Pharmacists' Guide to the Management of Organ Donors After

MANAGEMENT OF ORGAN DONORS CLINICAL REVIEW

Pharmacists’ guide to the management of organ donors after brain death

Catherine Korte, Pharm.D., BCPS, Truman Medical Center, Kansas City, MO. Purpose. This article reviews organ donor pathophysiology as it relates Jennifer L. Garber, Pharm.D., to medication use with the goal of maximizing the successful procurement Legacy Good Samaritan Medical Center, and transplantation of donor organs. Portland, OR. Jillian L. Descourouez, Pharm.D., Summary. The number of patients requiring organ transplantation con- BCPS, University of Wisconsin Hospital and Clinics, Madison, WI. tinues to grow, yet organ donation rates remain flat, making it critical to appropriately manage each organ donor in order to ensure viability of all Katelyn R. Richards, Pharm.D., BCPS, Beth Israel Deaconess Medical transplantable organs. The care given to one organ donor is tantamount Center, Boston, MA. to the care of several transplant recipients. Aggressive donor manage- Karen Hardinger, Pharm.D., BCPS, ment ensures that the largest number of organs can be successfully pro- Division of Pharmacy Practice and cured and improves the organs’ overall quality. Hospital pharmacists are Administration, University of Missouri- Kansas City, Kansas City, MO. responsible for processing orders and preparing the medications outlined in donor management algorithms developed by their respective medical systems. It is important that pharmacists understand the details of the medications used in these protocols in order to critically evaluate each medication order and appropriately manage the donor. Typical medications used in organ donors after brain death include medications for blood pressure management and fluid resuscitation, medications necessary for electrolyte management, blood products, vasopressors, hormone replacement therapy, antiinfectives, anticoagulants, paralytics, and organ preservation solutions.

Conclusion. It is essential to provide optimal pharmacotherapy for each organ donor to ensure organ recovery and donation. Typical medications used in organ donors include agents for blood pressure management and fluid resuscitation, medications necessary for electrolyte management, blood products, vasopressors, hormone replacement therapy, antiinfectives, anticoagulants, paralytics, and organ preservation solutions.

Am J Health-Syst Pharm. 2016; 73:1829-39

olid organ transplantation re- Donor evaluation begins when the Smains a vital area of healthcare, local organ procurement organiza- with over 24,000 transplants per- tion (OPO) is contacted. A member of formed in 2014 alone.1 As of August the OPO will explain the procurement 2016, approximately 120,000 patients process to the family, obtain consent, were in need of a lifesaving organ. Ev- coordinate evaluation of the donor, ery 10 minutes, 1 person is added to and communicate with the United the list of those needing a transplant, Network for Organ Sharing (UNOS) to while 21 people die each day waiting aid in matching the donor to appro- for a transplant.1 The number of pa- priate recipients. A critical pathway tients on this list continues to grow, for the organ donor has been devel- Address correspondence to Dr. Hardinger yet organ donation rates remain flat.1 oped that outlines the phases of organ ([email protected]). Thus, it is critical to appropriately donation, including referral, declara- manage each potential organ donor in tion of brain death and consent, donor Copyright © 2016, American Society of Health-System Pharmacists, Inc. All rights order to ensure optimal functioning of evaluation, and donor management reserved. 1079-2082/16/1102-1829. the donated organ and the viability of or recovery.2 The pathway also pro- DOI 10.2146/ajhp150956 all transplantable organs. vides guidance to providers regarding

AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 1829 CLINICAL REVIEW MANAGEMENT OF ORGAN DONORS appropriate laboratory tests, diag- ic criteria (brain death) or circulatory– nostics, respiratory care, treatments, KEY POINTS respiratory criteria (cardiac death). medications, and outcomes in each • Aggressive donor manage- The determination of death using phase of donation. ment ensures that the larg- either criterion may differ among in- The care of potential organ do- est number of organs can be stitutions; however, a consensus state- nors differs from that of other criti- successfully procured and ment released in 2015 outlines clear cally ill patients. At the end of life, improves the organs’ overall recommendations for making this organ donors are frequently medi- quality. determination.6,7 We refer the reader cally unstable, and this instability in- to either the consensus statement6,7 or • Typical medications admin- creases as the length of time between UNOS guidelines for a more compre- istered to organ donors after declaration of brain death and organ hensive review.2 brain death include medica- procurement grows.3 Timely manage- Neurologic determination of tions for blood pressure man- ment of the donor is imperative in death. A donor may experience com- agement and fluid resuscita- order to minimize the occurrence of plete loss of neurologic function due tion, medications necessary somatic death and increase the num- to traumatic or anoxic brain injury. A for electrolyte management, ber of organs that can be successfully donor with complete loss of neuro- blood products, vasopressors, procured and transplanted. Manage- logic function will exhibit many signs hormone replacement therapy, ment must balance the need to pre- of brain injury, including nonreactive antiinfectives, anticoagulants, serve multiple organs. Treatment that pupils, absence of gag reflex, and ap- paralytics, and organ preser- improves the function of one organ nea. Once the provider concludes that vation solutions. may be harmful to that of another or- medical management is futile, the fo- gan. For example, the renal transplant • It is important that hospital cus changes from maintaining cere- team may want to optimize renal per- pharmacists understand the bral perfusion to managing the donor fusion with fluids and diuretics, while medications used in organ for organ procurement.6 This includes the lung transplant team may want donor management protocols maintaining hemodynamic stability to avoid excessive hydration and the in order to critically evaluate and organ perfusion. risk of fluid overload and pulmonary each medication order and ap- Circulatory determination of edema. propriately manage the donor. death. Organ donation after circu- The Organ Procurement and Trans- latory determination of death has plantation Network (OPTN) has issued increased in frequency due to the in- policies that govern all transplant hos- creased need for organs. The process pitals and organizations in the United is different from that of organ dona- States.4 While these policies are exten- protocols in order to critically evaluate tion after neurologic death. Donors sive and detail many aspects of organ each medication order and appropri- in this category must have permanent transplantation, they are broad in ately manage the donor. This article circulatory arrest (observed for a min- their overall scope and do not provide briefly reviews organ donor patho- imum of two minutes) before declara- specific details regarding medication physiology as it relates to medication tion of death and the initiation of or- use in and management of the organ use with the goal of maximizing the gan transplantation.6,8 donor. As such, the policies serve as successful procurement and trans- The information in this article ap- guidelines by which OPOs practice plantation of donor organs. plies to the management of donors and develop organization-specific al- after brain death, unless otherwise gorithms to manage potential organ Determination of death specified. donors. Currently, no document exists After a deceased person is identi- that describes the unique pathophysi- fied as a potential organ donor, an Blood pressure management ology of the donor, how this patho- OPO is typically contacted by the pri- and fluid resuscitation physiology affects medication use, or mary team to determine the suitability Donors may experience hemo- the details of drug therapy manage- of organ donation.3 Donors undergo dynamic instability as a result of ment in this patient population. standardized treatment algorithms to hormonal, neurohormonal, and pro- Hospital pharmacists are responsi- maintain organ perfusion. The basic inflammatory responses after brain ble for processing orders and prepar- goal is to maintain the hemodynamic death.6 Brain death occurs in two ing the medications outlined in donor stability and function of transplant- phases: progressive ischemia and management algorithms developed able organs.5 Organ donors undergo brainstem death. After a neurologic by their respective medical systems. It an evaluation by an OPO in which the insult, intracranial pressure elevates, is important that pharmacists under- criteria for death will be assessed. Do- leading to high mean arterial pressure stand the medications used in these nors are evaluated based on neurolog- and subsequent cerebral edema and

