Xanthine oxidase activation reportedly produces free radicals, further impairing organ function. Histopathologic changes reported

in experimental animals reveal various degrees of focal myo-cyte necrosis located predominantly in the subendocardial area consisting of contraction bands and myocytolysis with mononuclear cell infiltrates precipitating edema proximate to the necrotic areas. Contraction bands were observed in the smooth muscle of coronary arteries, and electron microscopy revealed a hypercontractile state of the sarcomere visualizing mitochondrial deposition of electron-dense material and sec-ondary lysosome containing injured mitochondrial. The loss of ATP production jeopardizes myocardial energy stores and mediates the transition from the aerobic to anaerobic metabo-lism compromising myocardial function.

Animal data and observations from human series have defined multiple abnormalities related to the catecholamine surge and brain death including impaired coronary endothelial dysfunction (19), selective expression of inflammatory mole-cules (20), downregulation of myocardial contractility (21), abnormalities in loading conditions and impaired coronary perfusion (22), abnormalities of left ventricular myocardial gene expression (23), and changes in myocardial beta-adrener-gic receptor function and high-energy phosphates along with beta-adrenergic receptor deregulation (24,25). From animal models, it appears that a sudden rise in ICP is more provoca-tive of the hyperdynamic–hemodynamic response, with sig-nificantly higher catecholamine levels, and is associated with greater histopathologic damage. A more gradual increase in ICP resulting in brain death is associated with a milder hyper-dynamic response, less catecholamine release, and milder ischemic changes in the myocardium (26). Clinically, this has been correlated with the development of cardiac allograft vas-culopathy in the recipient. The coronary artery vasoconstric-tion, subendocardial ischemia, and focal myocardial necrosis associated with the autonomic storm have been reported to be associated with a high incidence of intimal thickening of the transplanted heart coronary arteries, myocardial infarction, and the need for subsequent revascularization surgery (27).

The hemodynamic abnormalities and their impact are illus-trated in a study comparing postbrain death cardiac function in a group of potential organ donors whose autonomic storm was attenuated with donors whose autonomic system storm

TABLE 119.1 Central Herniation

Stage of Herniation Diencephalon Midbrain to Upper Pons Lower Pons Medulla

consciousness lethargy (early), agita-tion, progresses to coma (late)

coma coma coma

pupils Small (1–3 mm),Sluggishly reactive

Mid-position (3–5 mm),Sluggish to not reactive

Mid-position, not reactive

Dilated, not reactive

respirations pauses, sighs, cheyne–Stokes

central neurogenic hyperventilation,

cheyne–Stokes

central neurogenic hyperventilation

ataxic (i.e., irregular), apneas

eyes Doll’s eyes and cold water calorics intact

Doll’s eyes and cold water calorics impaired



Motor function Gegenhalten ipsilater-ally (early), decorti-cate (late)

Decorticate, decerebrate no response except triple flexion

no response except triple flexion

Survivability often reversible rarely reversible, only 3% of trauma patents recover after having bilaterally fixed pupils (12)

unlikely to survive terminal

adapted from plum f, posner JB. Diagnosis of Stupor and Coma. philadelphia, pa: fa Davis & co; 1966.

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was untreated. Using a definition of autonomic storm charac-terized by a systolic blood pressure ≥200 mmHg and tachycar-dia with heart rates >140 beats per minute, the authors treated this hemodynamic response in the study group, which was observed in 63% of donors for a mean duration of 1.2 hours, with beta-blockers. Treatment resulted in a significantly higher postbrain death left ventricular ejection fraction (LVEF) (63.9% vs. 49.0%), a higher rate of cardiac transplantation (91.7% vs. 41.2%), and better heart recipient survival at 2 months (100% vs. 43%). The investigators concluded that treatment of the autonomic storm enabled better cardiac func-tion postbrain death, higher rates of cardiac transplantation, and better recipient outcomes (28). Recommendations regard-ing the treatment of the autonomic surge should be viewed with caution, as this physiologic compensatory mechanism represents the patient’s attempt to maintain cerebral perfusion in the face of herniation. Abolition of this response constitutes active intervention and donor management in patients who have not been declared brain dead which raises significant ethical concerns.

Globally, the intense systemic vasoconstriction of the autonomic storm compromises blood flow to various organs. Subsequently, with herniation/brain death and associated denervation with vasodilatation, there is reperfusion which forms the basis of the global IR injury, thought to contribute significantly to organ dysfunction in the donor, and facilitate the development of an immunologic continuum between the donor and recipient. In addition to the IR injury that occurs with the brain death process, IR may occur antecedent to the brain death event during resuscitation from the initial trauma, or may follow brain death during the periods of cold storage and transplantation. Ischemia precipitates the loss of aerobic oxidative metabolism, associated cellular energy loss along with changed ion gradients which promote calcium influx. With reperfusion of oxygen-rich blood, there is generation of oxygen radicals, lipid peroxidation, and further membrane permeability to calcium. IR activates the vascular endothelium and donor leukocytes with resultant cytokine expression. This precipitates local inflammation, which is thought to contribute to graft immunogenicity by producing major histocompatibil-ity antigens and adhesion molecules.

In concert with the above, there is substantial animal and some human data to support that hypothalamic pitu-itary destruction produces an endocrinopathy of brain death which is additive to the above. Dominated by the thyroid and adrenal deficiencies, it is proposed that the absence of these key hormones contributes to cellular dysfunction, metabolic abnormalities, and hemodynamic deterioration. Deficiency of thyroid hormone is proposed to impair mitochondrial func-tion and consequently diminishes energy substrate with the resultant transition from aerobic to anaerobic metabolism. Proponents of HRT propose that diminished cardiac con-tractility consequent to low thyroid hormone levels can be reversed with exogenous hormone supplementation. However, significant disparities exist related to hypothalamic–pituitary axis dysfunction when comparing animal and human studies. An abundance of animal data suggests that low-circulating thyroid hormone levels are responsible for abnormal energy sources, impaired cardiac function, and hemodynamic insta-bility (15,16,29). Animal studies and some human reports suggest that there is a dramatic reversal of the anaerobic metabolism, improvement in cardiovascular stability, and

normalization of laboratory parameters and EKG changes, as well as improved organ suitability for transplantation when the exogenous hormonal therapy is employed (15,16).

Nonetheless, several studies have failed to define the pres-ence of endocrine dysfunction (30–32), show improvement with the addition of exogenous hormones (33,34), or correlate hemodynamic instability with hormone levels (31,32). Conse-quently, the use of HRT remains controversial; this is further discussed under cardiovascular management.

The impact of brain death upon graft function and trans-planted organs was first recognized in the early 1980s. Cooper et al. (29) observed that hearts procured from healthy anes-thetized baboons and stored for 48 hours, when subsequently transplanted functioned immediately with no evidence of car-diac dysfunction. However, hearts procured from brain-dead donors and stored in a similar fashion required several hours to achieve adequate function. These investigators recognized that the only difference between the two groups was brain death, and determined that the brain death process was a risk factor for poor outcomes after transplantation. These observa-tions began to establish that the brain death process was not static, and that the graft not biologically inert. Tilney et al. (35,36) proposed the existence of an immunologic continuum between donors and recipients as a mechanism to understand the influence of brain death on recipient organ function. Uti-lizing this model, they hypothesize that IR events associated with brain death and pre/postbrain death events precipitate immunologic and nonimmunologic injuries that impact upon short- and long-term graft function. A major component of the immunologic continuum is the IR injury, proposed to initiate a significant inflammatory response, which triggers and ampli-fies the acute postimmunologic activity, impacting multiple organs and contributing to their dysfunction in the short and long terms.

It has been noted that increased plasma IL-6 levels in donors is associated with lower recipient hospital-free survival after cadaveric organ transplantation (37). Similarly, elevated plasma IL-6 levels in donors were associated with greater degrees of preload responsiveness that correlated with fewer organs transplanted (38). In cardiac donors, serum and myo-cardial levels of tumor necrosis factor-alpha (TNF-α) and IL-6 were elevated in all, but were more markedly elevated in the dysfunctional unused donor hearts (39). An intense inflam-matory environment defined by elevated levels of IL-1, IL-6, TNF-α, C-reactive protein (CRP), and procalcitonin (PCT) has been reported in potential heart and lung donors. In this series, elevated PCT levels were correlated with worse cardiac func-tion and, potentially, thought to attenuate any improvement in cardiac function gained by donor management (40). Similar elevations of inflammatory markers have been reported in liver transplantation. In a comparison study of hepatic tissue from brain-dead and living donors, investigators reported significant elevations in inflammatory cytokines in brain-dead, as com-pared to living, donors. Cellular infiltrates were appreciably increased in parallel to the cytokine levels; this correlated with elevated liver enzymes, bilirubin levels, and increased rates of rejection and primary graft nonfunction (41). Attenuation of the increased inflammatory response with methylprednisolone was shown to significantly decrease soluble interleukins and the inflammatory response, which significantly ameliorated IR injury in the posttransplant course, and was accompanied by a decreased incidence of acute rejection (42). In summary,

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there is appreciable evidence that brain death and the associ-ated inflammatory response have a substantial impact upon the transplanted organs. Future strategies will likely seek to preserve not simply organs, but to attenuate the donor inflam-matory response.

BraIn Death DeclaratIOn

After the 1959 description of “Le coma depasse” by Mollarat and Goulon, the description and understanding of coma and death were forever changed (43). These authors presented 23 cases from their Paris hospital in which they described irrevers-ible or “irretrievable coma.” This coma was associated with a lack of cognitive and vegetative functions, going beyond any coma previously described. This case series formed the basis of what is contemporarily recognized as brain death. The investi-gators noted the necessity of considering the circumstances of the injury, the role of the neurologic examination, the results of electroencephalography (EEG), and the consequence of brain death on other organs. They found that the majority of inju-ries to the brain were confined to trauma, SAH, meningitis, cerebral venous thrombosis, massive stroke, and brain death after craniotomy for posterior fossa tumor. The investigators detailed problems including deterioration of pulmonary func-tion, polyuria, hyperglycemia, and tachycardia. It is intriguing that this paper, even though published in a relatively well-known European journal, took more than 15 years before it became known in the United States and Great Britain.

