Cardiac donor management: another point of view

DONOR MANAGEMENT

Cardiac Donor Management: Another Point of View C. Chamorro, J.A. Silva, and M.A. Romera ABSTRACT The shortage of suitable donor hearts is an important limiting factor in heart transplantation and continues to produce discussion about adequate donor management with regard to graft quality. Recent recommendations, such as limiting the doses of catecholamines for maintenance therapy of cardiac donors, have causes up to two thirds of cardiovascular surgeons to refuse a heart graft from a donor treated with dopamine doses greater than 10 ␮g/kg/min although endogenous catecholamines may cardiac and pulmonary complications in organ donors, these conditions may be treated using similar agents. Perhaps it is the magnitude of the endogenous catecholamine surge that produces the pathology; thereafter, the levels, may quickly decrease to the point of catecholamine depletion at the receptor level so that exogenous administration is not deleterious and even can have beneficial effects. In the hemodynamic management of organ donors, administration of catecholamines with alpha and beta-1 effects may be needed in sufficient doses to reverse the loss of sympathetic tone at the vascular and cardiac level. Hemodynamic responses display a great individual variability; therefore, a maximal dose should not be set. Catecholamine administration increases coronary artery perfusion pressure, thus optimizing the cardiac performance. Furthermore, it is posible that immunomodulatory effects of catecholamines influence acute allograft rejection rates.

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HE SHORTAGE of suitable donor hearts is an important limiting factor in heart transplantation. It continues to raise controversies about adequate donor management to optimize graft quality. The role of administration of catecholamines in the management of organ donors is one of the most controversial points. Recently, the International Consensus Conference published recommendations for the optimal management of cadaveric donors to maximize heart graft donation.1 Many recommendations are not different from those made by the University Cardiac Transplant Group of Stanford 30 years ago, which urged a maximal dose of 10 ␮g/kg/min dopamine.2 Nevertheless, a critical review of studies on hemodynamic disturbances and cardiac dysfunction at the time of brain death and the factors associated with primary heart graft failure does not support this recommendation. The importance of this controversy stems from the large number of donors refused by

cardiovascular surgeons, exclusively due to the use of “high” doses of catecholamines during maintenance therapy. A recent survey revealed that up to two thirds of cardiovascular surgeons would refuse a heart graft for implantation if doses of ⬎10 ␮g/kg/min of dopamine were used in donor maintenance.3 In our opinion, the rational use of catecholamines, dopamine including doses ⬎10 ␮g/kg/min and/or noradrenaline, is not only not deleterious during the maintenance of organ donors but frequently needed and possibly even beneficial to maximize the harvesting of all donor organs. From the Hospital Universitario Clı´nica Puerta de Hierro C/San Martı´n de Porres 4, Madrid 28035, Spain. Address reprint requests to C. Chamorro, Hospital Universitario Clı´nica Puerta de Hierro C/San Martin de Porres 4, Madrid 28035, Spain. E-mail: [email protected]

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0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00565-7

Transplantation Proceedings, 35, 1935–1937 (2003)

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CATECHOLAMINES ADMINISTRATION DURING THE MAINTENANCE OF CARDIAC DONORS IS NOT DELETERIOUS

The published studies involving the administration of catecholamines to cardiac transplant donors, which claim this treatment to be responsible for early mortality, are few and their conclusions are debatable. Wahlers et al.4 evaluated 39 of 174 patients undergoing heart transplantation. In comparison to the survivors, the 9 recipients who died early had the characteristics of longer ischemia times (166 ⫾ 44 vs 132 ⫾ 41 minutes), higher mean donor age (29 ⫾ 7 vs 22 ⫾ 7 years), and greater doses of dopamine (9 ⫾ 7 vs 4.2 ⫾ 2.6 ␮g/kg/min). In a univariate analysis Young et al.5 observed that early graft failure seemed to be related to high inotropic support in donors; nevertheless, this factor was not a categorical variable to refuse heart procurement, but must be cautiously evaluated together with echocardiographic findings, anticipated ischemia time, and recipient characteristics. It is important to remark that variable “high inotropic support” included dobutamine, dopamine, and noradrenaline, in spite of the different hemodynamic effects of these agents. Schnuelle et al,6 using data from the Eurotransplant International Foundation registry of patients who underwent cardiac transplantation since 1993, reported that noradrenaline, but not dopamine, was predictive of initial nonfunction after heart transplantation (HR, 1.66; 95% confidence interval, 1.14 –2.43). In this analysis, use of catecholamines was simply coded dichotomously and divided into 3 strata, according to zero, single, and combined applications. Data were only evaluated during the maintenance phase of organ donors; neither dosage nor length of administration were analyzed. Surprisingly, another study performed at this institution7 between 1997 and June 1998, failed to show that administration of catecholamines to organ donors was a risk factor to develop primary heart graft failure. Other authors argue that administration of high doses of catecholamines can have major histopathological and functional effects on the myocardium, compromising their viability. These authors make reference to experimental studies concerning the effects of catecholamines on cardiac myocytes in vitro,8 or their influence on cardiac dysfunction in patients with pheohromocytoma or chronic heart failure; but these situations are different from brain death processes. What nobody discusses is that at the moment of brain death, when catecholamines and other vasoactive substances are massively released, histological changes may occur9 in cardiacmyocytes. These changes are greater in the presence of explosive brain death10 and, although usually diffuse, the extent of myocardial structural damage predominates in the right ventricle. This myocardial dysfunction of neurogenic origin is responsible for a exclusion of at least 10% to 20% of potential cardiac donors despite no previous cardiac illness. Although always reversible, this cardiac dysfunction may get worse after the inescapable preservation period before implantation of the graft.11 Nevertheless,

