in the Potential BrainDead Organ Donor HarborUCLA Critical Care Organ Donation Symposium April 12 2010 Brant Putnam MD FACS Trauma Acute Care Surgery Surgical Critical Care HarborUCLA Medical Center ID: 529140
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Thyroid Hormone Replacementin the Potential Brain-Dead Organ Donor
Harbor-UCLA Critical Care – Organ Donation SymposiumApril 12, 2010Brant Putnam, MD FACSTrauma / Acute Care Surgery / Surgical Critical CareHarbor-UCLA Medical CenterSlide2
The Problem
2008: 99,166 patients waiting for transplantsOf the 10,000 eligible brain-dead donors per year, approximately half are usedInability to obtain consent25% die with cardiovascular collapseLoss of organs due to high dose vasopressor requirementsSlide3
Sequence of Events
in Brain DeathRostral – caudal progression of ischemiaMedulla oblongataAutonomic storm to maintain CPPElevated levels of catecholaminesSpinal cordSympathetic deactivation
Bradycardia
Loss of vasodilatory tone
Ischemia / reperfusion
Diffuse endothelial injury
Hypotension
HerniationSlide4
Sequelae of Brain Death
Cardiovascular instabilityHypotensionArrhythmiasNeurogenic pulmonary edemaDiabetes insipidusCoagulopathy / DICHyperglycemiaHypothermiaAcidosisSlide5
Wood KE and McCartney J.
Transplantion Rev 2007; 21:204-218Slide6
Hemodynamic Instability
Causes in the potential organ donorHypovolemiaVasodilationCardiac dysfunctionCoronary vasoconstrictionSubendothelial ischemiaFocal myocardial necrosisEndothelial injuryImpaired LV contractility / hypokinesisSlide7
Hemodynamic Instability
Shift of cellular metabolism from aerobic to anaerobicDepletion of glycogen and myocardial high-energy cellsAccumulation of lactateSlide8
Hypothalamic – Pituitary Axis
HypothalamusLocated at base of brainSHA blood supplyPituitaryAnterior (adenohypophysis)Portal venous system from HTMRelease of ACTH, GH, LH, FSH, TSHPosterior (neurohypophysis)IHA blood supplyNeuronal connections from HTM SO and PV nucleiRelease of vasopressin and oxytocinSlide9
Thyroid Hormone Synthesis
T3, T4 sequestered in thyroid colloid until releaseSynthesis, storage, and release of thyroid hormones regulated by TSH from anterior pituitaryIodine concentrated and incorporated into thyroglobulin to form MIT, DITMIT, DIT combine to form T3, T4Slide10
Effects of Thyroid Hormones
Release of T4:T3 in 20:1 ratioT3 more biologically activeT4 converted to T3 in target tissues by various deiodinasesSlide11
Effects of Thyroid Hormoneson Heart
Increase in cardiac outputChronotropy via beta-adrenergic receptor upregulationVasodilatationNon-shivering thermogenesisDirect vasodilatory effects on smooth muscleIncreased blood volumeStimulate production of erythropoeitinActivation of RAA axisIncrease myocardial contractility via increased Ca++Slide12
Severe Brain Injury and Brain Death
Diffuse vascular regulatory impairmentDiffuse metabolic cellular injuryProgressive deterioration of organ functionSlide13
Neuroendocrine Dysfunction
40% of patients with acute brain injuriesAutopsy studies: evidence of pituitary hemorrhage or necrosis in 80% of patients following TBIDiffuse brain injuryHemorrhageHerniationMay develop subacutely after TBISlide14
Thyroid Hormone Production following Severe TBI / Brain Death
ControversyNormal anterior pituitary functionDiminished levels of T4, free T4, T3, and TSHReciprocal rise in reverse T3Euthyroid sick syndromeReduced mitochondrial energy storesImpaired mitochondrial function and energy substrate usePoor correlation between HD instability and endogenous hormone levels
Howlett
TA, et al.,
Transplantion
1989; 47:828-834
Mariot
J, et al.,
Transplant Proc
1995; 27:793-794Slide15
Thyroid Hormone Replacement“T4 Protocol”
T4 protocolKeep CVP > 6Monitor K+ levels carefullyAdminister boluses of:D50 1 amp IVSolumedrol 2 grams IVRegular insulin 20 units IVLevothyroxine 20 mcg IVStart T4 drip (200mcg in 500cc NS) at 25 cc/hr and titrate up to 40 mcg/hr to attain desired BPSlide16
Thyroid Hormone Replacement“T4 Protocol”
Prospective study of 19 HD unstable donorsReduced vasopressor requirement53% had discontinuation of pressorsAll went on to organ donation
Salim A, et al.,
Arch Surg
2001; 136:1377-1380Slide17
Thyroid Hormone Replacement“T4 Protocol”
LAC-USC implemented aggressive donor management protocol 2001-2005PA catheterAggressive IVF resuscitationVasopressors for MAP < 70Hormonal therapy if vasopressor > 10 mcg/kg/minPrompt identification and treatment of brain death-related complications (DIC, DI, neurogenic pulmonary edema, etc)Salim A, et al., Clin Transpl
2007; 21:405-409Slide18
Thyroid Hormone Replacement “T4 Protocol”
123 patients underwent successful organ donation78% had T4 infusionT4 group had significantly more OTPDNo differences in types of organs recoveredNo differences in brain death-associated complicationsSalim A, et al.,
Clin Transpl
2007; 21:405-409Slide19
Reversal of Cardiac Dysfunctionwith Thyroid Hormone Replacement
Likely effect at mitochondrial levelReversal of anaerobic to aerobic metabolismPotentiate effects of endogenous catecholaminesSlide20
Reversal of Cardiac Dysfunctionwith Thyroid Hormone Replacement
21 conventionally treated donors with progressive hemodynamic deteriorationAll required increments of inotropic support and bicarbonateSignificant improvement in hemodynamic statusRequire less vasopressor supportAll organs in all donors suitable for transplantationExcellent organ function following graft implantationPapworth program in EnglandResuscitated with TRH, up to 92% of heart donors previously deemed “unsuitable” for transplantation
Wheeldon DR, et al.,
J Heart Lung Transplant
1995; 14:734Slide21
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)Slide22
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; 75:482-487Slide23
UNOS Recommendation
2001 Crystal City Consensus ConferenceNovitzky D, et al., Transplantation 2006; 82:1396-1401Slide24
Use of T4 in Pediatric Donors
91 hemodynamically unstable patients received T4 infusion at clinician’s discretionDecrease in vasopressor scoreZuppa AF, et al., CCM 2004; 32:2318-22
Retrospective cohort study at CHOP
171 brain dead patientsSlide25
Earlier Use of T4 Replacement
in the Patient with Devastating Brain InjuryEthical dilemmaIs there a conflict of interest?Specialized multidisciplinary teamGood critical careSlide26
Devastating Brain Injury Order Set
Appropriate fluid resuscitation to euvolemiaCorrection of coagulopathyMaintain oxygen deliveryTransfuse to Hb 10Use of inotropesHormone replacementOptimize oxygenation and ventilationManagement of DISlide27
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 supportConsider earlier use of T4 replacement in severely brain injured patientsT4 protocol reduces need for vasopressors and improves number of organs transplanted per donor and graft function