Interestingly, Mollart and Goulan’s paper was not the first description of brain death (43). Lofstedt and von Reis (44) described six mechanically ventilated patients with absent reflexes, apnea, hypotension, hypothermia, and polyuria asso-ciated with absent angiographic cerebral blood flow; death was declared when cardiac arrest occurred, between 2 and 26 days after the clinical examination. In 1963, Schwab and asso-ciates (45) reported EEG as an adjunct for determining death when cardiac activity was present. These authors proposed the following criteria to determine death: (1) absence of spontane-ous respiration for 30 minutes; (2) no tendon reflexes of any type; (3) no pupillary reflexes; (4) absence of the occulocardiac reflex; and (5) 30 minutes of an isoelectric EEG.

This corpus of research, and the recommendations con-tained therein, generated substantial controversy in the organ transplant community, as some were uncomfortable procuring organs for transplantation from donors that were pronounced dead using brain death criteria. Nonetheless, in 1968, Harvard Anesthesiologist Henry Beecher chaired a committee at Har-vard Medical School which attempted to define irreversible coma as new criteria for death. The committee defined death as the irreversible loss of all brain functions and proposed the criteria necessary to make that determination (46). The Har-vard criteria included nonreceptivity and unresponsiveness, no movements or breathing, no reflexes, and a flat EEG. The committee suggested that the tests be repeated at 24 hours and, in the absence of hypothermia and central nervous system depressants and with no change in examination, the patient would fulfill criteria for the diagnosis of brain death.

Subsequently, concern regarding the relevance of EEG unfolded and, the Conference of the Royal Colleges and Fac-ulties of the United Kingdom published the Diagnosis of Brain Death first in 1976 and again in 1995, altering the definition

from brain death to brain stem death (47). They determined that if the brain stem was dead, the brain was dead, and if the brain was dead, the patient was dead. The conference required that the etiology of the condition that led to coma be established, and a search for reversible factors be undertaken. Examples of “reversible factors” included central nervous sys-tem depressant drugs, neuromuscular blocking agents, respira-tory depressants, and metabolic or endocrine disturbances. A period of observation was recommended and the technique for apnea testing was described (47,48).

The Quality Standards Subcommittee of the American Academy of Neurology formally redefined brain death in 1993, utilizing an evidence-based approach. They defined cri-teria for evaluating brain death as the presence of coma and evidence for the cause of the coma, with the absence of the fol-lowing confounding factors: hypothermia, intoxication, seda-tive drugs, neuromuscular blocking agents, severe electrolyte disturbances, severe acid–base abnormalities, endocrine crises. Fulfilling the preceding criteria, brainstem reflexes and motor responses needed to be absent, and a positive apnea test estab-lished the clinical diagnosis of brain death. An apnea test was finally established as a criterion and part of the examination to define brain death. The subcommittee recommended a repeat evaluation 6 hours after the initial evaluation, but recognized that the time was arbitrary and suggested that confirmatory studies should only be required when specific components of clinical testing could not be reliably evaluated (49). With the 2010 update, the subcommittee recognizes there is insufficient evidence for determination of the minimally acceptable time for an observation period (50).

The 1977 NIH-sponsored study (51) is the only prospective attempt to develop comprehensive guidelines for determina-tion of brain death based on neurologic criteria. Enrollment required demonstration of cerebral unresponsiveness and apnea, and at least one isoelectric EEG. This group recom-mended examinations at least 6 hours after the onset of coma and apnea. The examination required demonstration of cerebral unresponsiveness, dilated pupils, absent brain stem reflexes, apnea, and an isoelectric EEG. The apnea examina-tion, as defined in this study, only required that the patient not make any effort to breath over the ventilator. In the United States today, most institutional policies are modeled after the Quality Standards Subcommittee of the American Academy of Neurology (50).

Examination to Determine Brain Death

When the diagnosis of brain death is considered in the appro-priate clinical context, a very careful physical examination must be performed. Brain death testing requires first, definitive evidence of an acute catastrophic event that involves both cere-bral hemispheres or the brain stem in the appropriate clinical context so that irreversibility is assured; second, complicating medical conditions that could potentially compromise the clin-ical assessment must be ruled out. These include electrolyte, acid–base, and endocrine disturbances. There should be no evidence of drug intoxication, neuromuscular blocking agent use, poisoning, or any other agent that might compromise the clinical examination. Additionally, hypothermia needs to be corrected; ideally, the patient should have a core temperature between 35° and 38°C. Frequently, the computerized tomo-graphic (CT) scan of the head will provide evidence for the

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magnitude of the brain injury. These injuries may include mas-sive intraparenchymal hemorrhage or SAH, and/or epidural or subdural hemorrhage with mass effect. The CT scan may also appear slightly less dramatic after a cardiac arrest. Findings may be limited to the loss of sulci and the gray matter–white mater differentiation, effacement of the basilar cisterns, all of which reflect cerebral edema.

The patient must exhibit lack of consciousness. Determin-ing unresponsiveness usually implies the administration of some painful stimuli. While there are multiple approaches—sternal rubbing, rubbing knuckles on ribs, twisting nipples, and pin prick—we consider these to be somewhat abusive. Perhaps more appropriate, although not accepted as the stan-dard, is to utilize an instrument such as a pen, pencil, or the tip of a Kelly clamp to apply pressure at the lunula (junction of the cuticle and skin of the digit). This pressure will con-sistently elicit a response in patients with an intact nervous system and it is not construed as potentially “violent” as pin prick or nipple twisting. Furthermore, it does not leave bruis-ing that nipple twisting does and will not cause skin abrasions in the fragile skin of the elderly.

When painful stimulation is applied, there should be no responses such as eye opening or withdrawal and grimacing, although there may be an occasional “spinal” reflex with this stimulus; this spinal reflex is neither reproducible nor purpose-ful. Spinal movements have been described by Wijdicks (52) as brief, slow movements in upper limbs, flexion of the fin-ger, and arm lifting that is not a decerebrate or decorticate response; these movements are not persistent and usually not reproducible. The precise reflex pathway(s) is not understood; however, these are recognized as spinal reflexes. Moreover, tri-ple flexion (flexion of foot, knee, and hip) should be carefully considered whether it is withdrawal, or just represents a spinal reflex. In the examination for brain death, there should be no uncertainty, so triple flexion can lead to diagnostic uncertainty.

Each patient needs to be examined as prescribed by institu-tional and state standards which vary. Please be aware of your local standards. We give an accurate general description, but make no attempt to include local standards.

Brain Stem Reflexes

Pupillary Response

The pupillary response to light should be absent in both eyes. The pupils in brain-dead patients are most often dilated, mid-position, usually 4 to 6 mm. It is important to ensure that there is no pre-existing ocular abnormalities and that topical ocular agents have not been instilled. Wijdicks (52) suggests that neuromuscular blocking agents may cause a nonreactive light reflex, although in our experience this is quite rare. The cranial nerves (CrNs) evaluated in the pupil light response are CrN II and III.

Ocular Testing

In the presence of brain death, there should be no ocular move-ments either to brisk movement of the head from side to side (absence of dolls’ eyes) nor to instillation of cold water into the auditory canals. The nerves stimulated by these maneuvers include CrN VIII (efferent) with CrN III and VI (afferents). Prior to stimulating the oculocephalic reflex, one must ensure that the cervical spine is intact and the test should not be performed when

there is known or suspected cervical spine injury. With the head in neutral position, the head is briskly moved, first to the left and held there for approximately 30 seconds; if the CrNs are intact, the eyes will move from the direct frontal gaze, to the left and then back toward the previous midline focus. The same is true when head is moved to the right, if the nerves are intact, the eyes will move from the direct frontal gaze to the right, and then back to the previous midline frontal gaze. In the presence of brain death, the eyes will remain in the direction the head is moved.

Even though cold water calorics test the same nerves, they also need to be tested on both sides. Prior to the instillation of iced saline into the auditory canal, one must ensure that the tympanic membranes are intact and that there is no occlusion of the auditory canal. Approximately 50 mL of iced saline is instilled into the auditory cannel. The cold stimulus results in sedimentation of the endolymph and stimulation of hair cells in the vestibular apparatus; the response in a comatose patient with an intact neurologic system is a slow deviation of the eyes toward the cold stimulus. In the presence of brain death, the eyes stay fixed in midline position. Drugs such as aminoglyco-sides, tricyclic antidepressants, anticholinergic agents, any anti-epileptic drug, and some chemotherapeutic agents may ablate or abolish this caloric response in the presence of an intact brain stem (52). Basilar fracture may abrogate the response unilater-ally on the side of the fracture. Nurses appreciate placement of towels to capture the water which spills out. Cold water caloric testing is often performed immediately prior to apnea testing.

Corneal Reflexes

Corneal reflexes should be evaluated by carefully using a ster-ile cotton-tipped swab. Blinking requires an intact brain stem, but care must be taken so that the eyelashes are not stimulated. The CrNs involved are V (afferent) and VII (efferent). Blinking that occurs with stimulation of the cornea is not compatible with brain death. Severe facial and ocular trauma can compro-mise the interpretation of these findings.

Pharyngeal and Tracheal Reflexes

In the intact brainstem, pharyngeal and tracheal reflexes—cough, gag—may be stimulated by passing a catheter through the endotracheal tube into the trachea and suctioning for sev-eral seconds. The CrNs involved are IX and X; CrN IX is the afferent to the trachea and CrN X is the efferent from the brain stem back to the trachea. The presence of a cough reflex is not compatible with brain death; the gag response may be difficult to interpret and is unreliable in an intubated patient (52).

Apnea Study

The apnea study is usually the final portion of the clinical exami-nation to determine brain death. In principle, the arterial partial pressure of CO2 (PaCO2) must rise to at least 60 or 20 mmHg greater than the patient’s baseline. This relatively rapid rise in PaCO2 results in a decrease in the cerebral spinal fluid pH, which is sensed by the medullary respiratory center. When the respiratory center is functional, respiratory efforts will result; in the presence of brain death, there will be no respiratory effort.

Initially, one ensures that the patient’s core temperature is between 35° and 38°C, preferably normothermic. The patient is denitrogenated (“pre-oxygenated”) and stabilized, ensuring correction of any hemodynamic or electrolyte abnormalities.

