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Hormonal Therapy in Organ Donation: Is it a useful tool? Rui Maio MD, PhD, CETC, FEBS ETCO Past-President 2011 Organ Donation Congress Buenos Aires, November 2011
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Transplantation – Major problems . . .
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],REDUCTION OF WAITING LIST
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Aggressive donor management ?
[object Object],[object Object],[object Object],[object Object],Aggressive donor management ?
Antagonistic organs requirements Heart Lung Liver Kidney Pressure MAP >60 >60 >60 >60 Fluid balance pos neg pos pos Vasopressors neg pos - neg Sodium mmol/l <160 - <150 - Corticoids - pos - - Polyuria - pos neg pos
Unphisiological State of brain death Cardiovascular dysfunction Respiratory dysfunction Endocrine dysfunction Hyperglycemia Electrolytes disturbances Hypothermia  Coagulopathy  Inflammatory response Organ dysfunction
 
Brain dead donor retrieval
Warm ischemia Cold ischemia
Ischemia Reperfusion Injury ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Innate & Adaptive Immune Response S.Tullius,  Transplantation ,2008
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Donor treatment
[object Object],Endocrine Considerations ,[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Endocrine Considerations Pennefather  et al ; Transplantation , 1993  Peter Schnuelle  et al ;  ESOT, 2009
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Endocrine Considerations Novitzky D  et al, Transplantation  1987 Roels L  et al, Transplant Proc , 2000
Salim  et al. Clin Transplant  2007 Endocrine Considerations T 4  Use  (n=96) No T 4  (n=27) P-value Total Organs 375 86 Organs/donor 3.9 ± 1.7 3.2 ± 1.7 0.048 Age 32 38 0.15 Trauma donors    (%) 82 67 0.08
T 4  administration Total vasopressor  dose ( µ g/kg/min) Time interval (in hours) Time 0 is start of T 4 Endocrine Considerations ,[object Object],Salim  et al Arch Surg  2001;136:1377-1380
[object Object],Rosendale JD, Kauffman HM, McBride MA, et al. Links    Hormonal resuscitation yields more transplanted  hearts, with improved early function. Transplantation. 2003 Apr 27;75(8):1336-41. 96,2 % 92.1 % Endocrine Considerations
Wood KE.  N Engl Med J 2004; 351:2730-9 Endocrine Considerations
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Endocrine Considerations more donors Wheeldon DR. J Heart Lung Transplant 1995; 14:734-42 Pickett. Current opinion Anesthesiology 1994, 7:80-83 Rosendale JD. Am J Tranplant 2002;2:761-8. Rosendale JD. Transplantation 2003;75:482-7 Shemie SD. CMAJ 2006;174:S13-S30
Dopamine effect Donor dopamine is associated with less DGF and improved graft survival after renal transplantation Dopamine reduces susceptibility of  human endothelial cells (HUVECs) to prolonged cold preservation injury dopamine + dopamine  – Log rank p=0.017 Proportion surviving (%) Medium UW-solution Medium + DA UW + DA  -tubulin actin DA    24h at 4°C    37°C Medium    24h at 4°C    37°C Yard, AJT 2004; 4:22 Schnuelle, AJT 2004; 4:419 Goettmann, Kidney Int 2006; 70:321 Brinkkoetter, Transplantation 2006; 82:536   0 0.5 1 1.5 2 2.5 2 4 8 12 16 24 48 72 Time of cold preservation (hrs) LDH release (OD490) Years after transplantation 0 5 10 0 25 50 75 100
[object Object],[object Object],[object Object],Kaplan-Meier Allograft Survival by Dopamine Pretreatment dopamine no dopamine Log rank  P=0.26 Months after transplantation 0 6 12 18 24 30 36 0 10 20 30 40 50 60 70 80 90 100 dopamine no dopamine Log rank  P=0.04 Allograft survival (%) No. at risk Dopamine 227  200  193 183 155  130  98 No dopamine 260  232  225 201 171  140 104 No. at risk Dopamine 55  52  51 48 38  34 27 No dopamine 63  54  54 52 44  35 26 Months after transplantation 0 6 12 18 24 30 36 0 10 20 30 40 50 60 70 80 90 100 Allograft survival (%)
What is the underlying mechanism that confers protection?   Dopamine = 3,4-Dihydroxyphenethylamine
Dopamine ,[object Object],[object Object],[object Object]
What is the role of desmopressin (DDAVP)?
Kidney Graft Survival by Exposure to Desmopressin Kaplan-Meier graft survival Death censored graft survival No. at risk   DDAVP  362  321   258   158 No DDAVP  125   97   68   42 No. at risk  DDAVP  362  321   258   158 No DDAVP  125   97   68   42 Log rank P=0.02 DDAVP No DDAVP Cumulative survival, % Time after transplantation, mo 0 12 24 36 0 25 50 75 100 Time after transplantation, mo 0 12 24 36 0 25 50 75 100 Log rank P=0.03 DDAVP No DDAVP Cumulative survival, %
Hypothesis ,[object Object],[object Object]
Kidney Graft Survival by Exposure to DDAVP stratified by Assignment to Dopamine Cumulative survival, % Cumulative survival, % Assigned to receive dopamine Assigned to not receive dopamine Log rank P=0.009 Log rank P=0.37 No. at risk  DDAVP  196  174   137   79 No DDAVP  64   52   35   24 No. at risk  DDAVP  166  148   122   79 No DDAVP  61   46   34   18 Peter Schnuelle  et al ;  ESOT, 2009  Time after transplantation, mo 0 12 24 36 0 25 50 75 100 Time after transplantation, mo 0 12 24 36 0 25 50 75 100 DDAVP No DDAVP DDAVP No DDAVP
[object Object],[object Object],[object Object],[object Object],[object Object],Conclusions

