Wednesday, December 14, 2016

Early Pharmacotherapy Management for the Potential Organ Donor in the Trauma Bay

Thinking ahead is something most EM pharmacists are excellent at and we are – amongst other things – in the business of saving lives. On the (hopefully) rare occasion that the 30-something-year-old trauma patient rolls in with a blatantly obvious and observable poor prognosis, being steps ahead may be doing just that. In the back of your mind, you think this otherwise healthy patient could potentially be an organ donor. In the immediate, sense you are struggling to keep the mean arterial pressure (MAP) above 60 mmHg, and fluids alone are not cutting it. Oftentimes, you might reach for that norepinephrine drip after fluids and transfusions of blood products have failed, but this time you have other thoughts.
Donor management generally starts in the intensive care unit, but in certain situations, interventions may be justified as early as in the trauma bay. To be able to recognize these times, we must first understand some pathophysiology.
The pathways associated underlying the progression of brain death are complex. Increased intracranial pressure leads to cerebral herniation and brainstem ischemia. Initially, parasympathetic activation resulting in sinus bradycardia and hypotension may be seen due to mesencephalic ischemia. Pontine ischemia follows, resulting in sympathetic stimulation, causing hypertension and bradycardia (often described as a characteristic Cushing’s response). An autonomic storm ensues, causing massive catecholamine release due to medullary ischemia, leading to tachycardia and increased systemic vascular resistance. This phenomenon  is typically short-lived, with depletion of catecholamine stores resulting in autonomic collapse, causing diminished sympathetic activity, reduced vascular tone, decreased peripheral arterial and venous resistance, and impaired cardiac output.1 The severe vasodilation and cardiovascular collapse occurs is arguably most crucial in preventing and has been cited as the stage when medical failure often occurs in the management of a potential organ donor.2
Most donor management protocols are implemented after there is determination of brain death and consent is obtained – which inevitably takes time. Brain death is usually determined several hours after initial injury, and some states require two separate examinations, which can delay determination of brain death.3 While the complex pathophysiology above would seemingly provide time to initiate therapies in most patients, delays in the potential donor presenting with hemodynamic instability  initially can significantly impact the number of organs procured.4 It is in these situations that initiating the right therapies for hemodynamic stability prior to declared brain death in a potential donor can be justified.
Back to Our Trauma Patient

Because you read the recent AJHP article regarding organ donor management,5 maybe you are hesitating with norepinephrine as your next choice after volume resuscitation attempts. If you have encountered this patient scenario before, you know that maintaining organ perfusion while avoiding excessive vasopressor use is a United Network for Organ Sharing (UNOS)-defined donor management goal to increase the number of organs procured.6 With that being said, what approaches are reasonable?

Option 1: Start dopamine and/or vasopressin and titrate to effect
  • Traditionally, dopamine has been utilized as a first-line agent for inotropic support. However, current guidelines acknowledge there is no evidence that its use is superior over vasopressin. Up to 80% of brain dead donors will experience diabetes insipidus, which may be a compelling reason to take advantage of  vasopressin initially and gain multiple benefits from one drug.7
  • In patients with low systemic vascular resistance, norepinephrine and/or phenylephrine are recommended.7

Option 2: Start Hormone Replacement Therapy (HRT)
(Commonly some form of dextrose + methylprednisolone + thyroid hormone + insulin + vasopressin)
There has been controversy in the use of HRT as part of donor protocols. Randomized controlled trials – largely conducted in hemodynamically stable donors – have not shown the use of HRT to be beneficial. Subgroups of donors identified as hemodynamically unstable have been too small to detect a difference.8 Retrospective studies, however, have found significant benefit with regards to the number of organs procured and decreased vasopressor use, specifically in hemodynamically unstable donors.8–13 The premise of initiating these therapies has traditionally been based on presumed anterior pituitary hormone deficits causing hypocortisolism and hypothyroidism, although reports of decreased ACTH, TSH, and T4 have been widely variable. It has been proposed that a “sick euthyroid syndrome” may occur in brain death, with the body preferentially converting T4 to reverse T3 (rT3) instead of T3 as a physiological response. However, reports of increased rT3 have also been variable.14 There is recent evidence thyroid hormones have anti-inflammatory properties, which has been suggested as having an additional contributory benefit in organ donor management.15
Previous guidelines had strong recommendations in the use of hormone replacement therapy for all potential donors, which may entail the use of a multi-drug cocktail of T3, vasopressin, methylprednisolone, and insulin titrated to goal blood glucose of 140-180 mg/dL.16 In the past, retrospective data indicated higher organ procurement rates with this regimen.17 However, more recent data, though limited, has indicated hemodynamically unstable patients are the most likely to gain benefit from HRT, specifically the use of thyroid hormones.