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This is especially true when the technique used for the apnea study is the removal of the patient from the ventilator with no continuous positive airway pressure (CPAP). Denitrogenation usually requires 10 minutes of breathing an FiO2 of 1.0. Prior to initiation of the procedure, an arterial blood gas (ABG) analysis must be obtained both to ensure adequate oxygen-ation and to define a baseline arterial CO2 value. With the baseline arterial CO2 value, one can calculate the apnea time required for the PaCO2 to rise to 60 mmHg.

The technique is as follows: The measured PaCO2 value from the ABG is subtracted from 60 mmHg (delta-CO2). It is recognized that PaCO2 will climb approximately 3 mmHg, in the first minute of apnea and thereafter, it will climb by approximately 2 mmHg/min. Therefore, dividing the delta-CO2 by the lower value of 2 mmHg increase per minute will ensure an adequate apnea time, allowing the PaCO2 to achieve the minimal value of 60 mmHg in the presence of brain death–associated apnea, or a 20 mmHg rise from baseline.

Once the time required to achieve the delta value is deter-mined, there are three techniques that may be used for the apnea study. These include (1) simply removing the patient from mechanical ventilation, and placing a catheter through the ETT while insufflating O2 at approximate 6 L/min. This will most often ensure adequate apneic oxygenation. (2) Set the mechanical ventilator to spontaneous mode with no backup apneic mode. With this approach, the patient can be maintained on a low level of CPAP to preserve oxygenation. The monitoring modalities of the mechanical ventilator can be used to visualize respiratory efforts if these were to occur. (3) The patient may be taken off mechanical ventilation, and connected to a Mapleson D circuit with a Wright spirometer placed in line. With fresh O2 flow of 6 to 10 L/min, one can partially close the Mapleson D circuit pop-off valve, ensure that there is some CPAP, and then watch both the bag of the circuit and the Wright spirometer for respiratory efforts.

Whichever technique is used, the patient is kept off mechanical ventilation for the calculated time to achieve the delta CO2 value; pulse oximetric saturation is followed to ensure that desaturation does not occur. Desaturations, hemo-dynamic instability, or significant rhythm disturbances neces-sitate immediate replacement of full mechanical ventilation. Ideally, an ABG should be drawn at the onset of instability and used for assessment. A PaCO2 >60 mmHg is consistent with a failed apnea test. Failure to achieve a PCO2 ≥60 mmHg, in the absence of any respiratory efforts, suggests inadequate time for CO2 production to achieve threshold. In this case, the test may be reperformed after correcting metabolic/physiologic abnor-malities or moving directly to a confirmatory study. At the end of the newly calculated time period, an ABG is obtained. If the PaCO2 value is ≥60 mmHg, or has increased >20 mmHg above the patients known baseline value, and there have been no respiratory efforts, the result is compatible with brain death.

After the second ABG is drawn, the patient is reconnected to the mechanical ventilator and, if the PaCO2 from the previ-ous sample is ≥60 mmHg, the family is notified that the exami-nation is consistent with brain death. With a “failed” apnea study, the patient is pronounced clinically brain dead.

Common complications of the apnea study are hypoten-sion and cardiac dysrhythmias. If one is unable to adequately perform the apnea study because of these complications or because of hypoxia, confirmatory tests, such as a radionuclear cerebral blood flow study or a four-vessel angiogram, will be

required. Taylor et al. (53), in a meta-analysis of CT angiog-raphy as a confirmatory study in the setting of clinical brain death, found that based upon the extant data, CTA had a sensitivity, after the clinical determination of brain death, of only 85%. They suggest that this study not be used as a con-firmatory study as approximately 15% of patients clinically dead will not have this diagnosis confirmed; other studies—as above—are more appropriate. Finally, a single apnea examina-tion will suffice (43) for the declaration of brain death; when a repeat clinical examination is performed, a repeat apnea study is not an absolute requirement, although it is imperative to ensure that institution and state regulations are followed.

exclusIOns anD cOntraInDIcatIOns

Given the shortage of organs available for donation, exclu-sions and contraindications should be viewed as absolutely relative or relatively absolute (54). Consequently, all cases should be reviewed in conjunction with the OPO coordina-tor to determine suitability. Successful procurement has been undertaken in a broad array of cases that were previously deemed unsuitable including patients with sepsis and bacte-rial meningitis, provided appropriate anti-infective treatment is undertaken. However, organs should not be procured from potential donors when the etiology of the purported infection has not been determined. An evolving literature suggests that organ procurement from patients with known meningitis that has been appropriately treated has not resulted in significant transmission of the infectious agent nor organ compromise in the recipient (55). In a retrospective study performed over 10 years in 39 patients undergoing heart and lung transplan-tation, undertaken with organs from cadaveric donors with bacterial meningitis defined by either positive blood or cere-bral spinal fluid cultures and associated clinical signs and symptoms, no contraindications could be defined because none of the recipients died of infection-related causes. Com-mon organisms in the donor were reported to be Neisseria meningitides, 53.8%; Streptococcus pneumonia, 41%; and Haemophilus influenza, 5.2%. Importantly, adequate antibi-otic therapy was initiated before organ retrieval and continued after transplantation (56). Similarly, Satoi (57) reported that liver transplantation from donors with bacterial meningitis was safe, provided the donor and recipient received adequate antimicrobial therapy. In this study of 34 recipients, there were no infectious complications caused by the meningeal patho-gens. Although recommendations are difficult to establish, treatment of the donor for 24 to 48 hours and a minimum 7 to 10 days for the recipient appears to be adequate.

Frequently, potential organ donors in the ICU are bactere-mic; similar to the above literature for donors with meningitis, procurement of organs from bacteremic patients has been suc-cessfully undertaken and the presence of bacteremia should not preclude donor evaluation. In a study that reviewed heart transplantation from donors that expired from community-acquired infections with severe septic shock, meningitis, and/or pneumonia, no evidence of donor-associated infection and sepsis or rejection was observed in the recipient (58). In a report of transplantation from bacteremic donors with gram-negative septic shock, all recipients were alive with good graft

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function 60 days following transplantation with no infectious complications. It is recommended that appropriate antibiot-ics be given for at least 48 hours prior to organ retrieval and that recipients receive 7 days of culture specific antibiotics posttransplantation (59).

Patients with human immunodeficiency virus (HIV) rep-resent an absolute contraindication to donation. However, the occasional patient engaging in high-risk social behavior, but remaining HIV seronegative, may be considered for pos-sible organ donation. In this circumstance, there should be an extensive review of the medical record, interviews with the family, and active communication with OPO. It is recom-mended, however, that information about the donor’s high-risk behavior be conveyed to the transplant center, which ought to inform the potential recipient of the risks and benefits of donation from this individual.

Donor malignancy represents another area of concern that warrants careful evaluation when a donor is considered for procurement. Any active noncentral nervous system malig-nancy is viewed as an absolute contraindication to donation. A previous history of choriocarcinoma, lung cancer, melanoma, and patients with previous colon, breast, or kidney cancer are, similarly, precluded. Donors with a previous history of non-melanoma skin cancers and a select group of patients with cancer defined in situ or with very low-grade levels of malig-nancy may be considered as can be patients with a history of previous curative therapy; these cases should be discussed on an individual basis with the OPO and the transplant center. Central nervous system malignancies are not uncommon in the potential organ donor population. Given their rare metastasis and low incidence of development in the recipient, procure-ment is frequently undertaken. Potential donors with a low-grade tumor, absent craniotomy, and no ventricular shunts are better candidates than those donors with previously defined high-grade malignancy, craniotomy, and shunt placement.

cOnsent

Approaching and obtaining consent from the potential donor’s family is an absolute requirement for organ donation. In the case of previously defined, first-person consent, in which an individual firmly establishes their desire to donate via a driv-er’s license or donor card, it is imperative that the first-person consent be honored and recognized as the basis for consent. In 1998, the CMS established several parameters governing the organ donation process through the Federal Conditions of Participation. A change in the Conditions of Participation required timely notification of the OPO when death is immi-nent to ensure that families were provided the opportunity to discuss the option of organ and tissue donation. Similarly, the Conditions of Participation mandated that individuals spe-cially trained in requesting, termed “designated requestors” be responsible for making the request, and required that all individuals discussing organ donation with families receive the appropriate training.*∗The intent of this mandate was to ensure that individuals approaching families and discuss-ing organ donation were trained and sensitive to the family situation. Initially, this was interpreted by some to imply that physicians would be excluded from the request process and

only OPO-designated requestors could approach the family. Subsequent discussion and policy recommendations adopted by the American Medical Association suggested that the desig-nated requestor contacts the attending physician before organ donation requests and includes the attending physician in the discussion with the family. It is important to appreciate that OPO coordinators, physicians, and nurses may be defined as designated requestors, provided they undertake the appropri-ate training (60).

Family characteristics and the approach to the consent pro-cess have been shown to significantly impact upon the decision to donate. Nondonor families tend to be less satisfied with the quality of care, have a lesser degree of understanding of brain death, and remain under the impression that brain-dead patients could survive. These families felt that there was insuf-ficient time and privacy during the request process and that the requestor was not sensitive to their needs. Alternatively, con-senting families had a much clearer understanding of brain death and were more satisfied with the overall consent process and their decision-making (61). Siminoff (62) evaluated the roles of prerequest factors and decision process variables in the consent process in a large study of 11,555 deaths; of 741 poten-tial donors and a family request rate of 80%, the final consent rate was 48%. Decisions were made early, with 55% of families making their decision during the initial request. Of those fami-lies with an initial favorable view of consent (58%), 81% went on to complete the consent with consent not obtained in 19%. In families who initially had an unfavorable view of the dona-tion process (25%), consent was eventually obtained in 9% and no consent was sustained in the remaining 91%. In the 17% of families that were undecided during the initial donation request, 47% went on to consent and consent was not obtained in 53%. The initial response predicted a final donation decision in 70% of families. Prerequest factors that were associated with suc-cessful consent included patient characteristics of young, white males dying from trauma and family beliefs in donation, prior knowledge of organ donation, the presence of a donor card, explicit discussions, and a belief that the patient would have wished to donate and that the information provided was ade-quate and the health care provider was comfortable with ques-tions. There was no association noted between family education and income levels, hospital environmental factors, health care practitioner–associated demographics or the health care prac-titioner’s attitude toward donation. Decision process variables that correlated with donation were the correct initial assessment by the health care provider, instances when the family raised the donation issue, conversations and time spent with the OPO coordinator, and clear, unambiguous discussions related to cost, funeral homes, and choices. Decision process variables that had a negative correlation with donation included perceptions that the health care provider was not caring, surprise by the family when the request was made, or feeling harassed and pressured to make a decision. No correlation was found with the overall satisfaction of care, the timing of the request, or the belief that the patient was alive after the declaration of brain death. Haz-ard ratios for factors that directly related to donation included prerequest characteristics (7.68), optimal request pattern with the health care provider being a nonphysician and the OPO coordinator (2.96), OPO-related factors (3.08), and the topics discussed (5.22).

