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Kidney grafts from brain dead donors: Inferior quality or opportunity for improvement?

2007; Elsevier BV; Volume: 72; Issue: 7 Linguagem: Inglês

10.1038/sj.ki.5002400

1523-1755

Eelke M. Bos, Henri G. D. Leuvenink, Harry van Goor, R J Ploeg,

Organ Transplantation Techniques and Outcomes

Major improvements in immunosuppressive treatment, surgical techniques, and treatment of post-transplant complications have contributed considerably to improved outcome in renal transplantation over the past decades. Yet, these accomplishments have not led to similar improvements in transplant outcome when the results of living and deceased donors are compared. The enormous demand for donor kidneys has allowed for the increase in acceptance of suboptimal donors. The use of brain dead patients as organ donors has had a tremendous positive influence on the number of renal transplants. Unfortunately, the physiologically abnormal state of brain death has a negative effect on transplant outcome. The fact that transplanted kidneys derived from brain dead donors have a decreased viability indicates that potential grafts are already damaged before retrieval and preservation. In this review, we present an overview of the current knowledge of (patho)-physiological effects of brain death and its relevance for renal transplant outcome. In addition, several options for therapeutic intervention during brain death in the donor with the goal to improve organ viability and transplant outcome are discussed. Major improvements in immunosuppressive treatment, surgical techniques, and treatment of post-transplant complications have contributed considerably to improved outcome in renal transplantation over the past decades. Yet, these accomplishments have not led to similar improvements in transplant outcome when the results of living and deceased donors are compared. The enormous demand for donor kidneys has allowed for the increase in acceptance of suboptimal donors. The use of brain dead patients as organ donors has had a tremendous positive influence on the number of renal transplants. Unfortunately, the physiologically abnormal state of brain death has a negative effect on transplant outcome. The fact that transplanted kidneys derived from brain dead donors have a decreased viability indicates that potential grafts are already damaged before retrieval and preservation. In this review, we present an overview of the current knowledge of (patho)-physiological effects of brain death and its relevance for renal transplant outcome. In addition, several options for therapeutic intervention during brain death in the donor with the goal to improve organ viability and transplant outcome are discussed. Transplant outcome achieved with kidneys from living donors is far superior when compared to grafts obtained from deceased donors (Table 1).1.US Department of Health and Human Services 2004 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. 2005Google Scholar,2.Terasaki P.I. Cecka J.M. Gjertson D.W. et al.High survival rates of kidney transplants from spousal and living unrelated donors.New Engl J Med. 1995; 333: 333-336Crossref PubMed Scopus (1013) Google Scholar The persistent donor organ shortage has caused longer waiting lists and an increasing percentage of patients that die while waiting. As a consequence, a gradual shift toward accepting suboptimal donors has taken place. The use of older and more marginal donors is now routine, and the number of non-heart beating donors has increased significantly over the past years.1.US Department of Health and Human Services 2004 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. 2005Google Scholar,3.The Eurotransplant International Foundation 2005 Annual Report of the Eurotransplant International Foundation. 2006Google Scholar Twenty years ago, the typical donor was under the age of 30 years, fairly healthy and died of traumatic cerebral injury. Today, the average donor is over 50 years old and the main cause of death is intracranial hemorrhage. The improvements that were made in treatment regimen of the recipient, organ preservation, reduction of cold ischemia time, and better allocation of donor organs have been masked by the use of lower-quality donors. In the past, much effort was directed toward post-transplantation immunosuppression and preservation of organs during transport. Now, risk factors and conditions before organ recovery in the donor need to be recognized for their impact on donor organ viability. The detrimental effects of brain death on renal transplant outcome4.Pratschke J. Wilhelm M.J. Kusaka M. et al.Accelerated rejection of renal allografts from brain-dead donors.Ann Surg. 2000; 232: 263-271Crossref PubMed Scopus (160) Google Scholar,5.Pratschke J. Wilhelm M.J. Laskowski I. et al.Influence of donor brain death on chronic rejection of renal transplants in rats.J Am Soc Nephrol. 