Donor management: State of the art

ELSEVIER

Donor Management:

State of the Art

D. Novitzky

T

HE relevance of a well-functioning transplanted organ cannot be over-emphasized and is clearly crucial for the success of organs requiring immediate function, such as the heart and lung. Temporary failure of the liver, kidneys and pancreas may rely on hemodialysis and pharmacological intervention. Early graft failure accounts for approximately 30% of all causes of deaths of cardiac’ and lung recipients, 30% of liver and 5% of renal recipients. Patients who will become potential brain-dead organ donors will suffer multiple adverse events such as shock, hypoxia, infections, surgical procedures, and multiple blood transfusions, which together will precipitate generalized body injury from ischemia, reperfusion and a non-reflow phenomenon. During the death of the brain two major injuries have been identified: (a) catecholamine storm’,” and (b) rapid disintegration of the hypothalamic-hypophyseal axis and significant changes in circulating plasma hormones.’ Ischemia is a pathological process characterized by the lack of adequate blood flow and inadequate oxygen tissue delivery to meet the tissue-organ demands. The consequent cellular oxygen lack results in intracellular inhibition of aerobic oxidative respiration and cellular energy 10~s.~Ion gradients require constant ATP hydrolysis at various pumps and channels. The failure of the Ca” channels precipitate the Ca2+ induced injury.’ Reperfusion is the reestablishment of blood flow and oxygenation to ischemic tissue. Cellular homeostasis recovers and restoration of cellular energy takes place. However, during reperfusion, new injury may be added to tissues exposed to ischemia and results in a condition ischemia-reperfusion injury, during which toxic short-lived oxygen-free radicals induce lipid peroxidation of cell membranes.’ Membrane permeability opens the Ca2+ channels, which results in further calcium induced injury. The reperfusion tissue failure results in a non-reflow phenomenon. This event seems to be proportional to the ischemic time and nitric oxide appears to play a role in this event. The described events are of paramount relevance in the global understanding of tissue injury, prevention and/or recovery as transplanted organs undergo these detrimental events prior brain death, during and following brain death, cold storage and finally at the time of reperfusion in the recipient. 0 1997 by Elsevier Science Inc. 655 Avenue of the Americas,

New York, NY 10010

Transplantation

29, 3773-3775

Proceedings,

(1997)

PHYSIOPATHOLOGY Catecholamine

OF BRAIN

DEATH

Storm

Whatever the precipitating effects which will result of the death of the brain are associated to an autonomic storm (parasympathetic and adrenergic), the massive release of circulating and endogenous catecholamines will induce a major impact on the cardiovascular system.’ The impact on the heart will result in electrocardiographic ischemic changes, marked ST-T wave abnormalities and pseudo acute myocardial infarction.’ The adrenergic impact on the arteries will induce a significant increment of the systemic vascular resistance (SVR) and arterial hypertension. It is during this period there is acute left ventricular (LV) failure and significant reduction of the systemic cardiac output and mitral regurgitation. A significant left atria1 (LA) pressure elevation has been observed in animals on occasions above the pulmonary artery (PAP) pressure.’ It is during this period that capillary pulmonary integrity is disrupted as result of acute mitral regurgitation. This may precipitate neurological induced pulmonary edema as the LA pressure returns to baseline in 20 to 80 seconds and is no longer observed in the emergency room. The light and electron microscopy of organs procured from experimental animals and human brain dead organ donors shows the typical catecholamine-calcium induced injury,2~8~9which results from the tissue ischemia-reperfusion, which takes place at the peak of the SVR. In the heart, focal myocyte necrosis in the form of contraction bands and coagulative necrosis or myocytolysis is frequently observed, mainly in the subendocardial area, resembling in occasions sub-endocardial infarction. In the lung, disruption of the capillary integrity leads to alveolar wall edema-hemorrhage and alveolar space edema. In the kidneys, there is marked reduction of the capillary vascular spaces possibly as result of afferent arteriolar spasm. In the liver, there is loss of glycogen. In all organs examined under electron microscopy mitochondria injury was the most affected cellular organelle. The observed injuries include mild to severe dis-

From the Associate Professor of Surgery, University of South Florida, Tampa, Florida. Address reprint requests to Dimitri Novitzky, MD, FCS, Chief; Cardiothoracic Surgery, James A. Haley VA Hospital, 13000 Bruce l3. Downs Blvd (673/l 12T), Tampa, FL 33613.