The request for organ donation has undergone an evolu-tionary process from random or inconsistent requesting to the *(COP) (42CFR Part 482 {HCFA-3005-F} RIN:0938-A195).

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use of designated requestors to the use of an effective requestor to the currently recommended process of effective requesting. Key elements of the requesting process recommended by the Institute of Medicine (IOM) include a focus on the family and the continuation of compassionate care with an acknowledge-ment of the uniqueness of each family and avoiding scripted statements. A determination of the most appropriate requestor and the timing of the request should be individualized and done on a case-by-case basis. Families of patients with pro-tracted ICU stays frequently develop close associations with specific physicians or nurses, and may be willing to accept discussions related to impending death and donation at times earlier in the course than families with an acute crisis. The IOM panel recommended that donation be discussed as an opportunity, utilizing language that emphasizes the benefit to the transplant recipient and the potential of healing for the donor family. Importantly, the panel recommended that excel-lent EOL care be continued for the family, independent of the donation decision (63).

Although there is some variability, it has generally been accepted that decoupling or separating the request for dona-tion from the declaration of brain death notification be used as the model for requests (64,65). In this model, the notifi-cation of brain death is both temporally and geographically segregated from the organ donation request. This provides the opportunity for the family to process the notification of brain death before the request is made for consent, although it has been suggested that consent may occur after the fam-ily has accepted that further care is futile (66). In conjunction with the decoupling process, factors that have been associated with a successful consent rate include making the request in a private setting, and ensuring the engagement of the OPO Transplant Coordinator. When all three elements are present, the consent rate was reported to be 2.5 times greater than when none of the elements were present (64). The Council on Scientific Affairs for the American Medical Association recommended that the process focuses upon supporting the family of all potential donors, be consistent with quality EOL principles, decouple discussions of brain death from the organ donation requests, ensure that the opportunity to donate is presented to all families, and do so in a private setting. Ensur-ing that the OPO Transplant Coordinator is involved and assists with coordinating the efforts in the ICU was strongly recommended; for those wishing to participate in the request process, special training should be undertaken, and certifica-tion as a designated requestor obtained.

MeDIcal ManageMent

Hemodynamic and cardiovascular management form the cor-nerstone of potential organ donor management (ODM). A standardized and structured approach to hemodynamic man-agement ensures that the donor somatically survives for pro-curement and maintains the remainder of potential organs in the best possible condition. Similar to the care of any critical patient, a collaborative approach utilizing the skills of physi-cians, nursing, respiratory therapists, and the OPO coordina-tor is pivotal for optimum management. Standardization of donor management from the referral process through consent, followed by management and recovery has been shown to sig-nificantly increase the number of organs recovered and organs

transplanted. A 10.3% increase in organs recovered per 100 donors and a 3.3% increase in total organs transplanted per 100 donors was reported by Rosendale in a study that empha-sized standardization of general medical management, elimi-nating variability in laboratory and diagnostic studies, along with standardization of respiratory therapy, and IV fluids and medications (67). The Surgical Trauma Group at the Univer-sity of Southern California has been instrumental in pioneer-ing the standardized approach to ODM. The development of an aggressive ODM program was reported to significantly increase the number or organs available for transplantation. Employing a critical care team that accepted potential organ donors for management utilizing pulmonary artery catheters (PAC), fluid resuscitation and use of vasopressors, preven-tion and treatment of complications associated with brain death, and liberal use of thyroid hormone in unstable donors, resulted in a 57% increase in total referrals, a 19% increase in potential donors, an 82% increase in the number of actual donors and an 87% decrease in the number of donors lost to hemodynamic instability. Overall, the implementation of this aggressive donor management team resulted in a 71% increase in the number of organs recovered (68). In a follow-up study by the same group utilizing an aggressive approach to ODM, the authors evaluated the impact of the complications of brain death upon organ retrieval. They hypothesized that brain death–related complications would have no significant impact on the number of organs donated, provided there was an aggressive ODM protocol in place. With complications defined as the requirement for vasoactive support which occurred in 97.1%, coagulopathy in 55.1%, thrombocytopenia in 53.6%, diabetes insipidus in 46.4%, cardiac ischemia in 30.4%, lactic acidosis in 24%, renal failure in 20.3%, and adult respiratory distress syndrome noted in 13%, there was no appreciable impact of the complications on the average number of organs procured. Additional benefits included a dramatic diminution in the number of donors lost to cardiovascular collapse, and improvement in conversion rates (69). In a comparison with other Level I trauma centers that did not utilize an aggressive donor management protocol, dramatic benefits were similarly reported which included a significant decrease in the incidence of cardiovascular collapse, and the number of organs procured per potential donor (69).

Although the traditional management of the potential organ donor has been taken by the OPO transplant coor-dinator, there has been an evolution toward a collaborative approach between the Intensivist/critical care community and the OPO, as reflected in the above-mentioned studies. Inten-sivist-led management of potential organ donors has been reported to increase the organs recovered for transplantation. In a study that evaluated the implementation of an Intensivist-led donor management program, the overall number of organs recovered for transplantation increased significantly (44% vs. 31%), which was largely reflective of an increase in the num-ber of lungs procured and transplanted (24% vs. 11%). No appreciable change occurred in the number of hearts and livers recovered for transplantation. This study is reflective of the enormous impact that a collaborative and partnered approach between Intensivists and OPO coordinators can have upon donor management (70).

Although no clear current consensus exists, the tradi-tional approach to ODM was to minimize the time between brain death and procurement because of the perception that

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prolonged management was detrimental to the donor organs and bed utilization in busy ICUs necessitated admission for salvageable patients. However, this concept has recently been challenged as evolving literature reports that a longer period of donor management may be beneficial (71). In a retrospec-tive study with a mean time from brain death to procurement of 35 hours, it was reported that there was no decrease in the procurement to consented ratio with increasing time after brain death. When individual organs were analyzed separately, heart and pancreas procurement improved with an increased manage-ment period after brain death and some organs were successfully procured greater than 60 hours after brain death (72). Similarly, in a study of 100 consecutive organ donors whose mean donor management time was 23 hours, it was reported that donors managed in excess of 20 hours resulted in significantly more heart and lung procurements, more organs procured per donor (4.2 vs. 3.2) and more organs transplanted per donor (3.7 vs. 2.6). Interestingly, there was no significant difference noted in the obtainment of donor management goals (73).

Specific donor management goals during the donor manage-ment period have evolved as a standard. Attainment of these management goals has resulted in a significant increase in the number of organs procured and transplanted per donor. In an initial report by Hagan, consensus was developed for six spe-cific donor management goals among six OPO organizations. The following management goals were derived: mean arterial pressure greater than 60 mmHg, CVP less than 10 mmHg (or serum osmolarity 285 to 295 mOsm/kg), sodium less than 155 mMol/L, pH 7.25 to 7.5, pressors (1 or none—1 pres-sor plus vasopressin for diabetes insipidus was deemed appro-priate), and PaO2 greater than 300 mmHg while on 100% oxygen. These donor management goals were considered a bundle with compliance defined as achieving a minimum of five goals. The number of organs transplanted per donor was 4.87 in those meeting goals and 3.19 in those donors failing to meet the bundle goals for standard criteria donors. No sig-nificant change was noted for extended criteria donors (74). In a similar consensus-driven study, eight common goals were defined: mean airway pressure, CVP, pH, PaO2, sodium, glu-cose, vasopressor use, and urine output. Throughout the study period, there was a dramatic increase in the compliance with donor management goals, which was associated with a sig-nificant improvement in organs transplanted per donor. The authors reported that the success of transplantation was pre-dominantly associated with limitations in vasopressor use and achieving adequate PaO2. Thoracic organs were most sensi-tive to the donor management goals as there was a dramatic increase in lung transplantation with higher levels of PaO2. Interestingly, mean arterial pressure, CVP, pH, sodium, and urine output had little effect on the transplantation rate. The authors concluded that goals and standardization of endpoints of donor management are associated with increased rates of transplantation. However, it was evident that not all standard goals are necessary with the most significant parameters being the low use of vasopressors and ensuring adequate oxygen-ation, which should form the focus of donor management (75). Similarly, in a study that evaluated 10 donor manage-ment goals and defined success as the achievement of eight goals, the authors used binary logistic regression to determine the independent predictors of more than four organs trans-planted per donor. The authors reported that donors meeting donor management goals had more organs transplanted per

donor (4.4 vs. 3.3). Independent predictors of transplanting more than four organs were age, serum creatinine, thyroid hormone, and meeting donor management goals. Among the individual donor management goals, odds ratios (ORs) were higher for CVP 4 to 10 mmHg (OR = 1.9), EF greater than 50% (OR = 4.0), PaO2/FiO2 greater than 300 (OR = 4.6), and a serum sodium 135 to 168 mEq/L (OR = 3.4) (75,76). The impact of a structured and standardized approach to ODM has similarly been reported to dramatically increase the retrieval rate of lungs and hearts for transplantation. In a study where potential lung donors were aggressively man-aged through protocol-guided optimization of ventilatory and hemodynamic strategies that consisted of measurements of extravascular lung water, bronchoscopy, and invasive moni-toring, a dramatic increase in the rate of lung procurement was reported (40% vs. 27%) (77). Similarly, an aggressive and structured approach to the management of potential heart donors reported a significant increase in the numbers of hearts procured with a standardized approach using invasive moni-toring and critical care management techniques (78). It appears that over the past decade, there has been an overall increase in available donors and organs, as well as a moderate increase in the mean number of organs per TBI donor. Additionally, the increased use of hormone replacement therapy (HRT) appears to be key to the successful conversion of marginal donors and enhanced recovery from certain subsets leading to decreased transplant wait times (79). For example, in the decade studied by Callahan and colleagues (79) using the Organ Procurement and Transplant Network’s (OPTN) organ donor and thoracic recipient dataset (from July 1, 2001 to June 30, 2012), the most common causes of donor death were cerebrovascular disease (31,804 cases, 42.9%) and TBI (28,142 cases, 37.9%). A slow but significant increase in the raw number of donors per year, from 5,857 in 2002 to 6,945 in 2012 (p < 0.001) was noted, as was an increase in the raw number of total organs procured, from 20,558 to 24,308 (p < 0.001). These increases coincide with the increased use of HRT in donor management, from 25.1% to 72.3% (p < 0.001); high-yield donors showed a similar increase in the use of HRT, from 33% in 2002 to 76.6% in 2012 (p < 0.001) (79).