CHAMORRO, SILVA, AND ROMERA

no studies have reported that administration of catecholamines, after the initial “catecholamine storm,” increases the extent of myocardial injury. The study by Fyfe et al12 showed that the myocardial damage, which developed at the moment of brain death and during the total ischemic period, were not correlated with the delivery of vasopressors. The study by Novitzky et al,13 which is frequently referenced by authors who support the potential cardiotoxicity of catecholamines, did not show that administration of catecholamines increased previous myocardial lessions. However, all heart grafts after administration of large doses of dopamine to donors displayed normal function. In addition biochemical arguments have been raised against the use of catecholamines in cardiac donors: highenergy myocardial substrate depletion, intramyocardial noradrenaline depletion, and myocardial beta-adrenoceptor downregulation.14,15 These arguments, once more derived from other clinical situations, are more theoretical than real. Sakagoshi et al16 observed that administration of adrenaline at a dose of 1.3 ␮g/kg/min decreased myocardial beta-adrenergic receptors density in an experimental model. However, these results have never been confirmed by other authors. In addition, the high doses of adrenaline administered by Sakagoshi et al are not commonly used in clinical practice. Other studies17 reveal the loss of highenergy myocardial substrates during the brain death process. However, this may be due to concurrent hormonal alterations and not the exogenous administration of catecholamines. Bruinsma et al18 showed that treatment of brain death–related reduced myocardial workload with high dosages of dopamine did not alter myocardial energy reserves. Analogous to these studies, excellent outcomes have been observed in recipients of theoretically suboptimal heart donors due to administration of high doses of dopamine.19 –21 Our group recently found only a 4%22 incidence of primary heart graft failure among 27 recipients of heart transplants from donors managed with high doses of dopamine and/or noradrenaline. This is the first study that analyzes the effects of catecholamines in the maintenance of heart donors, including their administration before brain death, a factor that usually is not tested. It does not seem logical to think that administration of catecholamines for a few hours is deleterious, in the maintenance of organ donors, forgetting that they were previously used, sometimes for many days, to treat the patients before establishing brain death. ADMINISTRATION OF CATECHOLAMINES DURING THE MAINTENANCE OF HEART DONORS IS NEEDED

Experimental studies and clinical observations indicate that, after “catecholamine storm,” reduction in circulating serum levels of catecholamines takes place, even decreasing to lower levels than those before brain death, and producing great individual variability in the final serum catecholamine levels.23 The loss of sympathetic tone leads to a reduction in systemic vascular resistance (SVR) and possibly a reduction in inotropism also.24 Animal models of brain death have revealed that administration of intrave-

CARDIAC DONOR MANAGEMENT

nous fluids alone, in the absence of an inotropic support, only maintains an adequate hemodynamic status for 1 to 4 hours.25 Bittner et al reported that excessive volume administration may aggravate right ventricular dysfunction, the most sensitive parameter of brain death–related injury.26 These and other authors27 also demonstrate that, in the absence of catecholamines, control of vascular tone fails, and that fluid support increases hydrostatic pulmonary pressure and tissue edema, probably causing loss of lung procurement. Therefore, from a physiopathological viewpoint, the decrease in serum catecholamine levels must be corrected with exogenous administration of drugs that exert vasoconstrictor effects reversing the decrease in SVR, and by beta-1 effects, the loss of cardiac sympathetic tone. Dopamine and noradrenaline meet these criteria. Up to 60% of the hemodynamic effects of dopamine depend on peripheral noradrenaline release, hence using noradrenaline may be a more reasonable strategy. Various studies show a great individual variability in the dose of catecholamines to achieve the same hemodynamic effects. MacGregor et al28 demonstrated a 10- to 75-fold intersubject variability in plasma dopamine concentrations in healthy male patients, despite a weight-based dosing regimen. Some subjects with 3 ␮g/kg/min dopamine infusions may show higher plasma concentrations than those receiving 10 ␮g/kg/min. Therefore, the dosage of catecholamine infusion must be titrated to achieve the targeted hemodynamic effect. The response threshold is subjected to wide variability, depending on endogenous circulating catecholamine levels, variable vascular responses and great inter individual pharmacokinetic variability. ADMINISTRATION OF CATECHOLAMINES DURING THE MAINTENANCE OF HEART DONORS IS BENEFICIAL

