Thyroid Hormone Replacement in the Potential Brain
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Transcript Thyroid Hormone Replacement in the Potential Brain
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