thyroid hormone replacement in the potential brain-dead organ donor harbor-ucla critical care –...
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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