Various studies, such as the work of Szabo et al,29 show that the maintenance of coronary perfusion pressure (CPP) is essential to avoid myocardial deterioration or reverse induced damage after brain death. In the management of cardiac donors, the objective should be the maintenance of CPP ⬎60 to 70 mm Hg. Excessive fluid administration to maintain an elevated CVP may actually decrease CPP. Catecholamines increase SVR, and consequently aortic diastolic pressure, therefore increasing CPP. The study by Di Giantomasso et al30 demonstrated that noradrenaline significantly improves coronary blood flow. In addition, brain death causes a massive release of proinflammatory cytokines, leading to an increase in the expression of adhesion molecules (VCAM-1, ICAM-1).31 This inmunologic activation may accelerate acute allograft rejection episodes and explain the well-know reduced survival of recipients from brain death donors compared with living donors.32 Catecholamines posses immunomodulatory effects that diminish the expression of adhesion molecules. In renal recipients Schnuelle et al,33 demonstrated that administration of catecholamines to maintain of brain dead donors decreased the rate of acute allograft rejection, providing a major benefit on graft survival. This study

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suggests that further investigations concerning the use of adrenergic drugs to improve the viability of other transplanted organs are warranted. REFERENCES 1. Zaroff JG, Rosengard BR, Armstrong WF, et al: J Heart Lung Transplant 21:1153, 2002 2. Griepp RB, Stinson EG, Clark DA, et al: Surg Gynecol Obstet 133:792, 1971 3. El Oakley RM, Yonan NA, Simpson BM, et al: J Heart Lung Transplant 15:255, 1996 4. Wahlers T, Cremer J, Fieguth HG, et al: J Heart Lung Transplant 10:22, 1991 5. Young JA, Naftel DC, Bourge RC, et al: J Heart Lung Transplant 13:353, 1994 6. Schnuelle P, Berger S, De Boer J, et al: Transplantation 72:455, 2001 7. De Meester JMJ, Smits JM, Rutgerink E, et al: J Heart Lung Transplant 20:1099, 2001 8. Tood GL, Baroldi G, Pieper GM, et al: J Mol Cell Cardiol 17:317, 1985 9. Novitzky D, Wicomb WN, Cooper DKC, et al: J Heart Transplant 4:63, 1984 10. Shivalkar B, Van Loon J, Wieland W, et al: Circulation 87:230, 1993 11. Bittner HB, Kendall SWH, Chen EP, et al: Ann Thorac Surg 60:47, 1995 12. Fyfe B, Loh E, Winters GI, et al: Circulation 93:1133, 1996 13. Novitzky D, Rhodin J, Cooper DKC, et al: Transpl Int 10:24, 1997 14. Soifer BE, Gelb AW: Ann Intern Med 110:814, 1989 15. Robertson KM, Ryan CD: Anesth Analg 70:546, 1990 16. Sakagoshi N, Shirakura R, Nakano S, et al: J Heart Lung Transplant 11:1054, 1992 17. Pinelli G, Mertes PM, Carteaux JP, et al: Ann Thorac Surg 60:1729, 1995 18. Bruinsma GJ, Nederhoff MGJ, van de Kolk CWA, et al: J Heart Lung Transplant 18:1189, 1999 19. Ballester M, Obrador D, Abadal I, et al: Int J Cardiol 22:37, 1989 20. Sweeney MS, Lammermeier DE, Frazier OH, et al: Ann Thorac Surg 50:7, 1990 21. Menkis AH, Novick RJ, Kostuk WJ, et al: J Heart Lung Transplant 11:867, 1992 22. Silva JA, Chamorro C, Romera MA, et al: Intensive Care Med 28:S66, 2002 23. Powner DJ, Hendrich A, Nyhuis A, et al: J Heart Lung Transplant 11:1046, 1992 24. Herijgers P, Flameng W: Cardiovasc Res 38:107, 1998 25. Chen EP, Bittner HB, Kendall SWH, et al: Crit Care Med 24:1352, 1996 26. Bittner HB, Kendall SWH, Chen EP, et al: Chest 108:1358, 1995 27. Huber TS, Groh MA, Gallagher KP, et al: Crit Care Med 21:1731, 1993 28. MacGregor DA, Smith TE, Prielipp RC, et al: Anesthesiology 92:303, 2000 29. Szabo G, Sebening C, Hackert T, et al: J Thorac Cardiovasc Surg 46:339, 1998 30. Di Giantomasso D, May CN, Bellomo R: Intensive Care Med 28:1804, 2002 31. Pratschke J, Wilhelm MJ, Kusaka M, et al: Transplant Proc 3:1003, 1999 32. Terasaki PI, Cecka JM, Gjertson DW, et al: N Engl J Med 333:333, 1995 33. Schnuelle P, Lorenz D, Mueller A, et al: Kidney Int 56:738, 1999