At present, there are over 90,600 patients on the Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) organ waiting list and, in the year 2005, over 7,000 patients died on the waiting list or were too sick to transplant (1). Although there were 25,953 living and deceased donor transplants performed in 2005, there were 41,057 organ transplant candidates added to the waiting list that year (1). One solution to this dilemma is to increase the conversion rate of eligible brain-dead donors to actual donors (2). A second solution is to resuscitate potential donors who are hemodynamically unstable as a consequence of brain death and therefore unsuitable donor candidates. Substantial hemodynamic instability after conventional resuscitation has been observed in at least 35–45% of brain-dead donors (3–5).
Hormonal therapy for hemodynamic stabilization of brain-dead organ donors was initiated by cardiac surgeons at the University of Cape Town in the early 1980s because they were concerned that approximately 20% of hearts from human brain-dead donors were unsuitable for transplantation due to poor myocardial function (6). This led to a series of animal experiments that documented the electrocardiographic, hemodynamic, endocrine, metabolic, and histopathologic changes that occur as a consequence of brain death (7).
Hemodynamic Effects of Brain Death
Brain death in baboons was induced by placing a Foley catheter in the subdural space through a burr hole and instilling 20–30 mL of saline (7). This resulted in acute intracranial hypertension leading to brain stem herniation and brain death. In the pig, both brachiocephalic arteries were ligated, resulting in acute global cerebral ischemia (8, 9). In both models, during and following the agonal period there was a short-lived, but devastating, catecholamine “storm” (Fig. 1), which was the result of endogenous catecholamine release from postganglionic sympathetic nerve endings (7, 10, 11). The hemodynamic response was a significant elevation of the systemic vascular resistance (SVR), resulting in systemic hypertension, acute left ventricular failure, fall in cardiac output, acute transient mitral valve regurgitation, leading to a rise in left atrial pressure. These events led to blood volume displacement into the venous compartment, with pulmonary volume overloading (11, 12). The electrocardiogram showed multiple arrhythmias plus ischemic changes in all animals (10).
Subsequent experiments in dogs, by a separate group of investigators, confirmed the hemodynamic changes described above when brain death was caused by increasing the intracranial pressure suddenly (13). However, when the intracranial pressure is increased slowly, the animals underwent a lesser hyperdynamic response, and experienced only approximately 25% of the rise in epinephrine levels seen in animals undergoing sudden brain death (13). In the human clinical situation, there is a broad spectrum of adverse hemodynamic instability that is observed, which may, in part, reflect the speed at which brain death is induced.
Histological examination of the organs from brain-dead animal donors showed the adverse effects of endogenous catecholamine release (10, 11). In the heart, the myocardium suffered various modalities of cell necrosis (contraction bands, coagulative necrosis, myocytolysis), and infiltration of mononuclear cells (macrophages) around necrotic cells. This was manifest maximally in the left ventricular subendocardium and was similar in appearance to an acute rejection episode. In some animals, pulmonary edema and hemorrhage were observed (12).
Endocrine Changes After Brain Death
After the initial outpouring of catecholamines following the onset of brain death, catecholamine levels rapidly returned to control levels (Fig. 1) and subsequently to levels below baseline, when endocrine changes, reflecting pituitary failure, developed (7, 11). Cortisol levels were increased at five minutes and then declined progressively to subbaseline levels (7). Plasma levels of free triiodothyronine (T3) and free thyroxine (T4) fell to 50% of control levels within one hour after brain death and became undetectable within 9 and 16 hours, respectively, but thyroid stimulating hormone (TSH) showed no significant change (Fig. 2). Insulin levels declined to 50% within three hours, and to 20% within 13 hr (8). Antidiuretic hormone (ADH) was undetectable within six hours (8). Prompted by these results, the Cape Town group evaluated hormone replacement therapy, first in brain-dead animals (9) and then in brain-dead human organ donors (14).
Inflammatory Response After Brain Death
Shortly after the hemodynamic and endocrine changes associated with brain-death occur, both circulating and tissue inflammatory mediators, such as cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor-α [15–19]) and adhesion molecules (E-selectin, ICAM-1, VCAM-1 [18–21]), have been observed in experimental animals and in humans. These inflammatory mediators are not seen in nonbrain-dead animals or humans (18, 19). The presence of these cytokines and adhesion molecules is associated with accelerated graft rejection (18) and there is a possible association with acute vascular rejection (22).