2001; 12: 2474-2481PubMed Google Scholar have been convincingly shown in the experimental setting. In clinical studies, though, it is difficult to reveal that brain death itself has an independent influence on transplant outcome, since living and deceased donors differ on more aspects than just the death of the brain. However, when survival rates are stratified for age, grafts from deceased donors have worse survival within each age-group – even in the relatively young group of 25–36-year-old donors.2.Terasaki P.I. Cecka J.M. Gjertson D.W. et al.High survival rates of kidney transplants from spousal and living unrelated donors.New Engl J Med. 1995; 333: 333-336Crossref PubMed Scopus (1013) Google ScholarTable 11- and 5-year graft survival for living and deceased donors following renal or liver transplantation. Open table in a new tab In 2005, 16 481 renal transplantations were performed in the United States. Of those, 9913 kidneys originated from deceased donors and 6568 were recovered from living donors.1.US Department of Health and Human Services 2004 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. 2005Google Scholar Yet, at the end of 2004, 57 910 patients were on the waiting list to receive a renal transplant. For a patient enlisted in 2000, the median time to transplant was more than 3 years. Unfortunately, not every patient survived long enough to receive a transplant, which resulted in approximately 3000 deaths on the waiting list in that same year. The increased demand for donor kidneys has provoked a large shift toward living kidney donation in the United States.1.US Department of Health and Human Services 2004 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. 2005Google Scholar In fact, the number of living kidney donors in the United States surpassed the number of deceased donors in 2000.1.US Department of Health and Human Services 2004 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. 2005Google Scholar,6.Davis C.L. Delmonico F.L. Living-donor kidney transplantation: a review of the current practices for the live donor.J Am Soc Nephrol. 2005; 16: 2098-2110Crossref PubMed Scopus (252) Google Scholar Still, the total number of kidneys obtained from living donors is lower since in living donation only one kidney can be donated, while in deceased donors both kidneys are recovered. In many European countries, the use of living donors has increased as well over the past decade, albeit more modestly.3.The Eurotransplant International Foundation 2005 Annual Report of the Eurotransplant International Foundation. 2006Google Scholar In their 1995 landmark paper, Terasaki et al.2.Terasaki P.I. Cecka J.M. Gjertson D.W. et al.High survival rates of kidney transplants from spousal and living unrelated donors.New Engl J Med. 1995; 333: 333-336Crossref PubMed Scopus (1013) Google Scholar showed that graft survival for living unrelated donation is superior compared to deceased donation, even though the average human leukocyte antigen-haplotype matching is worse in living unrelated donation. Long-term outcome after living unrelated donation is similar to that of parental or offspring donors.7.Futagawa Y. Waki K. Gjertson D.W. et al.Living-unrelated donors yield higher graft survival rates than parental donors.Transplantation. 2005; 79: 1169-1174Crossref PubMed Scopus (16) Google Scholar This indicates that poor survival of grafts from deceased donors cannot be solely attributed to differences in immunogenicity. Graft performance is affected by many other factors. Donor variables such as age, gender, race, terminal serum creatinine, history of hypertension, and cause of death all affect transplantation outcome.8.Pirsch J.D. Ploeg R.J. Gange S. et al.Determinants of graft survival after renal transplantation.Transplantation. 1996; 61: 1581-1586Crossref PubMed Scopus (140) Google Scholar, 9.Port F.K. Bragg-Gresham J.L. Metzger R.A. et al.Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors.Transplantation. 2002; 74: 1281-1286Crossref PubMed Scopus (574) Google Scholar, 10.Ojo A.O. Wolfe R.A. Held P.J. et al.Delayed graft function: risk factors and implications for renal allograft survival.Transplantation. 1997; 63: 968-974Crossref PubMed Scopus (790) Google Scholar Deceased donors tend to be older than living donors;1.US Department of Health and Human Services 2004 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. 