0041-l 345/97/$17.00 PII so041 -1345(97)01150-1

3773

NOVITZKY

3774 Table 1. The Impact of T3 on the Dopamine Requirements Pre- and Postherapy Total T3 dose

Group

Dopamine Range

n

1 2 3 4 5

o-5 6-10 11-15 16-20 221

46 53 12 28 15

Pre T,

1.52 (0.31) 8.92 (0.19) 13.5(0.48) 18.69(0.34) 34.00(1.48)

Post Ts

1.24(0.29) 5.71 (0.40) 6.75 (1.52) 7.5 (0.69) 7.81(0.95)

P f-6

<.OOl <.0003 <.OOOl <.OOOl

(fig)

9.55 (0.78) 12.07 (0.73) 17.16(1.49) 19.76(1.32) 22.14

P

c.02 <.OOOl <.OOOl <.OOOl

Cardiac ischaemia time (min)

163.76 (8.32) 157.34(10.29) 194.63(7.63) 199.5 (8.07) 184.85(18.32)

The inotropic difference for each group is indicated. The total T2 dose of each group compared with Group 1. There is no significant difference in the cardiac ischaemic times.

ruption of the membrane, christi, matrix and of electron dense material, which eventually porated in secondary lysosomes. Obviously, injury will affect the aerobic production of from minimal impairment to total functional

accumulation will be incorthe degree of ATP, ranging loss.

ENDOCRINE CHANGES AND HORMONAL REPLACEMENT IN THE EXPERIMENTAL ANIMAL

Simultaneously to the adrenergic storm, a rapid alteration of the thyroid profile was observed. There was a significant reduction of plasma free triiodothyronine (Ta), thyroxine (TJ, elevation of reverse triiodothyronine (rT,) and normal TSH.‘sl’ This thyroid profile corresponds to the Euthyroid Sick Syndrome (ESS) observed in shock states and in critically ill patients.“~‘* Further endocrinological abnormalities such as reduction of cortisol, insulin and ADH have been observed.’ In experimental animals, following induction of braindeath, maintained on ventilatory support, the excised hearts tested ex vivo in a modified Langerndorlf model showed significant cardiac deterioration. There was reduction of the cardiac output, stroke volume, dp/dt and LVEDP elevation. In the same animals the heart had a significant reduction of high energy phosphates and glycogen. Tissue lactate was markedly elevated.r3 Following single IV bolus administration of labeled i4C-R (glucose, pyruvate and palmitate), the brain-dead animal had a reduced utilization of these cellular fuels, exhibiting a significant reduction of the plasma clearance and prolonged half life. The production and elimination of 14C02 was also markedly reduced.14 The Na/K ratios were measured in renal slices procured from brain-dead animals. There was a significant reduction of the ratio, indicating inadequate function of the Na/K pump which is ATP dependent.15 Hormonal replacement (T3, cortisol and insulin) to brain-dead animals restored the hemodynamic and biochemical abnormalities of the heart being no different from those observed in hearts procured from live animals.13 The administration of T3 alone to brain-dead animals restored the body utilization of 14C-R normalizing the aerobic utilization.15 The clearance, half life and CO, production was similar to the studies done in live animals. Following hormonal therapy to brain-dead animals, the Na/K ratio in renal slices was restored to values observed in alive animals.

Further studies of the effect of T3 therapy was done studying the deleterious effects of brain-death and dopamine administration. Transplanted kidneys in nephrectomized animals showed rapid creatinine elevation. The renal function was significantly impaired, however, the function of kidneys procured from brain-dead animals receiving dopamine and T, was no different from kidneys procured from alive animalsI

INITIAL RESULTS OF HORMONAL THERAPY IN THE HUMAN BRAIN-DEAD ORGAN DONOR

Hormonal therapy: T, 2 pg, cortisol100 mg, and insulin was initially administered at hourly intervals for four hours to 21 unstable organ donors on high inotropic support and compared to historical controls, observing a rapid dopamine reduction. Hemodynamic deterioration in the control group of 26 patients required further dopamine increments, no hemodynamic response was observed, four donors developed ventricular fibrillation and were excluded from the donor pool.” Two prospective randomized studies have shown the beneficial results of hormonal therapy and vasopresin administered to human brain-dead patients; confirming again the value of this therapeutic modality.‘8 In the second study, both groups underwent sequential cardiac catheterization. In the placebo group, a progressive significant hemodynamic deterioration was observed and half of the brain-dead patients had cardiac arrest. However, patients receiving hormonal therapy demonstrated excellent hemodynamics and none experienced ventricular fibrillation.” Triiodothyronine replacement dosage was modified according to the dopamine requirement. Donors supported with dopamine in excess of 21 and in occasion reaching up to 40 pg!kg/min requiring several boluses of T3 before dopamine support was reduced to 0 to 10 &kg/min. It became evident that T3 requirements for unstable braindead donors was much higher than in relatively stable patients. The T3 dosage was increased to 4 to 6 Fg bolus at 15 minute intervals until hemodynamic stability was obtained and the inotropic support reduced. The total Ta needs were 20 to 30 pg.” Triiodothyronine replacement for non-thyroid conditions was found to be beneficial in open heart surgery, hemorrhagic shock and in post-cardiotomy heart failure. In these