Vasopressin
  • Improves vasodilatory shock, counteracts diabetes insipidus, and reduces catecholamine use.
  • Dose: Initiate at 0.01-0.04 IU/min
  •  
Thyroid Hormone
  • Mechanism still not well understood – benefits may be due to sick euthyroid syndrome in the donor; improves hemodynamic stability, decreases need for vasopressor use, and increases the probability of successful organ recovery. Recommended for hemodynamically unstable patients or those with a LVEF <45% (predisposed to having existing sick euthyroid syndrome).7,18
  • T3 vs. T4: Liothyronine (T3) was previously preferred over T4 due to more rapid onset, but no obvious differences in efficacy have been noted in retrospective reviews, thus no preference is indicated in current guidelines. As UNOS will not reimburse until they have taken over donor management, T4 would appear to be the more reasonable option cost-wise ($100/day vs. $2700/day).
  • IV versus PO: Although serum concentrations in one small trial of brain dead donors (n = 32) indicated oral T4 to be 93% that of intravenous at 6 hours (2 mcg/kg given once), bioavailability of levothyroxine has historically been reported as 60-80% in euvolemic patients.19,20  Larger studies would be necessary to more fully evaluate the use of oral T4, especially in the setting of hypoperfusion and concern for GI ischemia.
  • Dose:
    • Levothyroxine (T4): 20 mcg bolus followed by 10 mcg/hr infusion
    • Liothyronine (T3): 4.0 mcg bolus, followed by 3 mcg/hr infusion

Methylprednisolone
  • Still recommended for all potential donors to reduce the negative effects of the inflammatory cascade on donor organ function. The incidence of adrenal suppression in brain death has been inconsistent.7
  • Dose: A bolus dose of 250-1000 mg IV or 15 mg/kg IV followed by continuous infusion of 100 mg/hr have been recommended
    • May suppress leukocyte antigen expression and should be administered after blood collection for tissue typing.7
Dextrose + Insulin
  • Most institutional protocols will often have this combination. Current guidelines support the use of insulin to target blood glucose levels < 180 mg/dL.7 A recent UNOS evaluation of glucose control in organ donors found that blood glucose levels < 180 mg/dL to be an independent predictor of at least four organs transplanted per donor. Kidney graft survival at 10 months was also found to be associated with blood glucose levels maintained at  < 200 mg/dL.21
  • Recently, Novitzky et al. conducted a follow-up analysis of their previous retrospective study in 63,593 organ donors,11 reporting the use of insulin may have been negatively associated with pancreas procurement and graft survival. This has not been previously reported, and as authors state, may be due to pathophysiological response of pancreatic islet cells in brain death or potentially a reflection of poor hemodynamic status of the donor. Despite being able to consistently evaluate glucose levels and insulin dosing regimens, they suggest high levels of insulin may indicate marginal pancreatic donor quality.15
  • Dose: Routine use of IV dextrose is not recommended.7 However, 1 ampule of 50% IV dextrose has traditionally been used and given first in the HRT regimen, followed by methylprednisolone, and then 20 units of regular insulin.22

It is an unfortunate reality in trauma that we are not always going to be able to save the immediate life brought to us. As responding pharmacists, having familiarity with the HRT regimen – as well as the ability to identify when it should be considered sooner rather than later – may be the lifesaving difference for another patient not in our direct care.
Christine Tafoya, PharmD (@ChrissieTPharmD)
Pharmacy Practice Resident (PGY-1)
Banner –  University Medical Center
Phoenix, Arizona

Reviewed by: 
Mark Culver, PharmD, BCPS (@EMdruggist);
Craig Cocchio, PharmD, BCPS (@iEMPharmD); and
Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