2005Google Scholar however, within each age category, survival rates of living donor grafts are significantly higher than those of deceased donor grafts.2.Terasaki P.I. Cecka J.M. Gjertson D.W. et al.High survival rates of kidney transplants from spousal and living unrelated donors.New Engl J Med. 1995; 333: 333-336Crossref PubMed Scopus (1013) Google Scholar Preservation and cold ischemia time influence transplant outcome, and for logistical reasons, cold ischemia time is longer on average in deceased donor transplantation. For renal transplantation, cold ischemia time of more than 24 h is associated with worse outcome after renal transplantation.2.Terasaki P.I. Cecka J.M. Gjertson D.W. et al.High survival rates of kidney transplants from spousal and living unrelated donors.New Engl J Med. 1995; 333: 333-336Crossref PubMed Scopus (1013) Google Scholar, 11.Ploeg R.J. van Bockel J.H. Langendijk P.T. et al.Effect of preservation solution on results of cadaveric kidney transplantation. The European Multicentre Study Group.Lancet. 1992; 340: 129-137Abstract PubMed Scopus (186) Google Scholar, 12.Koning O.H. Ploeg R.J. van Bockel J.H. et al.Risk factors for delayed graft function in cadaveric kidney transplantation: a prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. European Multicenter Study Group.Transplantation. 1997; 63: 1620-1628Crossref PubMed Scopus (189) Google Scholar Despite the fact that grafts obtained from deceased donors have inferior outcome, these transplants have prevented death for many people on dialysis. Deceased donor kidney recipients have a 68% reduced risk of mortality compared to similar patients who stay on the waiting list receiving dialysis treatment.13.Wolfe R.A. Ashby V.B. Milford E.L. et al.Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant.New Engl J Med. 1999; 341: 1725-1730Crossref PubMed Scopus (3581) Google Scholar The shortage of donor organs culminated in the use of extended criteria donation (ECD). ECD includes brain dead donors who are older than 60 years, or are aged over 50 years in combination with at least two of the following risk factors: a history of hypertension and a terminal serum creatinine >1.5 mg/dl or a cerebrovascular cause of death. The number of ECD-derived kidneys has seen marginal but steady increase over the past years,1.US Department of Health and Human Services 2004 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. 2005Google Scholar even though long-term allograft survival of ECD-derived kidneys is inferior compared to non-ECD kidneys (Figure 1).1.US Department of Health and Human Services 2004 Annual Report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1994–2003. 2005Google Scholar,14.Ojo A.O. Hanson J.A. Meier-Kriesche H. et al.Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates.J Am Soc Nephrol. 2001; 12: 589-597PubMed Google Scholar Initial doubt about the advantages of this type of donor has not been sustained. Relative mortality risk analysis has shown that the short-term risk of death in ECD kidney recipients is more than five times higher when compared to standard therapy with dialysis while waiting for a non-ECD kidney. At 226 days after transplantation, however, the risk becomes equal and is lower thereafter. In addition, the long-term cumulative mortality is significantly lower in ECD kidney recipients.15.Merion R.M. Ashby V.B. Wolfe R.A. et al.Deceased-donor characteristics and the survival benefit of kidney transplantation.JAMA. 2005; 294: 2726-2733Crossref PubMed Scopus (501) Google Scholar Kidneys discarded by transplant centers twice or more for reasons of poor organ quality showed worse initial non-function and long-term renal performance. Five-year graft and patient survival, however, were not significantly different from control kidneys that were immediately accepted.16.Dahmane D. Audard V. Hiesse C. et al.Retrospective follow-up of transplantation of kidneys from ‘marginal’ donors.Kidney Int. 2006; 69: 546-552Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Counteracting the deleterious effects that brain death has on these already compromised organs could positively affect transplant outcome and reduce the number of discarded organs, thereby increasing the number of successfully transplanted kidneys. The beating heart has always been considered the classic sign of life. After the report by Mollaret and Goulon17.Mollaret P. Goulon M. The depassed coma (preliminary memoir).Rev Neurol (Paris). 1959; 101: 3-15PubMed Google Scholar in 1959 which described comatose patients with vital functions sustained by mechanical ventilation, the definition of death became a major point of discussion. Owing to improved techniques, the heart was kept functioning in these patients while mechanical ventilation oxygenated the blood. Judged by their appearance, patients did not look deceased; however, it was clear that normal, self-sustained function would never be regained. In 1963, before a consensus had been reached on the implications of this irreversible coma, the first kidney was recovered from a brain dead, heart-beating donor and transplanted by the Belgian surgeon Alexandre.18.Machado C. The first organ transplant from a brain-dead donor.Neurology. 