Finally, recent data (80) suggest that elevated glucose is common in patients who donate after determination of neu-rologic death. Glucose levels above 180 mg/dL are associated with lower organ transplantation rates and worse graft out-comes. It is recommended that serum glucose levels be targeted to a glucose of 180 mg/dL or less; in our practice, we aim for 150 to 180 mg/dL.

Cardiovascular and Fluid Goals

An algorithmic approach to the cardiovascular and hemody-namic management of the potential organ donor is suggested (Fig. 119.2). As depicted in the figure, age plays a major role in the initial cardiac evaluation. Traditionally, cardiac cath-eterization has been required for potential organ donors over 40 years of age. Given the significant myocardial stress associ-ated with brain death, echocardiography should not be per-formed immediately after brain death declaration as this may provide misleading information related to cardiac function. Initial attempts at stabilization should include normalizing blood pressure, metabolic abnormalities, and electrolyte dis-turbances. Transthoracic echocardiography (TTE) should be

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performed in all patients to evaluate structural abnormalities that may preclude cardiac donation and evaluate the LVEF. Since first reported in the evaluation of potential organ donors in 1988, TTE has proven invaluable for evaluation of cardiac function, particularly in circumstances where clinical events might have precluded cardiac utilization. In the original study, 29% of donor hearts that would have been previously excluded on clinical criteria were procured and successfully trans-planted (81). Echocardiographic abnormalities are reported to be responsible for 26% of nonused hearts with an OR of 1.48 per 5% decrease in EF (82). Although instrumental in the evaluation of cardiac function in the potential organ donor, several issues warrant consideration regarding echocardio-graphic evaluation. These include the difficulty in securing the test, technical challenges with imaging in critically ill patients, and the accuracy and impact of the echocardiographic inter-pretation. Similarly, it is important to appreciate that LVEF is a load-dependent measure of contractility with variance noted when there are changes in preload and afterload (83). It is also important to recognize that temporal changes occur in left ventricular systolic function. In a study that evaluated sequential echocardiograms in potential organ donors, with

EFs less than 50% or regional wall motion abnormalities on the initial cardiogram, 12 of 13 patients improved after donor management. Utilizing a strategy that employed high-dose corticosteroids and dopamine without the use of thyroid hor-mone, these 12 donor hearts were transplanted with a survival rate of 92% with an average follow-up of 16 months (84). In a series that evaluated clinical characteristics, echocardio-graphic and pathologic findings of myocardial dysfunction in potential donors, echocardiographic evidence of systolic dys-function was appreciated in 42% of potential organ donors; this was not predicted by clinical findings, the EKG findings, or the type of neurologic injury. Histopathologically, there was a very limited correlation to the area of echocardio-graphic dysfunction in the histopathology of hearts that were not procured, suggesting, again, that brain death is associated with significant myocardial dysfunction and the potential for reversibility needs to be appreciated. Consequently, no heart should be rejected on the basis of a first initial abnormal echo-cardiogram. In instances where TTE evaluation is difficult, consideration should be given to the use of transesophageal echocardiography (TEE); limited literature comparing TTE with TEE suggests that the TTE assessment may be inadequate

Cardiac Donor ManagementSTABILITY AND ECHOCARDIOGRAPHIC ASSESSMENT

PULMONARY ARTERY CATHETER ASSESSMENT

CAPACITANCEVOLUME

PCWP 8 to 12 mmHgCVP 6 to 8 mmHg

GOALS

INITIALSPECIFIC

TREATMENT

CI ê 2.4 L/minLVSWI>15 g-m/m2

UO>1.0 cc/kg/hr

MAP ê 60 mmHgSVR = 800 to 1200 dyne s cm–5

FLUIDS INOTROPES VASOPRESSORS

HYDRAULICPUMP

• REASSESS GOALS AND STABILITY• DEFINE ORGANS APPROPRIATE FOR PROCUREMENT

CONSIDER DOBUTAMINE ECHOCARDIOGRAPHICVIABILITY STUDY

REVERSIBLEDYSTUNCTION

NO REVERSIBLEDYSTUNCTION

NO CARDIACDONATION

HORMONE REPLACEMENT THERAPY

RESISTANCE

MONITORING &CONTINUOUSASSESSMENT

MONITORING &CONTINUOUSASSESSMENT

PATIENT AGE

Ä 40 YEARS >40 YEARS

CARDIAC CATHERIZATION

NORMAL

PCWP – Pulmonary capillary wedge pressure; CVPCentral venous pressureCI - Cardiac indexLVSWI - Left ventricular stroke work indexUO - Urine outputMAP - Mean arterial pressureSVR - System vascular resistance

PROCEED TO CARDIACTRANSPLANE

NO CARDIACDONATION

ABNORMAL

YES NO

YES

Instability

(CONSIDER)

Mean arterial pressure ê 60 mmHg AND vasoactive requirement Ä 10 lg/kg/min ANDurine output ê 1.0 cc/kg/hr AND left ventricular ejection fraction ê 45%

• Goals met stability obtained with vasopressor/inotropic requirements Ä 10 lg/kg/minAND left ventricular ejection fraction ê 45%

• Tri-iodothyronine (T3)or

Thyroxine (T4)and

Bolus Infusion

• Methylprednisolone

• Vasopressin

• Insulin

3.0 lg/hr

20 lg/hr

Repeat in 24 hours

0.5 to 0.4 u/hr

150 mg/dl ê maintain ê 80 mg/dlglucose

minimum 1 u/hr

4.0 lg

20 lg

15 mg/kg

1u

10u/50% Dextrose

YES

NO

FIgure 119.2 algorithmic approach to the cardiovascular and hemodynamic management of the potential organ donor.

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in almost one-third of the patients. A substantial increase in the number of abnormalities was detected with TEE, although no outcome difference was established (85). Recent literature suggests that more than 50% of the hearts with initial abnor-mal function may attain hemodynamic transplantation criteria with aggressive donor management. In this prospective study of 66 potential organ donors, an initial normal LVEF inde-pendently predicted end assessment hemodynamic suitability for transplantation. An initial abnormal left ventricular sys-tolic function was identified in almost half of donor hearts, of which 58% achieved hemodynamic stability criteria for pro-curement (86). Although there is limited data from small case series, low-dose dobutamine stress tests may be able to detect myocardium that appears dysfunctional in the donor and may be capable of recrudescing function in the recipient (87).

In potential organ donors failing to achieve the stability thresholds identified in Figure 119.2, direct measurements of intravascular pressures and cardiac function should be under-taken. Traditionally, a PAC has been used to assess cardiac pressures, CO, and calculate systemic vascular resistance and use measured and derived data to manipulate fluid resusci-tation and vasoactive support; this approach was pioneered by the donor management program at the Papworth Hospi-tal in Cambridge, United Kingdom. In a landmark study by Wheeldon (88), 35% of potential organ donors were ini-tially deemed unacceptable based upon the following criteria: mean arterial pressure less than 55 mmHg, CVP exceeding 15 mmHg, inotropic support requirement exceeding 20 mg/kg/min, pulmonary capillary wedge pressure greater than 15 mmHg and a left ventricular stroke work index less than 15 g. Utilizing invasive monitoring with a PAC and HRT, 44 of the 52 initially unacceptable donors were successfully pro-cured and transplanted. The authors concluded that 92% of organs that initially fell outside of transplant acceptance cri-teria were capable of functional resuscitation and the optimi-zation of cardiovascular performance had significant benefits for the viability of all organs. Given the current speculation regarding the use of PACs, it may be that the dramatic suc-cess seen in this and other studies reflect the time, effort, and vigilant commitment to the donor management process as much as the placement of a PAC. Recently, the commonly accepted practice of inferring volume status from pressure measurements has been questioned. In a systematic review of the literature assessing the accuracy of CVP to predict fluid responsiveness found an exceedingly poor correlation between CVP and blood volume. The inability of the CVP/change in CVP with fluid challenge to predict a hemodynamic response led to the conclusion that CVP should not be used to make decisions regarding fluid management (89). Consequently, other measurements have been proposed to evaluate intravas-cular volume and fluid responsiveness in critically ill patients, which are equally applicable to the management of the poten-tial organ donor. Dynamic changes in the arterial waveform–derived variables have been shown to be an accurate predictor of fluid responsiveness in mechanically ventilated patients (90) and has been applied to the management of potential organ donors (38). In a study that utilized a pulse pressure varia-tion (PPV) greater than 13% to define preload responsiveness, 48% of potential organ donors were characterized as preload responsive. IL-6 and TNF concentrations were greater in pre-load responsive donors, suggesting that there was inadequate volume resuscitation in the early phase donor management.

When comparing preload responsive donors to those potential organ donors that were not preload responsive (PPV <13%), fewer organs were transplanted from the preload responsive donors; the number of organs transplanted per donor from the preload responsive versus unresponsive donors was 1.8 versus 3.7. As illustrated in Figure 119.2, it is important to define hemodynamic profiles for optimum management utiliz-ing tools that are both available and familiar.