Elevated levels of the inflammatory cytokines, tumor necrosis factor (TNF)-α and IL-6, have been shown to be present in the myocardium and serum of brain-dead human heart donors (17). TNF-α was 1.6 times higher in unused (poor cardiac function) than in used (satisfactory cardiac function) donor hearts. IL-6 levels were 2.4 times greater in unused donor hearts than in used donor hearts. Both TNF-α and IL-6 are elevated in congestive heart failure, and TNF-α has been shown experimentally to produce myocardial depression. It has also been shown that a specific TNF-α antagonist (etanercept), when given intravenously to patients with New York Heart Association class III heart failure, results in significant improvement in ejection fraction and significant reduction in circulating levels of TNF-α and IL-6 (23). Peak improvement in ejection fraction (12% of baseline) and significant reduction in TNF-α and IL-6 occurred within six hours following a single intravenous dose of etanercept. We are unaware of any clinical use of etanercept in human organ donors.
Overall survival of rat kidneys from brain-dead donors was significantly less than that of kidneys from living donors (21). Kidneys from brain-dead donors treated with either steroids or with a specific selectin binder (sPSGL) survived significantly longer than kidneys from untreated brain-dead donor rats (21).
Hormone Replacement Therapy After Brain Death
Four hours after ischemic brain death had been induced in pigs, intravenous hormone therapy, consisting of T3 (2 μg), cortisol (100 mg), and insulin (5–10 units), was administered, and repeated after one hour (9). When compared to brain-dead, nontreated pigs, treated animals demonstrated a return of cardiac output and stroke volume to values that were not statistically different from prebrain death control levels; however, the left ventricular pressure remained significantly elevated (P<0.003) (9). In the first human trial of hormone replacement therapy, 21 consecutive brain-dead donors were treated with traditional therapy of intravenous (i.v. fluids, inotropes, and bicarbonate, but in addition received 2 μg of T3, 100 mg of cortisol, and 10–30 units of insulin, and had those dosages repeated every hour for a mean of 5.5 hours (14). These hormone-treated donors were compared with 26 historical control donors treated only with standard therapy. Hormone-treated donors showed restoration of their low T3 levels to normal, accompanied by significant improvements in mean arterial and central venous pressures in conjunction with significant reductions in the need for inotropic support and bicarbonate (14). All electrocardiographic abnormalities disappeared. The hearts from all 21 hormone-treated donors were transplanted with satisfactory immediate cardiac performance (14).
Metabolic Responses to Brain Death and Hormonal Therapy
Studies in brain-dead baboons showed a marked reduction in utilization of glucose, pyruvate, and palmitate, with an accumulation of tissue and plasma lactate and plasma free fatty acids (24). The administration of intravenous T3 resulted in a substantial increase in glucose, pyruvate, and palmitate utilization, accompanied by a reduction of plasma lactate and free fatty acids, indicating a reversal from anaerobic to aerobic metabolism (24). Similar results were seen for plasma pyruvate and lactate in 21 human donors receiving hormonal therapy (14).
Studies Failing to Confirm Benefits of Hormonal Therapy
The studies by the Cape Town group on the benefits of hormonal therapy did not achieve rapid universal acceptance, in part because of published studies that failed to confirm low levels of T3, T4, cortisol, and insulin after brain death (25, 26) and/or published studies that failed to demonstrate any beneficial cardiac and circulatory effect of T3/T4 administration (27, 28). This may have been for a number of reasons: not all brain-dead donors have total absence of anterior pituitary function (and therefore some have measurable T3 levels), some groups failed to measure free T3, not all donors are hemodynamically unstable (3, 29, 30) and the benefit from T3/T4 therapy might not be seen, and an inadequate dosage of T3/T4 may have been administered.
Studies Confirming Benefits of Hormonal Therapy
At least four groups of investigators subsequently demonstrated a beneficial effect of hormonal therapy on the unstable donor (3, 29–32). Papworth Hospital surgeons, using a pulmonary artery catheter, obtained full hemodynamic data on 150 multiorgan donors (3). After conventional donor management consisting of ventilation, fluid replacement, and optimizing serum electrolytes, 52 donors failed to meet minimal acceptance criteria for heart donation due to low mean arterial pressure (MAP; <55 mm Hg), elevated central venous pressure (CVP; >15 mm Hg), elevated pulmonary capillary wedge pressure (PCWP; >15 mm Hg), low left ventricular stroke work index (<15 g), or high inotrope requirements (>20 μg/kg/min). Hormonal replacement therapy, consisting of a 15 mg/kg i.v. methylprednisolone bolus, 4 μg T3 bolus followed by infusion of 3 μg per hour, 1 U arginine vasopressin bolus followed by 1.5 U per hour, and a minimum of 1 U per hour of insulin (+dextrose) was administered to these 52 hemodynamically suboptimal donors. After this therapy, 44 of the 52 donors had improved enough to be used as heart donors. Thirty-day recipient survival was 89% (39/44) and none of the five early deaths was due to cardiac failure (3).