2005; 64: 1938-1942Crossref PubMed Scopus (39) Google Scholar In an effort to overcome problems that led to controversy in obtaining organs from deceased donors, but also to decrease the burden on the relatives of brain dead patients on life support, an ad hoc committee of the Harvard Medical School proposed to add irreversible coma to the death criterion in 1968.19.A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death.JAMA. 1968; 205: 337-340Crossref PubMed Scopus (1255) Google Scholar This report generated considerable medico-legal discussion and resulted in most countries adopting a concept of death that originates from this proposition. The definition of brain death that the committee proposed concerned the following mandatory criteria: (1) unawareness of and unresponsiveness to external stimuli, (2) no spontaneous movements or breathing, (3) absent reflexes, and (4) a flat electroencephalogram. Caution is required for conditions that can elicit similar symptoms, such as hypothermia, hypotension, or intoxication, and therefore these have to be ruled out. Brain death as such is the terminal phase of a sequence of events frequently commencing with cerebral trauma or cerebrovascular hemorrhage. When the patient is declared brain dead, this chain of events has already affected the organs. Systemic and hormonal changes arise immediately when intracranial pressure increases. Hence, brain death is not the stationary condition as perceived from the outside, but a dynamic and rather unphysiological course of events that influences a number of (patho-)physiological processes in the human body (Figure 2). Following cerebral trauma or injury, the primary rise in intracranial pressure causes additional damage to the cerebrum, which triggers parasympathetic activity and results in a decreased systemic blood pressure. The continued rise in intracranial pressure leads to herniation of the brain stem through the foramen magnum, which is accompanied by arterial compression and ultimately occlusion with progressive ischemic damage. When the pontine part of the brain stem becomes ischemic, sympathetic stimulation, together with the persisting parasympathetic activity, will cause the Cushing reflex, which was already described in 1902 by the American neurosurgeon Harvey Cushing.20.Cushing H. Some experimental and clinical observations concerning states of increased intracranial tension.Am J Med Sci. 1902; 124: 375-400Crossref Google Scholar The Cushing reflex consists of multiple disturbances in the physiology of cerebrally injured patients, including bradycardia, hypertension and an irregular breathing pattern. Ultimately, when the entire brain stem has become ischemic, the vagal cardiomotor nucleus is affected and solitary sympathetic stimulation will occur. As a result, massive catecholamine release, systemically as well as from myocardial sympathetic nerve endings, cause an increase in heart rate and leads to vasoconstriction with increased vascular resistance and blood pressure.21.Novitzky D. Selection and management of cardiac allograft donors.Curr Opin Cardiol. 1996; 11: 174-182Crossref PubMed Scopus (26) Google Scholar, 22.Novitzky D. Wicomb W.N. Cooper D.K. et al.Prevention of myocardial injury during brain death by total cardiac sympathectomy in the Chacma baboon.Ann Thorac Surg. 1986; 41: 520-524Abstract Full Text PDF PubMed Scopus (177) Google Scholar, 23.Shivalkar B. van Loon J. Wieland W. et al.Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function.Circulation. 1993; 87: 230-239Crossref PubMed Scopus (274) Google Scholar This process is referred to as the sympathetic or catecholamine storm, and is considered to be an attempt of the body to raise arterial blood pressure above the elevated intracranial pressure as an ultimate effort to restore perfusion of the cerebrum. The rise in serum epinephrine levels has been reported to be as high as 100–1000-fold higher compared to normal values in animal models of brain death.23.Shivalkar B. van Loon J. Wieland W. et al.Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function.Circulation. 1993; 87: 230-239Crossref PubMed Scopus (274) Google Scholar, 24.Chen E.P. Bittner H.B. Kendall S.W. et al.Hormonal and hemodynamic changes in a validated animal model of brain death.Crit Care Med. 1996; 24: 1352-1359Crossref PubMed Scopus (127) Google Scholar, 25.Sebening C. Hagl C. Szabo G. et al.Cardiocirculatory effects of acutely increased intracranial pressure and subsequent brain death.Eur J Cardiothorac Surg. 1995; 9: 360-372Crossref PubMed Scopus (46) Google Scholar, 26.Herijgers P. Leunens V. Tjandra-Maga T.B. et al.Changes in organ perfusion after brain death in the rat and its relation to circulating catecholamines.Transplantation. 