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Rui Maio - Portugal - Tuesday 29 - Organ Donor Care. New Alternatives

  • 1. Hormonal Therapy in Organ Donation: Is it a useful tool? Rui Maio MD, PhD, CETC, FEBS ETCO Past-President 2011 Organ Donation Congress Buenos Aires, November 2011
  • 2.
  • 3.
  • 4.
  • 5.
  • 6. Antagonistic organs requirements Heart Lung Liver Kidney Pressure MAP >60 >60 >60 >60 Fluid balance pos neg pos pos Vasopressors neg pos - neg Sodium mmol/l <160 - <150 - Corticoids - pos - - Polyuria - pos neg pos
  • 7. Unphisiological State of brain death Cardiovascular dysfunction Respiratory dysfunction Endocrine dysfunction Hyperglycemia Electrolytes disturbances Hypothermia Coagulopathy Inflammatory response Organ dysfunction
  • 8.  
  • 9. Brain dead donor retrieval
  • 10. Warm ischemia Cold ischemia
  • 11.
  • 12.
  • 13.
  • 14.
  • 15.
  • 16.
  • 17. Salim et al. Clin Transplant 2007 Endocrine Considerations T 4 Use (n=96) No T 4 (n=27) P-value Total Organs 375 86 Organs/donor 3.9 ± 1.7 3.2 ± 1.7 0.048 Age 32 38 0.15 Trauma donors (%) 82 67 0.08
  • 18.
  • 19.
  • 20. Wood KE. N Engl Med J 2004; 351:2730-9 Endocrine Considerations
  • 21.
  • 22. Dopamine effect Donor dopamine is associated with less DGF and improved graft survival after renal transplantation Dopamine reduces susceptibility of human endothelial cells (HUVECs) to prolonged cold preservation injury dopamine + dopamine – Log rank p=0.017 Proportion surviving (%) Medium UW-solution Medium + DA UW + DA  -tubulin actin DA  24h at 4°C  37°C Medium  24h at 4°C  37°C Yard, AJT 2004; 4:22 Schnuelle, AJT 2004; 4:419 Goettmann, Kidney Int 2006; 70:321 Brinkkoetter, Transplantation 2006; 82:536 0 0.5 1 1.5 2 2.5 2 4 8 12 16 24 48 72 Time of cold preservation (hrs) LDH release (OD490) Years after transplantation 0 5 10 0 25 50 75 100
  • 23.
  • 24. What is the underlying mechanism that confers protection? Dopamine = 3,4-Dihydroxyphenethylamine
  • 25.
  • 26. What is the role of desmopressin (DDAVP)?
  • 27. Kidney Graft Survival by Exposure to Desmopressin Kaplan-Meier graft survival Death censored graft survival No. at risk DDAVP 362 321 258 158 No DDAVP 125 97 68 42 No. at risk DDAVP 362 321 258 158 No DDAVP 125 97 68 42 Log rank P=0.02 DDAVP No DDAVP Cumulative survival, % Time after transplantation, mo 0 12 24 36 0 25 50 75 100 Time after transplantation, mo 0 12 24 36 0 25 50 75 100 Log rank P=0.03 DDAVP No DDAVP Cumulative survival, %
  • 28.
  • 29. Kidney Graft Survival by Exposure to DDAVP stratified by Assignment to Dopamine Cumulative survival, % Cumulative survival, % Assigned to receive dopamine Assigned to not receive dopamine Log rank P=0.009 Log rank P=0.37 No. at risk DDAVP 196 174 137 79 No DDAVP 64 52 35 24 No. at risk DDAVP 166 148 122 79 No DDAVP 61 46 34 18 Peter Schnuelle et al ; ESOT, 2009 Time after transplantation, mo 0 12 24 36 0 25 50 75 100 Time after transplantation, mo 0 12 24 36 0 25 50 75 100 DDAVP No DDAVP DDAVP No DDAVP
  • 30.

Notes de l'éditeur

  1. Prospective study of 19 hemodynamically unstable donors, thyroid was associated with sig reduction in vasopressor use, with 53% of patients completely weaned off pressors.
  2. BACKGROUND: Brain death results in adverse pathophysiologic effects in many cadaveric donors, resulting in cardiovascular instability and poor organ perfusion. Hormonal resuscitation (HR) has been reported to stabilize and improve cardiac function in brain-dead donors. The goal of this study was to examine the effect of HR on the brain-dead donor on the number of organs transplanted per donor. METHODS: A retrospective analysis of all brain-dead donors recovered in the United States from January 1, 2000, to September 30, 2001, was conducted. HR consisted of a methylprednisolone bolus and infusions of vasopressin and either triiodothyronine or L-thyroxine. Univariate analyses and multivariate logistic regression analyses were used to detect differences between the HR group and those donors who did not receive HR. RESULTS: Of 10,292 consecutive brain-dead donors analyzed, 701 received three-drug HR. Univariate analysis showed the mean number of organs from HR donors (3.8) was 22.5% greater than that from nonhormonal resuscitation donors (3.1) (P &lt;0.001). Multivariate analyses showed that 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%. Extrapolation of these probabilities to the 5,921 brain-dead donors recovered in 2001 was calculated to yield a total increase of 2,053 organs. CONCLUSION: HR stabilizes certain brain-dead donors and is associated with significant increases in organs transplanted per donor.