Cardiac surgeons at Temple University initially reported on six (31) and later on 22 potential donors (29) who had depressed left ventricular function (mean ejection fraction [EF] 39.2±5.5), elevated left atrial pressures, and high inotrope requirement. Each of these donors received a 0.6 μg bolus of T3, and all 22 donors demonstrated an improvement in cardiac and circulatory function concomitant with a significant reduction in inotrope requirement. In 17 of the 22 donors, the heart was recovered and transplanted; cardiac function was satisfactory at one week and all 17 patients were discharged from the hospital (29).
Surgeons at Los Angeles County Hospital studied 19 brain-dead donors who manifested hemodynamic instability exhibited by a mean arterial pressure <70 mm Hg despite adequate fluid resuscitation and use of greater than 10 ug/kg/min of inotropes (30). Hormonal resuscitation consisted of methylprednisolone (2 g), T4 (levothyroxine 20 μg, followed by an intravenous infusion of 10 μg/hr), and insulin (20 U + 50% dextrose). Eleven of the 19 donors had a decrease in inotropic requirement within 2 hours, and within four hours all donors had decreased requirements, with 10 donors being completely weaned off vasopressors (30). Permission for organ retrieval was obtained in 10 donors and 33 organs were recovered. No data were presented on the functional status of these 33 organs.
Intensivists from the University of Pennsylvania reported on 91 brain-dead pediatric patients who were organ donor candidates and who received a bolus of T4 followed by a T4 infusion as a maneuver to reduce high ionotrope requirements (32). Additionally, 57% of these patients received vasopressin and 40% received steroids. Patients receiving T4 had a significant reduction in their vasopressor requirements. No data were given on organ yield or quality (32).
The Crystal City Consensus Conference
In March 2001, a conference designed to develop guidelines for maximizing the number of organs recovered and transplanted from deceased donors was attended by nearly 100 transplant professionals (33, 34). Very similar guidelines were developed by the Canadian Council for Donation and Transplantation Forum, “Medical Management to Optimize Donor Organ Potential” in 2004 (35). The Cardiac Work Group of the Crystal City Conference recommended a heart donor management algorithm (Fig. 3) that included four-drug hormonal resuscitation for donors with a left ventricular EF <45% and/or with unstable hemodynamics (34, 36). Recommended hemodynamic management included a pulmonary artery catheter to assess the effect of hormonal resuscitation in meeting six target criteria: 1) MAP >60 mm Hg, 2) CVP 4–12 mm Hg, 3) PCWP 8–12 mm Hg, 4) SVR 800-1200 dyne/sec-cm5, 5) cardiac index >2.4 L/min-m2, and 6) dopamine or dobutamine <10 μg/kg-min (Fig. 3).
The conference further recommended that the heart donor management algorithm be included in the UNOS Standardized Donor Management Protocol (37). UNOS implemented this recommendation, and the UNOS Protocol was endorsed by the American Society of Transplant Surgeons, the American Society of Transplantation, the North American Transplant Coordinators Organization, and the Association of Organ Procurement Organizations (37).
UNOS Reports on Hormonal Resuscitation of the Brain-Dead Organ Donor
The Crystal City Conference led UNOS to perform a retrospective analysis of all brain-dead potential donors in the Organ Procurement and Transplantation Network OPTN/UNOS database from January 1, 2000 to September 30, 2001 (38). In the cohort of 10,292 brain-dead donors, 701 received three-drug (methylprednisolone, T3/T4, arginine vasopressin) hormonal resuscitation (HR) (38). The mean number of organs transplanted from three-drug HR donors (3.8) was 22.5% greater than that from non-HR donors (3.1) (P<0.001). Furthermore, the number of organs transplanted from three-drug HR donors >age 40 years (3.1) was significantly greater than that from non-HR donors in the same age range (2.5) (P<0.01). Logistic regression analyses showed that three-drug HR was associated with the following statistically significant increased probabilities of an organ being transplanted from a donor: kidney 7.3%, heart 4.7%, liver 4.9%, lung 2.8%, and pancreas 6.0% (38).
A second UNOS study of 4,543 heart recipients indicated the Kaplan-Meier one-month survival of three-drug HR hearts (89.9%) was significantly greater (P<0.01) than the survival of non-three-drug HR hearts (83.9%) (39). One-month graft loss was 3.8% for three-drug HR hearts versus 7.9% for hearts in which the donor received none of the three drugs. Early graft dysfunction occurred in 5.6% of three-drug HR hearts and in 11.6% of hearts in which the donor received none of the three drugs (P<0.01). Corticosteroids alone, or steroids plus T3/T4 also significantly reduced prolonged graft dysfunction. Multivariate analyses showed a 46% reduced odds of death within 30 days and a 48% reduced odds of early graft dysfunction when three-drug HR was utilized (39).
