Hormonal Therapy in Organ Donation: Is it a useful tool? Rui Maio MD, PhD, CETC, FEBS ETCO Past-President 2011 Organ Donat...
<ul><li>Persistent donor shortage </li></ul><ul><li>Increase in older, ECD and DCD donors </li></ul><ul><li>More complex r...
<ul><li>Reduction of the needs </li></ul><ul><li>Increase organ donation </li></ul><ul><ul><li>Extended  Criteria Donor (E...
<ul><li>Donor management remains one of the most  neglected areas of transplantation </li></ul><ul><li>Wheeldon,  J Heart ...
<ul><li>Success of transplantation depends on the quality of the organs and the quality of the organs depend on the qualit...
Antagonistic organs requirements Heart Lung Liver Kidney Pressure MAP >60 >60 >60 >60 Fluid balance pos neg pos pos Vasopr...
Unphisiological State of brain death Cardiovascular dysfunction Respiratory dysfunction Endocrine dysfunction Hyperglycemi...
 
Brain dead donor retrieval
Warm ischemia Cold ischemia
Ischemia Reperfusion Injury <ul><li>Complex, multifactorial inflammatory event </li></ul><ul><li>Local and systemic reacti...
<ul><li>Brain death and I/R injury </li></ul><ul><ul><li>Negative impact on organ quality </li></ul></ul><ul><ul><li>Enhan...
<ul><li>Standard ICU care = donor care: </li></ul><ul><ul><li>Haemodynamic control </li></ul></ul><ul><ul><li>Hydro-electr...
<ul><li>Hormone Depletion in Brain Death </li></ul>Endocrine Considerations <ul><li>Vasopressin </li></ul><ul><li>Insulin ...
<ul><li>DIABETES INSIPIDUS (30-85 %) </li></ul><ul><ul><li>Hypernatraemia </li></ul></ul><ul><ul><li>Hypotonic polyuria > ...
<ul><li>Thyroid  hormone  depletion </li></ul><ul><ul><li>T 3  deficiency is seen in 85% of patients after BD </li></ul></...
Salim  et al. Clin Transplant  2007 Endocrine Considerations T 4  Use  (n=96) No T 4  (n=27) P-value Total Organs 375 86 O...
T 4  administration Total vasopressor  dose ( µ g/kg/min) Time interval (in hours) Time 0 is start of T 4 Endocrine Consid...
<ul><li>Hormone Replacement and Heart Survival </li></ul>Rosendale JD, Kauffman HM, McBride MA, et al. Links    Hormonal r...
Wood KE.  N Engl Med J 2004; 351:2730-9 Endocrine Considerations
<ul><li>Hormone replacement therapy </li></ul><ul><ul><li>Antidiuretics hormone  </li></ul></ul><ul><ul><li>Steroids  </li...
Dopamine effect Donor dopamine is associated with less DGF and improved graft survival after renal transplantation Dopamin...
<ul><li>Entire Study Population </li></ul><ul><li>Recipients transplanted after </li></ul><ul><li>cold ischemic time >17 h...
What is the underlying mechanism that confers protection?   Dopamine = 3,4-Dihydroxyphenethylamine
Dopamine <ul><li>Dopamine ’ s mechanism of action is not mediated through hemodynamic stabilization of the DBD </li></ul><...
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   ...
Hypothesis <ul><li>If donor dopamine has the capability to prolong the endothelial integrity of the graft during cold pres...
Kidney Graft Survival by Exposure to DDAVP stratified by Assignment to Dopamine Cumulative survival, % Cumulative survival...
<ul><li>Donor care is simultaneous care of multiple recipients </li></ul><ul><li>Better understanding of the pathophysiolo...
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Rui Maio - Portugal - Tuesday 29 - Organ Donor Care. New Alternatives

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  • Prospective study of 19 hemodynamically unstable donors, thyroid was associated with sig reduction in vasopressor use, with 53% of patients completely weaned off pressors.
  • 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.
