1. 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

2. 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

3. 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
Cushing originally described the process as “coning” following his experiments in dogs
Autonomic surge lasts average of 1.2 hrs (range of 30 min – 6hrs)
In a recent study of organ donors, hypotension NEVER present without precedent autonomic storm.
Controversy about treating the autonomic storm – patients treated with beta- or calcium channel blockers had increased probability of successful heart transplantation (treatment of autonomic storm may attenuate brain-death induced myocardial dysfunction)

4. Sequelae of Brain Death
Cardiovascular instability
Hypotension
Arrhythmias
Neurogenic pulmonary edema
Diabetes insipidus
Coagulopathy / DIC
Hyperglycemia
Hypothermia
Acidosis

5. Hypovolemia: related to initial injury loss, 3rd spacing, dehydration after tx ICPs, hyperglycemia, DI, venodilatation
Vasodilatation: related to spinal shock, depletion of catecholamine stores, loss of vasomotor tone, relative adrenal insufficiency
Wood KE and McCartney J. Transplantion Rev 2007; 21:

6. 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
Hypovolemia: related to initial injury loss, 3rd spacing, dehydration after tx ICPs, hyperglycemia, DI, venodilatation
Vasodilatation: related to spinal shock, depletion of catecholamine stores, loss of vasomotor tone, relative adrenal insufficiency
BOTTOM LINE:
Shift of cellular metabolism from aerobic to anaerobic
Depletion of glycogen and myocardial high-energy cells
Accumulation of lactate

7. Hemodynamic Instability
Shift of cellular metabolism from aerobic to anaerobic
Depletion of glycogen and myocardial high-energy cells
Accumulation of lactate
Hypovolemia: related to initial injury loss, 3rd spacing, dehydration after tx ICPs, hyperglycemia, DI, venodilatation
Vasodilatation: related to spinal shock, depletion of catecholamine stores, loss of vasomotor tone, relative adrenal insufficiency
BOTTOM LINE:
Shift of cellular metabolism from aerobic to anaerobic
Depletion of glycogen and myocardial high-energy cells
Accumulation of lactate

8. 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
Portal system allows close regulation of pituitary function WITHOUT significant interference from systemic mediators and factors

9. 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

10. 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

11. 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++

12. Severe Brain Injury and Brain Death
Diffuse vascular regulatory impairment
Diffuse metabolic cellular injury
Progressive deterioration of organ function

13. 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
Catastrophic brain injury causes elevated ICPs and subsequent herniation, disruption of HTM-pit vascular network, both arterial supply (SHA and IHA) and through venous drainage.
Effect of acute TBI on systemic hormone production and regulation, and the impact upon hemodynamic instability in the potential organ donor remains controversial.

14. 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
85% of heart donors have T3 deficiency
Howlett TA, et al., Transplantion1989; 47:
Mariot J, et al., Transplant Proc 1995; 27:

15. Thyroid Hormone Replacement “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
For patients requiring a combined vasopressor need greater than 15 mcg (all vasopressor added)

16. 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:

17. Thyroid Hormone Replacement “T4 Protocol”
LAC-USC implemented aggressive donor management protocol
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:

18. 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:

19. Reversal of Cardiac Dysfunction with Thyroid Hormone Replacement
Likely effect at mitochondrial level
Reversal of anaerobic to aerobic metabolism
Potentiate effects of endogenous catecholamines

20. 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

21. Reversal of Renal Dysfunction with Thyroid Hormone Replacement
Recent unpublished OPTN / UNOS data
Significantly improved one-year kidney graft survival in both SCD and ECD with administration of hormone replacement (p<0.001)

22. 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:

23. UNOS Recommendation 2001 Crystal City Consensus Conference
Novitzky D, et al., Transplantation 2006; 82:

24. 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:

25. 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

26. 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

27. 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