Hemodynamic instability is reported to occur in a vast majority of potential organ donors and can be sustained in 20% of donors, despite ongoing vasoactive support (91). The broad differential diagnosis of hemodynamic instability in the potential organ donor includes the following:• Brainstem vasomotor center infarction• Volume depletion from diabetes insipidus• Myocardial injury from catecholamine storm• Reduction in circulating thyroid hormone

Recognizing that the brain death event jeopardizes cardiac function and produces vasodilatation, these are usually coin-cident events. As previously discussed, a significant number of potential organ donors are hypovolemic after brain death. This may reflect inadequacy of the initial resuscitation, third spacing of fluids secondary to the inflammatory response, or misinter-pretation of pressure-derived variables. The previous focus upon minimizing ICP with fluid restriction, diuretics, or mannitol will significantly contribute to decreased intravascular volume. Volume depletion may also be precipitated by hyperglycemia-induced osmotic diuresis, diabetes insipidus, or a cold diuresis in the hypothermic patient. Cardiac dysfunction may be conse-quent to the brain death event, reflective of initial injury to the myocardium, or result from metabolic depression secondary to acidosis, hypophosphatemia, or hypocalcemia. Vasodilatation is a consistent feature in the potential organ donor predominantly related to herniation-mediated denervation and the loss of vaso-motor control and autoregulation. However, other contributing factors may include the relative adrenal insufficiency associated with trauma/critical illness, the endocrinopathy of brain death, or a superimposed/acquired sepsis. Ongoing hypotension fur-ther compounds the initial IR injury, which may result in cardiac arrest and loss of the potential organ donor. Consequently, an aggressive approach to defining the adequacy of intravascular volume, cardiac function, and the degree of vasodilatation is of paramount importance in managing the potential organ donor. Whenever possible, fluid resuscitation in the potential organ donor should be guided by objective measurements and defined endpoints. Traditionally, normal saline has been used as the ini-tial fluid for volume resuscitation to achieve either the previously described central venous pressure endpoints or abolition of pre-load responsiveness determined by PPV. Inadequacy of initial volume resuscitation has been shown to precipitate a significant increase in inflammatory mediators with fewer organs procured and transplanted (38). Diabetes insipidus is common in poten-tial organ donors and predisposes toward hypernatremia. After achieving intravascular volume repletion, a transition to more hypotonic solutions such as dextrose and water may be under-taken to ensure correction of the serum sodium. Serum sodium levels greater than 155 mMol/L have been shown to adversely affect liver transplantation with a higher incidence of graft loss and metabolic abnormalities. Totsuka (92) reported that a serum sodium above 155 was associated with a higher incidence of graft loss, compared to donors whose serum sodium was below 155 mMol/L. In patients who initially had a serum sodium exceeding

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155 mMol/L and were effectively treated to achieve a prepro-curement sodium less than 155 mMol/L, graft dysfunction was minimized. Therefore, cautious attention to correcting the serum sodium and appropriately transitioning from normal saline to a hypotonic solution is appropriate once intravascular volume has been replete and there is evidence of adequate perfusion. Simi-larly, it is important to recognize that the infusion of significant amounts of hypotonic solutions containing dextrose, which are frequently used to treat diabetes insipidus, may precipitate hyper-glycemia, osmotic diuresis, and hyperglycemia-mediated immune dysfunction. Similar to other critical care scenarios, the use of colloid for resuscitation remains controversial. Initial reports suggested that the use of colloid may facilitate minimizing extra-vascular lung water, and result in an increased rate of lung pro-curement (93). In the context of marginal donors and potential hepatic dysfunction, Oliver et al. (94) conducted a case-control study of brain-dead donors (BDDs) at a single OPO to evaluate the clinical characteristics of BDDs undergoing percutaneous pre-recovery liver biopsy (PLB), whether PLB delays organ recovery, the safety of PLB, the concordance between donor hospital and transplant center pathologists in the interpretation of PLB, and whether PLB decreases futile liver recovery and increases the uti-lization of livers. With each case (n = 23) matched to sequential (n = 48) and clinical (n = 69) controls, the investigators found that PLB cases had no difference in primary or secondary complica-tions as compared to the two control groups; the interval from commencement of donor management to organ recovery was significantly longer in the cases (22.4 ± 8.5 hours) as compared to the controls (sequential 16.5 + 8.8, clinical 15.9 ± 7 hours) (p = 0.01 for both comparisons). While the proportions of livers transplanted in the study and clinical control groups were similar (60.9% vs. 59.4%), the proportion of livers for which recovery was ruled out was higher for cases as compared to the clinical controls (30.4% vs. 8.7%) and, as expected, the proportion of liver recoveries without transplantation was lower for the cases versus the controls (8.7% vs. 31.9%) (p = 0.009). The implica-tion of this work is that PLB patients at risk for liver pathology is safe, and that its use minimizes futile recovery (94). The duration of “brain death time” before procurement and transplant does not seem to impact outcome in a major way (94,95).

Frequently, there are antagonistic and competing strategies related to fluid resuscitation in the potential organ donor. Exces-sive fluid resuscitation with the resultant increase in extravascu-lar lung water has been reported to be the single largest reason for lung procurement failure. In a study of potential organ donors with a lung procurement rate of 17.1%, progressive pulmonary dysfunction occurred in 31% of donors who had a significant positive fluid balance of approximately 7,000 mL (96). Traditionally, there has been an emphasis upon overhydra-tion to maximize renal function; this stems from a large body of literature originating during the renal transplantation surgery in the recipient, which has emphasized significant positive fluid balance, as evidenced in the following study that evaluated the impact of the timing of maximal crystalloid hydration on early graft function during renal transplantation. Early graft dysfunc-tion was minimized when intraoperative CVP was maintained at 15 mmHg and 3 L of fluid was given with an average infu-sion rate of 48.3 mL/min during the 48 minutes of renal isch-emia. Older donor management literature suggested that urine output greater than 100 mL/hr during the hour prior to expla-nation and a decrease in the creatinine, reflective of increased hydration, were associated with improved renal function in the

recipient (97). Consequent to these and multiple other studies, there has been an emphasis upon maximal hydration for below-the-diaphragm organs, which contrasts with the more mini-malist volume resuscitation approach believed to enhance lung procurement. Recently, several studies have sought to clarify the approach to an appropriate fluid balance that will ensure the optimum procurement of both lungs and kidneys. In a study that compared the relationship between HRT and CVP on increasing organs for transplantation, the authors reported that when HRT was infused for greater than 15 hours and a CVP was maintained at less than 10 mmHg, there was a dramatic increase in the number of hearts and lungs procured. When a final CVP was less than 10 mmHg, 44% more hearts, 95% more lungs, and 13% more kidneys were transplanted (98). A similar retrospective study sought to evaluate the impact of a restrictive fluid balance that focused upon increasing lung procurement and evaluating renal function after kidney transplantation. The authors reported that a negative or equal fluid balance with a CVP less than or equal to 6 mmHg had no effect on kidney recipient graft function or the development of delayed graft function. A positive fluid balance between the brain death event and organ procurement did not reduce the risk of graft survi-vorship of delayed graft function. The authors concluded that a restrictive fluid management approach, focused upon enhancing lung procurement with a CVP less than 6 mmHg avoided vol-ume overload, minimized the effects of neurogenic pulmonary edema, and increased the rate of lung procurement without an adverse effect on either kidney graft survivorship or delayed graft function (99). In summary, fluid resuscitation should be guided by objective measurements and defined endpoints simi-lar to that used in the management of other critically ill patients. Previous strategies that focused upon aggressive overhydration to enhance renal perfusion have been shown to jeopardize pul-monary function and preclude procurement. A moderate or restrictive fluid resuscitative strategy is appropriate for both lung procurement and maintenance of renal function similar to the management approach for other critically ill patients.

In patients failing to achieve stability and defined endpoints in Figure 119.2, vasopressors are frequently necessary to main-tain perfusion pressures and are used in a majority of potential organ donors. Clear recommendations regarding the choice of vasopressors remain handicapped by an absence of controlled trials and perceived negative effects of catecholamines from studies that did not reliably measure the adequacy of intravas-cular volume. When employed, vasopressor and the endpoints of therapy should be clearly defined and vasopressor use titrated to specific physiologic abnormalities. Once intravascu-lar volume resuscitation has been adequately undertaken, the choice of vasoactive support depends upon the predominant physiologic abnormalities in organ donors. In those with pre-dominant myocardial dysfunction and inadequate flow, despite adequate volume resuscitation, dobutamine should be used for inotropic support. In potential organ donors whose hemody-namic instability is dominated by vasodilatation, vasopressors should be used to maintain mean arterial pressure and ensure adequacy of perfusion pressure gradients. Traditionally, alpha agents such as phenylephrine or norepinephrine were used to maintain vascular tone in the face of brain death–induced vasodilatation. However, recent recommendations have sup-ported the use of vasopressin as a first-line agent to maintain vascular tone (100). In one of the few large randomized pro-spective controlled trials of HRT in potential organ donors,

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the transition from norepinephrine to vasopressin was associ-ated with a significant increase in CO (3.18 to 3.72 L/min/m2) and a fall in systemic vascular resistance (1,190 to 964 Dyne cm sec). Consequently, vasopressin has begun to supplant the use of phenylephrine and norepinephrine for patients whose hemodynamic profile is dominated by vasodilatation.

Although not well appreciated, catecholamines have immunomodulatory properties. A large retrospective study conducted by Schnuelle (101,102), reported that the donor use of dopamine and/or norepinephrine was associated with beneficial results related to acute rejection that were attrib-uted to the immunomodulatory ability of catecholamines. This benefit was dominantly confined to renal graft survivorship, although a potential negative impact of norepinephrine was noted on heart transplantation. Recent literature suggests that the use of low-dose dopamine (4 μg/kg/min), independent of hemodynamic instability, was associated with a decrease in the need for dialysis after kidney transplantation (103). Similarly, a recent review of donor pretreatment with dopamine on sur-vivorship after heart transplant was reported. In this study, donor dopamine was associated with an improved survival after 3 years (87% vs. 67.8%). The authors concluded that fewer recipients of a pretreated graft required hemofiltration after transplantation (21.7% vs. 40.4%), and that treatment of potential brain-dead donors with dopamine of 4 μg/kg/min did not harm cardiac allographs and improved the clinical course of the recipient (104).