1996; 62: 330-335Crossref PubMed Scopus (152) Google Scholar The magnitude of catecholamine release is related to the severity of brain damage. The faster the rise in intracranial pressure, the higher the peak in catecholamine levels.23.Shivalkar B. van Loon J. Wieland W. et al.Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function.Circulation. 1993; 87: 230-239Crossref PubMed Scopus (274) Google Scholar Also, serum norepinephrine and dopamine concentrations are vastly increased after onset of brain death. The values of catecholamine release in animal experiments appear to be similar to those described in the clinical situation.27.Powner D.J. Hendrich A. Nyhuis A. et al.Changes in serum catecholamine levels in patients who are brain dead.J Heart Lung Transplant. 1992; 11: 1046-1053PubMed Google Scholar In addition, a parallel cardiac response to brain injury is seen, as demonstrated by even higher levels of myocardial catecholamines compared to the serum28.Mertes P.M. Carteaux J.P. Jaboin Y. et al.Estimation of myocardial interstitial norepinephrine release after brain death using cardiac microdialysis.Transplantation. 1994; 57: 371-377Crossref PubMed Scopus (119) Google Scholar leading to injury of myocytes.21.Novitzky D. Selection and management of cardiac allograft donors.Curr Opin Cardiol. 1996; 11: 174-182Crossref PubMed Scopus (26) Google Scholar,29.Biswas S.S. Chen E.P. Bittner H.B. et al.Brain death further promotes ischemic reperfusion injury of the rabbit myocardium.Ann Thorac Surg. 1996; 62: 1808-1815Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The catecholamine-induced increase in vascular resistance can be severe, reaching four times higher levels than basal values in the rat kidney.26.Herijgers P. Leunens V. Tjandra-Maga T.B. et al.Changes in organ perfusion after brain death in the rat and its relation to circulating catecholamines.Transplantation. 1996; 62: 330-335Crossref PubMed Scopus (152) Google Scholar This causes renal blood flow to decrease by a factor of 2.4 and supports the hypothesis that the rigorous decline in organ perfusion leads to ischemic damage of potential grafts. Over time, sympathetic pathways are deactivated due to ischemia of the spinal cord. This leads to a gradual decrease of the hyperdynamic state with a subsequent decline in blood pressure, heart rate, and cardiac output to normal or subnormal values. Ultimately, a state of hypoperfusion is reached, which is harmful to the potential donor kidneys. Prolonged brain death results in high rates of tubular necrosis.30.Nagareda T. Kinoshita Y. Tanaka A. et al.Clinicopathology of kidneys from brain-dead patients treated with vasopressin and epinephrine.Kidney Int. 1993; 43: 1363-1370Abstract Full Text PDF PubMed Scopus (39) Google Scholar Many brain dead patients need hemodynamic support during this phase, and receive vasopressors and/or anti-diuretic hormone. In addition to the catecholamines, other hormonal alterations take place. There is evidence that some residual cerebral blood flow and hypothalamic function can persist after brain death.31.Arita K. Uozumi T. Oki S. et al.The function of the hypothalamo–pituitary axis in brain dead patients.Acta Neurochir (Wien). 1993; 123: 64-75Crossref PubMed Scopus (46) Google Scholar, 32.Sugimoto T. Sakano T. Kinoshita Y. et al.Morphological and functional alterations of the hypothalamic–pituitary system in brain death with long-term bodily living.Acta Neurochir (Wien). 1992; 115: 31-36Crossref PubMed Scopus (36) Google Scholar, 33.Petty G.W. Mohr J.P. Pedley T.A. et al.The role of transcranial Doppler in confirming brain death: sensitivity, specificity, and suggestions for performance and interpretation.Neurology. 1990; 40: 300-303Crossref PubMed Google Scholar In most brain dead patients, however, a gradual decrease in the release of adrenocorticotropic hormone and anti-diuretic hormone is seen,24.Chen E.P. Bittner H.B. Kendall S.W. et al.Hormonal and hemodynamic changes in a validated animal model of brain death.Crit Care Med. 1996; 24: 1352-1359Crossref PubMed Scopus (127) Google Scholar, 25.Sebening C. Hagl C. Szabo G. et al.Cardiocirculatory effects of acutely increased intracranial pressure and subsequent brain death.Eur J Cardiothorac Surg. 1995; 9: 360-372Crossref PubMed Scopus (46) Google Scholar, 34.Gramm H.J. Meinhold H. Bickel U. et al.Acute endocrine failure after brain death?.Transplantation. 