Thyroid Hormone Replacementin the Potential Brain-Dead Organ DonorHarbor-UCLA Critical Care – Organ Donation Symposium

April 12, 2010

Brant Putnam, MD FACSTrauma / Acute Care Surgery / Surgical Critical Care

Harbor-UCLA Medical Center

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

Sequence of Eventsin Brain Death

Rostral – caudal progression of ischemia Medulla oblongata

Autonomic storm to maintain CPPElevated levels of catecholamines

Spinal cordSympathetic deactivation

BradycardiaLoss of vasodilatory tone

Ischemia / reperfusion Diffuse endothelial injury Hypotension

Herniation

Sequelae of Brain Death Cardiovascular instability

Hypotension Arrhythmias

Neurogenic pulmonary edema Diabetes insipidus Coagulopathy / DIC Hyperglycemia Hypothermia Acidosis

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

Hemodynamic Instability Causes in the potential organ donor

Hypovolemia Vasodilation Cardiac dysfunction

Coronary vasoconstrictionSubendothelial ischemiaFocal myocardial necrosisEndothelial injury Impaired LV contractility /

hypokinesis

Hemodynamic Instability

Shift of cellular metabolism from aerobic to anaerobic

Depletion of glycogen and myocardial high-energy cells

Accumulation of lactate

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

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

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

Effects of Thyroid Hormoneson Heart

Increase in cardiac output Chronotropy via beta-adrenergic receptor

upregulation Vasodilatation

Non-shivering thermogenesisDirect vasodilatory effects on smooth muscle

Increased blood volumeStimulate production of erythropoeitinActivation of RAA axis

Increase myocardial contractility via increased Ca++

Severe Brain Injury and Brain Death

Diffuse vascular regulatory impairment Diffuse metabolic cellular injury Progressive deterioration of organ function

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 subacutelyafter TBI

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 T3Euthyroid sick syndrome

Reduced mitochondrial energy stores Impaired mitochondrial function and energy

substrate use Poor correlation between HD instability and

endogenous hormone levelsHowlett TA, et al., Transplantion1989; 47:828-834Mariot J, et al., Transplant Proc 1995; 27:793-794

Thyroid Hormone Replacement“T4 Protocol”

T4 protocol Keep CVP > 6 Monitor K+ levels carefully Administer boluses of:

D50 1 amp IVSolumedrol 2 grams IVRegular insulin 20 units IVLevothyroxine 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

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

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

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-associatedcomplications

Salim A, et al., Clin Transpl 2007; 21:405-409

Reversal of Cardiac Dysfunctionwith Thyroid Hormone Replacement

Likely effect at mitochondrial level

Reversal of anaerobic to aerobic metabolism

Potentiate effects of endogenous catecholamines

Reversal of Cardiac Dysfunctionwith 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

Reversal of Renal Dysfunctionwith Thyroid Hormone Replacement

Significantly improved one-year kidney graft survival in both SCD and ECD with administration of hormone replacement (p<0.001)

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

UNOS Recommendation

2001 Crystal City Consensus Conference

Novitzky D, et al., Transplantation 2006; 82:1396-1401

Use of T4 in Pediatric Donors

91 hemodynamically unstable patients received T4 infusion at clinician’s discretion

Decrease in vasopressor score

Zuppa AF, et al., CCM 2004; 32:2318-22

Retrospective cohort study at CHOP 171 brain dead

patients

Earlier Use of T4 Replacementin the Patient with Devastating Brain Injury

Ethical dilemma Is there a conflict of interest?

Specialized multidisciplinary team Good critical care

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

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