  • Rui Maio - Portugal - Tuesday 29 - Organ Donor Care. New Alternatives

    1. 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. 2. <ul><li>Persistent donor shortage </li></ul><ul><li>Increase in older, ECD and DCD donors </li></ul><ul><li>More complex recipients </li></ul><ul><li>International sharing = longer cold ischemia </li></ul><ul><li>Increase in PNF and DGF </li></ul><ul><li>Chronic dysfunction remain substantial problem </li></ul>Transplantation – Major problems . . .
    3. 3. <ul><li>Reduction of the needs </li></ul><ul><li>Increase organ donation </li></ul><ul><ul><li>Extended Criteria Donor (ECD) </li></ul></ul><ul><ul><li>Living Donation </li></ul></ul><ul><ul><li>Donation after cardiac death (DCD) </li></ul></ul><ul><ul><li>Aggressive donor management </li></ul></ul><ul><li>Increase graft survival </li></ul>REDUCTION OF WAITING LIST
    4. 4. <ul><li>Donor management remains one of the most neglected areas of transplantation </li></ul><ul><li>Wheeldon, J Heart Lung Transplant 1995 </li></ul><ul><li>Failure to provide adequate physiological </li></ul><ul><li>support to potential donors accounts for about 25 % of lost donor organs </li></ul><ul><li>Pickett, Current opinion in Anesthesiology 1994 </li></ul><ul><li>Grossman MD. Crit Care Med 1996 </li></ul>Aggressive donor management ?
    5. 5. <ul><li>Success of transplantation depends on the quality of the organs and the quality of the organs depend on the quality of management </li></ul><ul><li>Possible the recovery of organs that were initially assessed as unsuitable </li></ul><ul><li>Increase the number of organs per donor </li></ul><ul><li>Minimize the loss of donors during maintenance </li></ul>Aggressive donor management ?
    6. 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. 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
    9. 10. Warm ischemia Cold ischemia
    10. 11. Ischemia Reperfusion Injury <ul><li>Complex, multifactorial inflammatory event </li></ul><ul><li>Local and systemic reactions </li></ul><ul><li>Biphasic lesion </li></ul><ul><ul><li>Ischemia (apoptosis; necrosis) </li></ul></ul><ul><ul><li>Reperfusion (paradoxically causes further injury) </li></ul></ul><ul><li>Adversely affects both short-term and long term allograft function (PNF; DGF; CD) </li></ul><ul><li>Major challenge in clinical transplantation </li></ul>
    11. 12. <ul><li>Brain death and I/R injury </li></ul><ul><ul><li>Negative impact on organ quality </li></ul></ul><ul><ul><li>Enhance the allogenicity of the graft </li></ul></ul><ul><ul><li>Augment the recipient’s immune response </li></ul></ul><ul><li>Donor age and co-morbilities </li></ul><ul><ul><li>Synergistically augment innate immunity </li></ul></ul><ul><li>Donor graft immune-activated at the time of transplantation </li></ul>Innate & Adaptive Immune Response S.Tullius, Transplantation ,2008
    12. 13. <ul><li>Standard ICU care = donor care: </li></ul><ul><ul><li>Haemodynamic control </li></ul></ul><ul><ul><li>Hydro-electrolyte balance </li></ul></ul><ul><ul><li>Ventilation </li></ul></ul><ul><ul><li>Endocrino-metabolic balance </li></ul></ul><ul><ul><li>Coagulation </li></ul></ul><ul><ul><li>Body temperature </li></ul></ul><ul><ul><li>Sepsis and infection prophylaxis </li></ul></ul><ul><ul><li>Etc... </li></ul></ul><ul><li>Established guidelines sufficient for donor care </li></ul><ul><li>Except for a few special situations </li></ul>Donor treatment
    13. 14. <ul><li>Hormone Depletion in Brain Death </li></ul>Endocrine Considerations <ul><li>Vasopressin </li></ul><ul><li>Insulin (resistance) </li></ul><ul><li>Cortisol </li></ul><ul><li>T3 and T4 </li></ul>
