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
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 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
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
vasoconstriction
 Subendothelial ischemia
 Focal myocardial necrosis
 Endothelial 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
Iodine concentrated and incorporated into
thyroglobulin to form MIT, DIT
 MIT, DIT combine to form T3, T4
 T3, T4 sequestered in thyroid
colloid until release
 Synthesis, storage, and release of
thyroid hormones regulated by
TSH from anterior pituitary

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 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++
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 subacutely
after 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 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
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
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-associated
complications
Salim A, et al., Clin Transpl 2007; 21:405-409
Reversal of Cardiac Dysfunction
with Thyroid Hormone Replacement
Likely effect at mitochondrial
level
 Reversal of anaerobic to
aerobic metabolism
 Potentiate effects of
endogenous catecholamines

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
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)
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

Retrospective
cohort study at
CHOP
 171
brain dead
patients
 91
hemodynamically unstable patients received
T4 infusion at clinician’s discretion
 Decrease in vasopressor score
Zuppa AF, et al., CCM 2004; 32:2318-22
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

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