3775 conditions, the ESS was evident. Similarly, the low FT, state was present in patients awaiting organ transplantation. The experimental data clearly indicates presence of progressive aerobic inhibition and mitochondrial injury of the transplanted organs, thus following reperfusion in the recipient who also has a low T, state may result in a relapse of the anaerobic metabolism resulting in slow organ recovery. Of the consecutive 196 T, treated organ donors, 154 donors and recipients received T,. The loading dose in the recipient was of 0.1 to 0.2 &kg and continued in the postoperative period.

8. Shivalkar B, Van Loon J, Wieland W, et al: Circulation 87:230, 1993

DISCUSSION

9. Novitzky D, Rhodin J, Cooper DKC, et al: Transplant Intl 19:24, 1997

The impact of T, at cellular level is multifactorial. The initial effects are nongenomic and do not require RNAprotein synthesis, The observed hemodynamic effects occur within minutes. There is direct effect on the mitochondria stimulating aerobic pathways and ATP production.13 T, has an extremely important role in the intracellular Ca2+ homeostasis activating the sarcoplasmic reticulum and sarcolemmal Ca2+ channels2’ as result of this rapid Ca” mobilization from the cytosol in to the mitochondria and the sarcoplasmic reticulum,” thus avoiding or reducing the previously described Ca2+ induced injury.22 The recovery of the cell following T, therapy is multifactional and also depends on the stimulation of normal and less injured mitochondria. T, has direct impact on the up-regulation of beta receptors,23 activation of multiple ATPases, such as the Na/K,” myosin and others. Organs procured from brain-dead T, treated donors and following reperfusion in the recipient, may have less cellular injury from ischemia, reperfusion and no-reflow phenomenon, thus yielding organs in an optimized state for transplantation. REFERENCES 1. Fragomeni LS, Kaye MP: J Heart Transplant 7:249, 1988 2. Novitzky D, Wicomb WN, Cooper DKC, et al: Heart Transplant 463, 1984

3. Shanlin R. Sole MJ, Rahimifar M, et al: J Am Call Cardiol 12:727, 1988 4. Lehninger Al: In Bioenergetics, ed 2. Menlo Park, Calif: WA Benjamin; 1971, p 53 5. Hearse DJ: Cardiovasc Drugs Ther 5:853, 1991 6. Novitzky D, Horak A, Cooper DKC, et al: Transplant Proc 21:2567, 1989 7. Novitzky D. Wicomb WN, Rose AG, et al: Ann Thorac Surg 43:288, 1987

10. Wartofsky L, Burman KD: Endoc Rev 3:164, 1982 11. Madsen M: Medical Dissertations No. 229, 1986. Sweden: Linkoping University 12. Slag MF, Morley JE, Elson MK: JAMA 245:43, 1981 13. Novitzky D, Wicomb WN, Cooper DKC, et al: Cryobiology 24:1, 1987 14. Novitzky D, Cooper DKC, Morrell D, et al: Transplantation 4532, 1988 15. Wicomb WN, Cooper DKC, Novitzky D: Transplantation 41:29, 1986 16. Pienaar H, Schwartz I, Roncone A, et al: Transplantation 50:580, 1990 17. Novitzky D, Cooper DKC, Reichart B: Transplantation

43:852, 1987 18. Darracott-Cankovic S, Cbiol DW, Cankovic M, et al: J Thorat Cardiovasc Surg (in press) 19. Taniguchi S, Kitamura S, Kawachi K, et al: Eur J Cardiothorac Surg 6:96, 1992 20. Novitzky D, Cooper DKC, Chaffin JS, et al: Transplantation 49:311, 1990 21. Warnick PR, Davis FB, Cody V, et al: Proceedings of the Annual Meeting of the Endocrine Society, New Orleans, p 356 (Abstract) 22. Segal J: Endocrinology 127:17, 1990 23. D’Amico TA, Meyers CH, Koutlas TC, et al: Thoracic Cardiovasc Surg 110:746, 1995