The use of HRT is predicated upon the assumption that the ischemic damage to the hypothalamic pituitary axis occurring with brain death creates an endocrinopathy domi-nated by the absence of thyroid and adrenal hormones that contribute to donor instability. Although beyond the scope of the textbook chapter to review in great detail, it is impor-tant to recognize that the anterior pituitary and posterior pituitary have distinct differences in blood supply, innerva-tion, and hormonal production. There is no specific direct arterial blood supply to the anterior pituitary, which receives its blood supply via drainage from the hypothalamus. Blood emerging from the hypothalamus empties into a portal sys-tem that bathes the anterior pituitary. Blood supply for the posterior pituitary is via the inferior hypophyseal artery and the connection to the hypothalamus is predominantly neu-ronal. HRT proposes that there is significant damage to the blood supply to the hypothalamic and pituitary areas that precipitate an endocrinopathy with the attendant physiologic sequelae of a low thyroid hormone state and adrenal insuf-ficiency. As previously discussed, there is substantial animal data and some human data to support a state of profound thyroid/adrenal depletion with exogenous supplementation reported to dramatically improve hemodynamic instability and suitability for transplantation (15). In the original work utilizing HRT, which consisted of thyroid hormone, cortico-steroids, and insulin, dramatic improvements in organ donor stability was achieved resulting in significant improvements in transplant suitability, diminutions in the requirements for vasoactive support and dramatic improvements in car-diac function (16). Large retrospective reviews of brain-dead donors reported significant benefit through the use of ste-roids, vasopressin, and utilization of either triiodothyronine or thyroxine. In the group of potential organ donors that received HRT, the number of organs procured was signifi-cantly higher than the donors that did not receive HRT. This

resulted in a 23% increase in the number of organs procured with dramatic improvements in the likelihood of an organ being transplanted (105). However, a review of thyroid hor-mone administration during adult donor care concluded that no publications support the routine administration of thy-roid hormone for all donors. Rescue replacement for cardiac inotropic support was supported by some studies, although the methodologic designs were not detailed enough to sup-port a recommendation for routine use (106). In one of the few prospective randomized double-blind trials, 80 potential cardiac donors were allocated to receive triiodothyronine (0.8 mg/kg/ bolus followed by a 0.113 mg/kg/hr infusion), methylprednisolone 1,000 mg bolus, both drugs, or placebo following an initial hemodynamic assessment. Independent of the use of HRT, an explicit donor management algorithm with optimization variables was initiated that used vaso-pressin as the primary vasoactive agent. During the 6-hour management period, cardiac index was noted to significantly increase in virtually all donors. However, the administration of thyroid hormone and methylprednisolone, either alone or in combination, did not affect the hemodynamics nor have any impact upon heart retrieval. Importantly, 35% of the hearts initially deemed marginal or dysfunctional were suitable for transplantation at the end of the assess-ment. The authors concluded that donor circulatory status can be improved by active management with the potential to increase transplantable hearts when organ acceptance is deferred until a period of resuscitation and assessment is completed. Hemodynamic management utilizing a PAC was felt to be the cornerstone of donor management and the introduction of hormonal therapy was not a substitute for a detailed hemodynamic assessment and management opti-mization approaches (78). Consequently, the use of HRT in potential ODM remains controversial and of uncertain ben-efit. Pragmatically, it would appear that this therapy should be utilized in hemodynamically unstable donors with ongo-ing instability, despite aggressive optimization management.

Pulmonary Status

Management of the potential organ donor with a focus upon optimizing the respiratory status has assumed a greater degree of importance as the overall lung procurement ratings are usually below 20%. The overall poor procurement rate may be explained by many factors such as an unknown past his-tory, multiple associations with the causative brain death event, including aspiration, pulmonary contusion, shock, and resuscitation, or the complications of mechanical ventilation to include atelectasis, barotrauma, and oxygen toxicity. How-ever, it is important to recognize that several recent studies have shown dramatic increases in the rate of lung procurement when an aggressive strategy focused upon ventilator manage-ment and respiratory care was employed.

Pathophysiologically, multiple factors conspire to jeopar-dize pulmonary function. These include the aforementioned events that transpire before brain death, and similar to the cardiovascular consequences of brain death, pulmonary con-sequences have been increasingly recognized. Traditionally, this has been dominated by neurogenic pulmonary edema consisting of the initial blast injury associated with brain death. Consequent to the catecholamine surge, there are sig-nificant elevations in systemic vascular resistance that result

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in elevations in left arterial pressure. This represents a tran-sient massive hydrostatic pressure gradient generating fluid flux into the lung that is coupled with structural damage to the capillary endothelium. Against this background of capil-lary permeability, ongoing fluid resuscitation is purported to increase extravascular lung water, which is associated with changes in the chest x-ray appearance and diminution in lung function which have precluded procurement. Initial work in animal models revealed a dramatic distribution of blood to the right atrium and right ventricle consequent to venocon-striction and augmentation of venous return. Increases in pul-monary artery pressure were reported that resulted in 72% of the effective circulating volume contained in the lungs for several minutes during the brain death event (17). Subsequent to this hydrostatic and capillary burst injury pattern associ-ated with brain death, Fisher (107) recognized the presence of an inflammatory response associated with brain death. In a study that compared inflammatory signals in brain-dead patients to controls, dramatic increases in neutrophil con-centration and lavage concentrations of IL-8 were reported. In a subsequent study by Fisher et al. (108), the magnitude of the inflammatory response in the donor was evaluated in the recipient. The IL-8 signal in the donor was found to be correlative with the degree of impairment in graft oxygen-ation, the development of severe early graft dysfunction, and early recipient mortality. Avlonitis (109,110) has proposed that a combination of hydrostatic forces and inflammatory responses conspire to jeopardize pulmonary function during the donor management period. The inflammatory response is derived from events that are antecedent to brain death in conjunction with IR injury of brain death. Allowing time for the lung to recover in the immediate brain death period could potentially mitigate the reperfusion injury, hemodynamic mechanisms of lung injury, and systemic response following brain death to the transplant donor.

The criteria for ideal lungs suitable for procurement were defined during the early phase of transplantation and included a PaO2/FiO2 ratio greater than 300 mmHg, a clear chest x-ray, positive end-expiratory pressure (PEEP) require-ments of no more than 5 cm of H2O, age less than 55 years, minimal tobacco abuse, and the absence of significant chest trauma, pulmonary secretions, or aspiration. However, there has been a liberalization of these criteria, which were thought to be excessively stringent and capricious. In a large autopsy series of potential donors, 47% of those potential donors deemed suitable for lung procurement but not procured, had significant pulmonary disease, and 25% had bronchopneu-monia. In those potential donors that were deemed not suit-able, only 15% had minor pulmonary abnormalities (111). Similarly, autopsy assessment of lungs rejected for transplan-tation reveals that 41% of rejected lungs were potentially suitable for transplantation. In this case-matched study of lungs rejected for donation, 83% were found to have absent or mild pulmonary edema, 74% had an intact alveolar fluid clearance, and 62% had normal or only mildly abnormal cystopathology (112). Additionally, Fisher (113) reported the traditional criteria were poor discriminators of pulmonary injury and infection, which led to the exclusion of potentially usable lungs. Utilizing bronchial alveolar lavage samplings of inflammatory mediators, there was no difference between those lungs that were accepted and those excluded by clinical criteria. Finally, Shafaghi and colleagues (105a) found that

27/30 (90%) brain-dead patients, on whom bronchoalveo-lar lavage (BALs) were performed, had positive bacterial and fungal cultures. They suggest that such patients—donors and recipients—must be more aggressively managed if the lungs are to be used; for example, combined intravenous and aero-solized antibiotics in donors and recipients can reduce the incidence of recipient pneumonia. Nonetheless, recipients would be expected to have longer ICU length of stay and ventilator days, as well as decreased survival.

Traditionally, donor lung ventilator management was not aggressively pursued and frequently suboptimal for pres-ervation of lung function. This is illustrated in a study of 34 brain-dead patients, of whom 11 were considered eligible lung donors, yet only two donated lungs. In this potential lung donor population, no ventilator changes were made after confirmation of brain death, no recruitment maneuvers were undertaken to preserve gas exchange, saline infusion was increased from 187 to 275 mL/hr, and CVP was permitted to increase; 45% of the potential lung donors experienced decrements in the PaO2/FiO2 ratio, making them ineligible for donation.

In contrast, several studies that focused upon optimization of donor lungs have reported dramatic improvement in the rate of lung procurement. In one of the original studies of lung donor management that included antibiotic therapy, strict fluid management, physiotherapy, bronchoscopy, and pulmo-nary toilet, along with alterations in ventilator status including the initiation of pressure ventilation, dramatic improvements in lung procurement were reported. In a study population with an initial PaO2/FiO2 ratio less than 300 mmHg, 31% of lungs were clearly unsuitable and were not subjected to aggres-sive donor management. However, the remaining 69% were aggressively managed to include manipulations in mechanical ventilation, adjustments in PEEP, and bronchoscopy; 49% of those subjected to aggressive donor management were able to achieve a PaO2/FiO2 ratio higher than 300 mmHg and were successfully transplanted with outcomes indistinguishable from those with an initially acceptable ratios. Similar out-comes between the ideal and donor management lungs were achieved related to postoperative gas exchange, ICU length of stay, and short- or medium-term mortality (114). A sub-sequent study similarly reported the results of an aggressive donor management program to improve the rate of lung pro-curement. The San Antonio Lung Transplant (SALT) Donor Management Protocol hypothesized that the implementation of a donor lung management program would increase the rate of lung procurement without adversely impacting the overall survival rate of lung transplant recipients. Elements of the protocol included educational activity to enhance the interaction between transplant pulmonologists and OPO staff related to donor selection and management, emphasis upon every donor as a lung donor, ensuring requests for donation for donation, and educating organ procurement coordinators about donor management strategies. These included the use of recruitment maneuvers which were defined as maintenance of a pressure-controlled ventilation of 25 cm of H2O and a PEEP of 15 cm of H2O for 2 hours with subsequent transi-tion to conventional volume control ventilation with a tidal volume of 10 mL/kg and a PEEP of 5 cm of H2O. Fluid bal-ance focused upon minimizing the use of crystalloid solutions, and diuretics to maintain a neutral or negative fluid balance. Aspiration risk was minimized by elevating the head of the bed to 30 degrees and inflating the endotracheal balloon to

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25 cm of H2O. Additionally, bronchoscopy with bronchial alveolar lavage was performed on all patients to evaluate the chest x-ray area of infiltrate. Despite poor donors accounting for 76% of the total donors during the trial period, a dramatic increase in actual lung donors (98 vs. 38) and a significant increase in lung transplantations (121 vs. 53) resulted. The authors concluded that an aggressive protocol focused on lung donor management significantly increased the number of lung donors and transplant procedures without compromising lung function, length of stay, or survival of the recipients (115).