    14. 15. <ul><li>DIABETES INSIPIDUS (30-85 %) </li></ul><ul><ul><li>Hypernatraemia </li></ul></ul><ul><ul><li>Hypotonic polyuria > 4ml/kg/h </li></ul></ul><ul><ul><li>Treatment is noncontroversial to maintain hemodynamic stability and prevent electrolyte imbalance </li></ul></ul><ul><ul><li>It reduces the need for large volume replacements by reducing urine output </li></ul></ul><ul><ul><li>Is best managed by vasopressin infusion </li></ul></ul><ul><ul><li>DDAVP is associated with improved long-term allograft survival </li></ul></ul>Endocrine Considerations Pennefather et al ; Transplantation , 1993 Peter Schnuelle et al ; ESOT, 2009
    15. 16. <ul><li>Thyroid hormone depletion </li></ul><ul><ul><li>T 3 deficiency is seen in 85% of patients after BD </li></ul></ul><ul><ul><li>Low levels of thyroid hormone </li></ul></ul><ul><ul><ul><li>Impaired mithocondrial function </li></ul></ul></ul><ul><ul><ul><li>Impaired use of metabolic substrate </li></ul></ul></ul><ul><ul><ul><li>Impaired production of ATP </li></ul></ul></ul><ul><ul><ul><li>Transition from aerobic to anaerobic metabolism </li></ul></ul></ul><ul><ul><li>T 3 treated donors </li></ul></ul><ul><ul><ul><li>Improvement cardiovascular stability </li></ul></ul></ul><ul><ul><ul><li>Reduction of ECG abnormalities </li></ul></ul></ul><ul><ul><ul><li>Reduction of acid-base disturbances </li></ul></ul></ul><ul><ul><ul><li>Improvement suitability of organs </li></ul></ul></ul>Endocrine Considerations Novitzky D et al, Transplantation 1987 Roels L et al, Transplant Proc , 2000
    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
    17. 18. T 4 administration Total vasopressor dose ( µ g/kg/min) Time interval (in hours) Time 0 is start of T 4 Endocrine Considerations <ul><li>The role of thyroid hormone </li></ul>Salim et al Arch Surg 2001;136:1377-1380
    18. 19. <ul><li>Hormone Replacement and Heart Survival </li></ul>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
    19. 20. Wood KE. N Engl Med J 2004; 351:2730-9 Endocrine Considerations
    20. 21. <ul><li>Hormone replacement therapy </li></ul><ul><ul><li>Antidiuretics hormone </li></ul></ul><ul><ul><li>Steroids </li></ul></ul><ul><ul><li>Insulin </li></ul></ul><ul><ul><li>T3/T4 </li></ul></ul><ul><li>Avoid diabetes insipidus and hypernatremia </li></ul>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
    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
    22. 23. <ul><li>Entire Study Population </li></ul><ul><li>Recipients transplanted after </li></ul><ul><li>cold ischemic time >17 hrs </li></ul>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 (%)
    23. 24. What is the underlying mechanism that confers protection? Dopamine = 3,4-Dihydroxyphenethylamine
    24. 25. Dopamine <ul><li>Dopamine ’ s mechanism of action is not mediated through hemodynamic stabilization of the DBD </li></ul><ul><li>The beneficial effect is related to the dihydroxy-phenolic ring structure of the dopamine molecule which provides antioxidant properties </li></ul><ul><li>Subsequent cellular processes that govern hypothermia-mediated cell death, such as ATP depletion and intracellular accumulation of calcium ions, occur with considerable delay </li></ul>
    25. 26. What is the role of desmopressin (DDAVP)?
    26. 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, %
    27. 28. Hypothesis <ul><li>If donor dopamine has the capability to prolong the endothelial integrity of the graft during cold preservation… </li></ul><ul><li>… the logical consequence would be that desmopressin exerts a larger benefit in kidneys pre-treated with dopamine </li></ul>
    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
    29. 30. <ul><li>Donor care is simultaneous care of multiple recipients </li></ul><ul><li>Better understanding of the pathophysiology of brain dead </li></ul><ul><li>Several studies that support new therapeutic approaches including hormonal therapy </li></ul><ul><li>Aggressive management ensures more organs retrieved and more organ quality </li></ul><ul><li>To fight against organ shortage we must not only seek to increase the number of donors but we must also explore methods of increasing the yield of the existing donor pool </li></ul>Conclusions

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