1992; 54: 851-857Crossref PubMed Scopus (146) Google Scholar which is associated with cardiovascular failure that eventually causes the requirement of hemodynamic support. The failure to keep anti-diuretic hormone levels in the range needed for a normal osmolarity24.Chen E.P. Bittner H.B. Kendall S.W. et al.Hormonal and hemodynamic changes in a validated animal model of brain death.Crit Care Med. 1996; 24: 1352-1359Crossref PubMed Scopus (127) Google Scholar, 25.Sebening C. Hagl C. Szabo G. et al.Cardiocirculatory effects of acutely increased intracranial pressure and subsequent brain death.Eur J Cardiothorac Surg. 1995; 9: 360-372Crossref PubMed Scopus (46) Google Scholar, 31.Arita K. Uozumi T. Oki S. et al.The function of the hypothalamo–pituitary axis in brain dead patients.Acta Neurochir (Wien). 1993; 123: 64-75Crossref PubMed Scopus (46) Google Scholar has been suggested as the cause of diabetes insipidus in up to 78% of patients.34.Gramm H.J. Meinhold H. Bickel U. et al.Acute endocrine failure after brain death?.Transplantation. 1992; 54: 851-857Crossref PubMed Scopus (146) Google Scholar,35.Howlett T.A. Keogh A.M. Perry L. et al.Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy.Transplantation. 1989; 47: 828-834Crossref PubMed Scopus (150) Google Scholar A more recent explanation is the downregulation of aquaporin-2 channels,36.Schuurs T.A. Gerbens F. van der Hoeven J.A. et al.Distinct transcriptional changes in donor kidneys upon brain death induction in rats: insights in the processes of brain death.Am J Transplant. 2004; 4: 1972-1981Crossref PubMed Scopus (72) Google Scholar which could affect water re-uptake in the renal collecting ducts. Free-circulating triiodothyronine (T3) gradually decreases after brain death,34.Gramm H.J. Meinhold H. Bickel U. et al.Acute endocrine failure after brain death?.Transplantation. 1992; 54: 851-857Crossref PubMed Scopus (146) Google Scholar, 35.Howlett T.A. Keogh A.M. Perry L. et al.Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy.Transplantation. 1989; 47: 828-834Crossref PubMed Scopus (150) Google Scholar, 37.Novitzky D. Cooper D.K. Reichart B. Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors.Transplantation. 1987; 43: 852-854Crossref PubMed Scopus (264) Google Scholar, 38.Amado J.A. Lopez-Espadas F. Vazquez-Barquero A. et al.Blood levels of cytokines in brain-dead patients: relationship with circulating hormones and acute-phase reactants.Metabolism. 1995; 44: 812-816Abstract Full Text PDF PubMed Scopus (130) Google Scholar, 39.Gifford R.R. Weaver A.S. Burg J.E. et al.Thyroid hormone levels in heart and kidney cadaver donors.J Heart Transplant. 1986; 5: 249-253PubMed Google Scholar, 40.Powner D.J. Hendrich A. Lagler R.G. et al.Hormonal changes in brain dead patients.Crit Care Med. 1990; 18: 702-708Crossref PubMed Scopus (102) Google Scholar but not every study has found comparable results concerning the serum concentrations of T3 and T3-related hormones, such as T4 and TSH.32.Sugimoto T. Sakano T. Kinoshita Y. et al.Morphological and functional alterations of the hypothalamic–pituitary system in brain death with long-term bodily living.Acta Neurochir (Wien). 1992; 115: 31-36Crossref PubMed Scopus (36) Google Scholar, 39.Gifford R.R. Weaver A.S. Burg J.E. et al.Thyroid hormone levels in heart and kidney cadaver donors.J Heart Transplant. 1986; 5: 249-253PubMed Google Scholar, 40.Powner D.J. Hendrich A. Lagler R.G. et al.Hormonal changes in brain dead patients.Crit Care Med. 1990; 18: 702-708Crossref PubMed Scopus (102) Google Scholar, 41.Masson F. Thicoipe M. Latapie M.J. et al.Thyroid function in brain-dead donors.Transpl Int. 1990; 3: 226-233Crossref PubMed Scopus (44) Google Scholar Any acute stress will enhance the condition known as ‘diabetes of injury,’ consisting mainly of hyperglycemia caused by increased gluconeogenesis and insulin resistance. Intensive insulin therapy is now applied in many intensive care units, and as a result mortality in intensive care units has been greatly reduced when strict glycemic control is achieved.42.Van den Berghe G. Wouters P. Weekers F. et al.Intensive insulin therapy in the critically ill patients.New Engl J Med. 2001; 345: 1359-1367Crossref PubMed Scopus (7822) Google Scholar,43.Van den Berghe G. Wilmer A. Hermans G. et al.Intensive insulin therapy in the medical ICU.New Engl J Med. 2006; 354: 449-461Crossref PubMed Scopus (2817) Google Scholar A lower incidence of newly acquired renal injury, earlier weaning from mechanical ventilation, and a faster discharge from the intensive care unit and from the hospital were observed.43.Van den Berghe G. Wilmer A. Hermans G. et al.Intensive insulin therapy in the medical ICU.New Engl J Med. 2006; 354: 449-461Crossref PubMed Scopus (2817) Google Scholar The rise in serum creatinine was attenuated by the maintenance of normoglycemia. Also, insulin therapy reduces the inflammatory response: ICAM-1 and C-reactive protein are both decreased in the serum of inten