In a recent comparison trial of lung donor management, a significant increase in the rate of lung procurement was reported—40% versus 27%—with an aggressive lung donor management strategy. In the control group, donor manage-ment commenced within 2 hours of consent for donation and continued for approximately 7 hours. Management strategies included early bronchoscopy, tidal volumes of 10 mL/kg with a PEEP of 5 cm of H2O, frequent suctioning and volume recruit-ment enabled by turning the potential donor every 2 hours. A specific hemodynamic algorithm titrating vasoactive support and fluid resuscitation to a cardiac index of greater than 2.5 L/min/m2, focusing on a low CVP and pulmonary capillary wedge pressures was employed. Fluid resuscitation was mini-mized and colloid solution was preferentially utilized. Donor lungs subjected to this aggressive management approach resulted in a procurement rate of 40% (77).

Miñambres and colleagues (116) showed in a before–after series that use of an aggressive lung management protocol led to a quadrupling of lung donors (transplanted lungs) with no change in postgraft dysfunction. These investigators followed a seven-step protocol:

1. Apnea test performed with ventilator in the continuous positive-pressure mode

2. Mechanical ventilation with PEEP of 8 to 10 cm H2O and tidal volume of 6 to 8 mL/kg

3. Recruitment maneuvers once per hour and after any dis-connection from the ventilator

4. Bronchoscopy with bilateral bronchoalveolar lavage5. Hemodynamics closely monitored with the PICCO sys-

tem, with a goal of extravascular lung water of 10 mL/kg or less, administering diuretics if needed, and a CVP of 6 to 8 mmHg

6. Methylprednisolone, 15 mg/kg after brain death declaration7. Alveolar recruitment with controlled ventilation—

peak pressure limit of 35 mmHg with PEEP of 18 to 20 cm H2O for 1 minute and decreased 2 cm H2O each minute—after that tidal volumes were increased by 50% for 10 breaths

They attributed their success at increasing lung donors to this protocol, as other issues remained unchanged.

Although a lung protective strategy has been adopted by the intensive care community for patients with acute lung injury (ALI), traditional donor management has utilized relatively high tidal volumes in an effort to minimize de-recruitment and improve gas exchange. In all likelihood, hyperinflation has cosmetically improved the chest x-ray, which is one of the tra-ditional criteria for procurement. However, these traditional concepts were recently challenged in a randomized controlled trial comparing the outcomes of conventional ventilator strat-egies with tidal volumes of 10 to 12 mL/kg, PEEP mainte-nance with 3 to 5 cm of H2O and the performance of apnea tests by disconnecting the ventilator with an open suction to a

protective ventilator strategy with tidal volumes of 6 to 8 mL/kg, PEEP of 8 to 10 cm of H2O with apnea tests performed by using CPAP and closed circuit for suction. In the conven-tional strategy group, only 54% of potential donors met lung donor eligibility after a 6-hour observation period compared to 95% in the protective strategy group. Only 27% of lungs were procured from donors in the conventional strategy group compared to a procurement rate of 54% in the protective strat-egy group. Six-month survivorship did not differ between those recipients receiving lungs from either category. Similar to data from patients with ALI, a significantly higher level of inflam-matory mediators was reported in the conventional ventilator strategy compared to the protective ventilator strategy. This study strongly suggests that hyperinflation has an adverse effect on lung function, compromises eligibility of lung donors, and should be replaced by a protective ventilator strategy similar to patients with acute lung injury. Similar to the evidence sup-porting aggressive donor cardiac management, an aggressive approach to lung donor management will result in a higher level of lung donor procurement, and no donor lung should be rejected upon the initial evaluation. Ongoing assessments for suitability are required in conjunction with aggressive donor management (117). Recent evidence suggests that the use of airway pressure release ventilation (APRV), as compared to assist control ventilation (ACV), results in a higher PaO2/FiO2 ratio (mean [SD], 498 [43] vs. 334 [104] mmHg, respectively; p < 0.001) after 100% O2 challenge. The ACV group ultimately donated 7 of 40 potential lungs (18%) compared with 42 of 50 potential lungs (84%) in the APRV group (p < 0.001) (118).

Supportive Care

Hemodynamic management forms the cornerstone of potential ODM. Ensuring adequate perfusion to all organs is the best approach to support liver, kidney, pancreas, and small bowel function, anticipating possible procurement. This requires ongoing hemodynamic measurements using the previously described donor management endpoints. A recent paper by Smith and colleagues (119) reported—in a prospective but non-randomized study—that direct peritoneal resuscitation (DPR), using of 2.5% glucose-based clinical peritoneal dialysis solu-tion, reduced IV fluid requirement and pressor use, increased hepatic blood flow, and organs transplanted per donor. The mechanism of action is thought to be its action as a nonphar-macologic vasodilator, increasing microcirculatory flow, as well as creating an osmotic gradient with the extracellular space that reduces cellular edema. The anti-inflammatory cytokine, IL-10, was significantly upregulated compared to controls. While DPR appears to be a safe, effective method to augment organ donor resuscitation, its use needs to be further studied.

Although there are extremely limited data, there is spec-ulation that hepatic glycogen stores may be depleted in the brain death period and that support with enteral nutrition may play an important role in modulating organ function after transplantation (120). In the absence of contraindica-tions, it is appropriate to continue enteral nutrition carefully following for any evidence of hyperglycemia. As previously mentioned, the liver is explicitly sensitive to hypernatremia, so serum sodium level should be corrected to less than 155 mEq/L. Diabetes insipidus is a frequent complication of brain death secondary to a deficiency of vasopressin after pituitary destruction. Vasopressin absence can contribute to multiple

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donor management issues, including hyperosmolarity, elec-trolyte disturbances, and intravascular volume depletion. It is important to differentiate diabetes insipidus from mannitol-induced osmotic diuresis. Diabetes insipidus is generally asso-ciated with serum sodium greater than 150 mEq/L, an elevated serum osmolarity, a urine output exceeding 300 mL/hr, and a urine osmolarity usually less than 200 mOsm/L with an asso-ciated normal serum osmolar gap. The preceding serves to dif-ferentiate diabetes insipidus from mannitol-induced polyuria. Diabetes insipidus should be treated with hypotonic solutions and, frequently, 5% dextrose in water is used to match urine output mL for mL. In instances of urine output greater than 200 to 300 mL/hr, desmopressin acetate (DVAVP) or arginine vasopressin may be utilized. Vasopressin exerts its effect on three receptors: V1 receptors on the smooth muscle and is responsible for vasopressor effects, V2 receptors located in the kidney which promote the antidiuretic effect, and V3 recep-tors in the pituitary which regulate corticotropin-releasing hormone. Arginine vasopressin has antidiuretic and vasopres-sor effects, whereas DVAVP has greater affinity for the V2 receptor and consequently a predominant antidiuretic affect. Clinically, 1 to 4 μg of DDAVP is given intravenously, follow-ing urine osmolarity, urine output, and serum sodium closely. Subsequent dosing is dependent upon the response. In the set-ting of hypotension, arginine vasopressin is preferred at a dose between 0.01 and 0.04 IU/min. Hyperglycemia is frequent in potential organ donors and often necessitates the use of insu-lin for control. Although the effects of hyperglycemia are not well established, hyperglycemia is believed to impair organ function. Consequently, hyperglycemia should be treated simi-larly to critically ill patients using an empiric level of 150 mg/dL to initiate therapy. Coagulation abnormalities are common in potential organ donors and ongoing assessment of coagu-lopathy and hemoglobin are necessary during the course of donor management. Although there is no outcome data for potential organ donors, the approach advocated is similar to that of other critically ill patients utilizing a transfusion threshold for hemoglobin of 8 mg/dL and normalization of coagulation parameters. Pituitary injury predisposes to ther-moregulatory impairment and it is imperative that the donor receives warmed fluids and body temperature be monitored routinely, as hypothermia can further impair coagulation and predispose to cardiac rhythm disturbances. Nonetheless, there is at least speculation that when ODM is properly applied, additional benefit of previously recommended drugs and hor-mones may be marginal (121).

DOnatIOn aFter carDIac Death

DCD refers to the recovery of organs from patients that are not brain dead, but die secondary to cardiopulmonary causes. This was previously known as a nonheart-beating donor. Donation may occur in several circumstances that are either controlled or uncontrolled. The vast majority of DCD occurs during controlled situations when care is withdrawn and the patient is pronounced dead from cardiopulmonary arrest. Uncontrolled DCD is far less common and occurs in emergent circumstances such as death from an acute trauma. Prior to 1968, there was no legal definition for brain death and DCD was the primary method for obtaining organs for transplantation. After the acceptance of brain death, dona-

tion from brain-dead donors has significantly exceeded those from DCD. The IOM formally evaluated the DCD practice into separate reports (122,123). Specifically, the IOM stipu-lated that the decision to withdraw or withhold care be under-taken based upon the patient’s wishes and not influenced by any potential for organ donation. It was further recommended that a separate team provides EOL care that was distinct from the transplant team. DCD must adhere to the dead donor rule, which stipulates that donor organs may only be procured from dead patients. When undertaking DCD, the withdrawal of care should be indistinguishable from the withdrawal of care in any other critically ill patient. Death is declared when there is cessation of cardiopulmonary function and after a period of time to ensure that there is no spontaneous recrudescence of respiratory function. Although the initial 1997 recommenda-tion from the IOM was a 5-minute period between the diagno-sis of death and the initiation of organ recovery, it is currently recommended that this period be at least 2 minutes and no more than 5 minutes (124).

Key Points

• Care must be taken in the ICU so that early identifica-tion of potential donors is made, the OPO is informed, and donor loss prevented.

• Patients who have become potential organ donors demand the same high-quality critical care as was given while they were alive.

• Intensivist involvement and protocolized/standardized care are the most important components of ODM.

• When ODM is properly applied, the additional benefit of previously recommended drugs and hormones may be limited.

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