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Thyroid Hormone Replacement in the Potential Brain-Dead Organ Donor Harbor-UCLA Critical Care – Organ Donation Symposium April 12, 2010 Brant Putnam, MD.

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Presentation on theme: "Thyroid Hormone Replacement in the Potential Brain-Dead Organ Donor Harbor-UCLA Critical Care – Organ Donation Symposium April 12, 2010 Brant Putnam, MD."— Presentation transcript:

1 Thyroid Hormone Replacement in the Potential Brain-Dead Organ Donor Harbor-UCLA Critical Care – Organ Donation Symposium April 12, 2010 Brant Putnam, MD FACS Trauma / Acute Care Surgery / Surgical Critical Care Harbor-UCLA Medical Center

2 The Problem 2008: 99,166 patients waiting for transplants Of the 10,000 eligible brain-dead donors per year, approximately half are used Inability to obtain consent 25% die with cardiovascular collapse Loss of organs due to high dose vasopressor requirements

3 Sequence of Events in Brain Death Rostral – caudal progression of ischemia Medulla oblongata Autonomic storm to maintain CPP Elevated levels of catecholamines Spinal cord Sympathetic deactivation Bradycardia Loss of vasodilatory tone Ischemia / reperfusion Diffuse endothelial injury Hypotension Herniation

4 Sequelae of Brain Death Cardiovascular instability Hypotension Arrhythmias Neurogenic pulmonary edema Diabetes insipidus Coagulopathy / DIC Hyperglycemia Hypothermia Acidosis

5 Wood KE and McCartney J. Transplantion Rev 2007; 21:204-218

6 Hemodynamic Instability Causes in the potential organ donor Hypovolemia Vasodilation Cardiac dysfunction Coronary vasoconstriction Subendothelial ischemia Focal myocardial necrosis Endothelial injury Impaired LV contractility / hypokinesis

7 Hemodynamic Instability Shift of cellular metabolism from aerobic to anaerobic Depletion of glycogen and myocardial high-energy cells Accumulation of lactate

8 Hypothalamic – Pituitary Axis Hypothalamus Located at base of brain SHA blood supply Pituitary Anterior (adenohypophysis) Portal venous system from HTM Release of ACTH, GH, LH, FSH, TSH Posterior (neurohypophysis) IHA blood supply Neuronal connections from HTM SO and PV nuclei Release of vasopressin and oxytocin

9 Thyroid Hormone Synthesis T3, T4 sequestered in thyroid colloid until release Synthesis, storage, and release of thyroid hormones regulated by TSH from anterior pituitary Iodine concentrated and incorporated into thyroglobulin to form MIT, DIT MIT, DIT combine to form T3, T4

10 Effects of Thyroid Hormones Release of T4:T3 in 20:1 ratio T3 more biologically active T4 converted to T3 in target tissues by various deiodinases

11 Effects of Thyroid Hormones on Heart Increase in cardiac output Chronotropy via beta-adrenergic receptor upregulation Vasodilatation Non-shivering thermogenesis Direct vasodilatory effects on smooth muscle Increased blood volume Stimulate production of erythropoeitin Activation of RAA axis Increase myocardial contractility via increased Ca ++

12 Severe Brain Injury and Brain Death Diffuse vascular regulatory impairment Diffuse metabolic cellular injury Progressive deterioration of organ function

13 Neuroendocrine Dysfunction 40% of patients with acute brain injuries Autopsy studies: evidence of pituitary hemorrhage or necrosis in 80% of patients following TBI Diffuse brain injury Hemorrhage Herniation May develop subacutely after TBI

14 Thyroid Hormone Production following Severe TBI / Brain Death Controversy Normal anterior pituitary function Diminished levels of T4, free T4, T3, and TSH Reciprocal rise in reverse T3 Euthyroid sick syndrome Reduced mitochondrial energy stores Impaired mitochondrial function and energy substrate use Poor correlation between HD instability and endogenous hormone levels Howlett TA, et al., Transplantion1989; 47:828-834 Mariot J, et al., Transplant Proc 1995; 27:793-794

15 Thyroid Hormone Replacement T4 Protocol T4 protocol Keep CVP > 6 Monitor K + levels carefully Administer boluses of: D50 1 amp IV Solumedrol 2 grams IV Regular insulin 20 units IV Levothyroxine 20 mcg IV Start T4 drip (200mcg in 500cc NS) at 25 cc/hr and titrate up to 40 mcg/hr to attain desired BP

16 Thyroid Hormone Replacement T4 Protocol Prospective study of 19 HD unstable donors Reduced vasopressor requirement 53% had discontinuation of pressors All went on to organ donation Salim A, et al., Arch Surg 2001; 136:1377-1380

17 Thyroid Hormone Replacement T4 Protocol LAC-USC implemented aggressive donor management protocol 2001-2005 PA catheter Aggressive IVF resuscitation Vasopressors for MAP < 70 Hormonal therapy if vasopressor > 10 mcg/kg/min Prompt identification and treatment of brain death-related complications (DIC, DI, neurogenic pulmonary edema, etc) Salim A, et al., Clin Transpl 2007; 21:405-409

18 Thyroid Hormone Replacement T4 Protocol 123 patients underwent successful organ donation 78% had T4 infusion T4 group had significantly more OTPD No differences in types of organs recovered No differences in brain death-associated complications Salim A, et al., Clin Transpl 2007; 21:405-409

19 Reversal of Cardiac Dysfunction with Thyroid Hormone Replacement Likely effect at mitochondrial level Reversal of anaerobic to aerobic metabolism Potentiate effects of endogenous catecholamines

20 Reversal of Cardiac Dysfunction with Thyroid Hormone Replacement 21 conventionally treated donors with progressive hemodynamic deterioration All required increments of inotropic support and bicarbonate Significant improvement in hemodynamic status Require less vasopressor support All organs in all donors suitable for transplantation Excellent organ function following graft implantation Papworth program in England Resuscitated with TRH, up to 92% of heart donors previously deemed unsuitable for transplantation Wheeldon DR, et al., J Heart Lung Transplant 1995; 14:734

21 Reversal of Renal Dysfunction with Thyroid Hormone Replacement Significantly improved one-year kidney graft survival in both SCD and ECD with administration of hormone replacement (p<0.001)

22 Organs Transplanted per Donor Statistically significant increase in OTPD with use of hormone replacement as part of donor management Rosendale JD, et al., Transplantation 2003; 75:482-487

23 UNOS Recommendation 2001 Crystal City Consensus Conference Novitzky D, et al., Transplantation 2006; 82:1396-1401

24 Use of T4 in Pediatric Donors 91 hemodynamically unstable patients received T4 infusion at clinicians discretion Decrease in vasopressor score Zuppa AF, et al., CCM 2004; 32:2318-22 Retrospective cohort study at CHOP 171 brain dead patients

25 Earlier Use of T4 Replacement in the Patient with Devastating Brain Injury Ethical dilemma Is there a conflict of interest? Specialized multidisciplinary team Good critical care

26 Devastating Brain Injury Order Set Appropriate fluid resuscitation to euvolemia Correction of coagulopathy Maintain oxygen delivery Transfuse to Hb 10 Use of inotropes Hormone replacement Optimize oxygenation and ventilation Management of DI

27 Summary Pathophysiology of brain injury / brain death includes insults to hypothalamic – pituitary axis Use thyroid hormone supplementation in brain dead organ donors who remain hemodynamically unstable despite vasopressor support Consider earlier use of T4 replacement in severely brain injured patients T4 protocol reduces need for vasopressors and improves number of organs transplanted per donor and graft function

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