Recent unpublished OPTN/UNOS data have shown significantly improved one-year kidney graft survival (P<0.01) with both conventional (n=14,637) and expanded criteria donors (n=4,089) when the donor received three-drug HR, as compared to donors receiving no HR drugs (Fig. 4). For heart recipients, one-year patient survival was significantly improved (P<0.01) when the donor received three-drug HR. However, for liver recipients, one-year patient survival was the same whether or not the donor had received three-drug HR therapy. In multivariate analyses, three-drug HR was associated with a significantly reduced risk of one-year graft loss in both kidney and heart recipients.
Hormonal resuscitation is becoming more widely accepted with an increase in three-drug HR use from 8.8% of brain-dead organ donors reported to the OPTN in the year 2000 to 19.9% of donors in 2004.
Comments on the Agents Used in Hormonal Resuscitation
We are unaware of any adverse effects of T3/T4, arginine vasopressin, or methylprednisolone on either the brain-dead organ donor or the organs to be transplanted.
T3 Versus T4
The Cardiac Consensus Report recommended T3 because the onset of action is rapid and not adversely affected by exogenous factors that can affect T4 (34, 36). However, UNOS data indicate that 93% of donors have received T4 and, thus far, analyses have not been able to detect any difference in effectiveness between T3 and T4. Thus, while the onset of action of T4 is slower, it appears to be effective, especially when administered in large doses intravenously (30).
Arginine Vasopressin Versus Desmopressin (DDAVP)
Low-dose arginine vasopressin, in addition to treating diabetes insipidus, results in reduced inotropic requirements, and has been associated with good kidney, liver, and heart graft function (3, 39, 40). Desmopressin is beneficial primarily for treatment of diabetes insipidus in organ donors and is not usually associated with reduction of inotrope requirements (41). Furthermore, there is one report indicating that desmopressin may be associated with a higher incidence of human pancreatic graft thrombosis (42).
Steroid (Methylprednisolone) Bolus
The optimal dose of i.v. methylprednisolone for the brain-dead donor remains uncertain. High doses have been recommended (34, 36) and the UNOS study (39) indicated a beneficial effect on the heart when it was the sole hormone administered. Because the half-life of i.v. methylprednisolone is short (43), we believe that it is desirable to repeat the dosage when organ retrieval is delayed.
Insulin and Glucose
Use of insulin and glucose in organ donors is not collected in the OPTN/UNOS database and therefore analyses of benefit, or lack of benefit, have not been reported. It was recommended by the Crystal City Consensus Conference (36) without using a specific reference to document its efficacy.
T3 Therapy in Heart Transplant Recipients
The Cape Town group also demonstrated experimentally that cardiopulmonary bypass is associated with a depletion of free T3, and that the i.v. administration of T3 improves cardiac function and reverses adverse metabolic changes (44, 45). They demonstrated a beneficial effect of treatment of both donor and recipient in a clinical series of 70 patients undergoing heart transplantation (46, 47). These observations were independently supported by a small, randomized study of heart recipients (29).
Experimental studies in Cape Town in the 1980s demonstrated that acute brain death is associated with a massive catecholamine release that results in systemic hypertension, acute left ventricular failure, and multiple cardiac arrhythmias, along with substantial decreases in cortisol, thyroid hormone, insulin, and antidiuretic hormone levels, and a change from aerobic to anaerobic metabolism. Both circulating and tissue inflammatory mediators, such as cytokines (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α) and adhesion molecules (e.g., E-selectin, ICAM-1, VCAM-1) are expressed, which are not normally seen in nonbrain-dead animals or humans. Hormonal replacement therapy, in the form of cortisol or methylprednisolone, triiodothyronine (T3) or thyroxine (T4), insulin, and antidiuretic hormone, has been reported to result in rapid recovery of cardiac function in both experimental animals and humans, and enables significantly more organs to be transplanted. Although a few studies have failed to show benefit of hormonal replacement therapy, there are an increasing number of reports showing a beneficial effect. The Crystal City Consensus Conference recommended that four-drug hormonal resuscitation be an integral component of the UNOS Donor Management Protocol. Analyses of the OPTN/UNOS database have shown that three drug (methylprednisolone, T3/T4, arginine vasopressin) hormonal resuscitation results in a greater number of organs deemed acceptable for transplantation, more organs transplanted per donor, and significantly better graft survival of kidneys and hearts. The use of three-drug hormonal resuscitation in donors reported to the OPTN has more than doubled from the year 2000 to 2004.
D.N. and D.K.C.C. thank their several former colleagues in Cape Town and Oklahoma City who contributed to the experimental and early clinical studies reviewed in this paper.
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