References:
  1. King R, Hinkle J, Werman H. Organ procurement in trauma. Trauma Reports. Atlanta, GA: AHC Media; 2010.
  2. Kwon Y, Baldisseri M. Care of the organ donor. In: O’Donnell J, Nacul F, eds. Surgical Intensive Care Medicine. 2nd ed. New York, NY: Springer Science; 2010:591-597.
  3. Wijdicks EF,  Varelas PN, Gronseth GS, Greer DM. Evidence-based guideline update: Determining brain death in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74(23):1911-1918.
  4. Lustbader D, O’Hara D, Wijdicks EFM, et al. Second brain death examination may negatively affect organ donation. Neurology. 2011;76(2):119-124.
  5. Korte C, Garber JL, Descourouez JL, Richards KR, Hardinger K. Pharmacists’ guide to the management of organ donors after brain death. Am J Health Syst Pharm. 2016;73:e592-e602.
  6. Patel MS, Zatarain J, De La Cruz S, et al. The impact of meeting donor management goals on the number of organs transplanted per expanded criteria donor: A prospective study from the UNOS Region 5 Donor Management Goals Workgroup. JAMA Surg. 2014;149(9):969-975.
  7. Kotloff RM, Blosser S, Fulda GJ, et al. Management of the potential organ donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement. Crit Care Med. 2015;43(6):1291-1325.
  8. Macdonald PS, Aneman A, Bhonagiri D, et al. A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors. Crit Care Med. 2012;40(5):1635-1644.
  9. Salim A, Vassiliu P, Velmahos GC, et al. The role of thyroid hormone administration in potential organ donors. Arch Surg. 2001;136(12):1377-1380.
  10. Salim A, Martin M, Brown C, et al. Using thyroid hormone in brain-dead donors to maximize the number of organs available for transplantation. Clin Transplant. 2007;21(3):405-409.
  11. Novitzky D, Mi Z, Sun Q, Collins JF, Cooper DKC. Thyroid hormone therapy in the management of 63,593 brain-dead organ donors. Transplantation. 2014;98(10):1119-1127.
  12. Joseph B, Aziz H, Pandit V, et al. Levothyroxine therapy before brain death declaration increases the number of solid organ donations. J Trauma Acute Care Surg. 2014;76(5):1301-1305.
  13. Lam L, Inaba K, Branco BC, et al. The impact of early hormonal therapy in catastrophic brain-injured patients and its effect on organ procurement. Am Surg. 2012;78(3):318-324.
  14. Novitzky D, Ekser B, Cooper D. Early clinical experience of hormonal therapy in the brain-dead potential organ donor. In: Novitzky D, Cooper D, eds. The Brain-Dead Organ Donor: Pathophysiology and Management. New York, NY: Springer Science; 2013:191-207.
  15. Novitzky D, Mi Z, Videla LA, Collins JF, Cooper DKC. Hormone resuscitation therapy for brain-dead donors - is insulin beneficial or detrimental? Clin Transpl. 2016;30(7):754-759.
  16. Zaroff J, Rosengard B, Armstrong W, et al. Consensus conference report: Maximizing use of organs recovered from the cadaver donor: cardiac recommendations. Circulation. 2002;106(7):836-841.
  17. Rosendale JD, Kauffman HM, McBride M a, et al. Aggressive pharmacologic donor management results in more transplanted organs. Transplantation. 2003;75(4):482-487.
  18. Novitzky D, Cooper DKC. Thyroid hormone therapy to the recipient of a heart from a brain-dead donor. In: Novitzky D, Cooper D, eds. The Brain-Dead Organ Donor: Pathophysiology and Management. New York, NY: Springer Science; 2012:321-331.
  19. Sharpe MD, van Rassel B, Haddarra W. Oral and intravenous thyroxine (T4) achieve comparable serum levels for hormonal resuscitation protocol in organ donors: A randomized double-blinded study. Can J Anesth. 2013;60:998–1002.
  20. Colucci P, Seng Yue C, Ducharme M, Benvenga S. A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. European Endocrinology. 2013;9(1):40–7.
  21. Sally MB, Ewing T, Crutchfield M, et al. Determining optimal threshold for glucose control in organ donors after neurologic determination of death: A United Network for Organ Sharing Region 5 Donor Management Goals Workgroup prospective analysis. J Trauma Acute Care Surg. 2014;76(1):62-69.  
  22. Salim A, Martin M, Brown C, Rhee P, Demetriades D, Belzberg H. The effect of a protocol of aggressive donor management: Implications for the national organ donor shortage. J Trauma. 2006;61(2):429-433.

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