1830 AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 MANAGEMENT OF ORGAN DONORS CLINICAL REVIEW ischemia. Ischemia within the pons antihypertensives, preservation of left should be replenished before initiat- results in a phenomenon known as ventricular function and increased ing vasopressor therapy in an attempt the Cushing reflex. Cushing reflex is viability of cardiac grafts have been to correct hypovolemia. The donor’s a result of sympathetic stimulation found when compared with no treat- fluid status should be assessed to de- leading to hypertension, bradycardia, ment of autonomic storm hyperten- termine the need for fluid resuscita- and irregular breathing. Once ische- sion.10 The preferred antihyperten- tion or maintenance. Volume deficits mia reaches the medulla, sympathetic sive agent has not been established. should be corrected with fluid bo- stimulation and autonomic storm oc- Agents used include nicardipine, a luses of 1–2 L of isotonic 0.9% sodium cur in an effort to maintain cerebral short-acting dihydropyridine calcium chloride injection administered as perfusion. Autonomic storm is char- channel blocker; and esmolol, a short rapidly as possible. Typical mainte- acterized by a significant increase in acting b-1 selective blocker. Theoreti- nance fluids include dextrose, isotonic circulatory dopamine, norepineph- cally, esmolol may be the preferred or half-isotonic 0.9% sodium chloride rine, and epinephrine and leads to agent due to its ability to attenuate injection, and electrolytes adminis- severe vasoconstriction. In addition to adrenergic stimulation.10 The use of tered at 30–50 mL/hr (Table 1).12 Se- sudden hypertension (systolic blood short-acting agents is preferred due to rum sodium, potassium, and glucose pressure of >200 mm Hg), tachycar- the short period of autonomic storm concentrations should be assessed dia (heart rate exceeding 140 beats/ during brain death.10 Dosing of esmo- when choosing the type of fluid to admin), and, potentially, arrhythmias, lol for autonomic storm is not stan- minister (Table 2).13 Sodium bicarbo- catecholamine-induced vasoconstric- dardized. Esmolol has a half-life of ap- nate (50–150 mmol/L) may be added tion will increase myocardial oxygen proximately 9 minutes and a duration to fluids in donors with metabolic aci- demand, creating a discordance of of action of 20–30 minutes. Esmolol dosis. For donors with hypernatremia, oxygen supply and demand. Suben- for hypertension is typically initiated 0.45% sodium chloride injection may docardial ischemia may occur during with a bolus dose of 100–500 mg/kg be administered. Studies addressing this phase. Catecholamines can also followed by an infusion of 150 mg/kg/ fluid choice are lacking. directly affect the myocardium, result- min, if needed.11 Hypotension should ing in myocyte injury and ventricular be avoided, and the donor should be Electrolytes dysfunction.6,9,10 closely monitored due to the unpre- Several electrolyte imbalances In the final stage of brain death, dictable duration of autonomic storm. may occur in the potential organ do- complete ischemia of the brainstem The profound vasodilation after nor, including hypernatremia and and spinal cord coincides with her- autonomic storm can be very diffi- acidosis (Table 2). Electrolyte imbal- niation and leads to total loss of sym- cult to manage. Hemodynamic goals ances may be due to the hyperglyce- pathetic tone, cardiac stimulation, for the potential donor include main- mic state occurring after brain death.3 and circulating catecholamines. This taining a mean arterial pressure of Hyperglycemia alters osmolality lead- phase is characterized by profound >60 mm Hg, central venous pressure ing to shifts in electrolytes. According vasodilation leading to hypotension of 6–10 mm Hg, urine output of 1–3 to the OPTN policies, electrolytes and hemodynamic instability as well mL/kg/hr, and cardiac index of >2.4 should be included in metabolic test- as cardiac conduction abnormalities L/min to avoid end-organ damage ing when evaluating organ donors. and arrhythmias. Additional factors and ischemia.3 Intravascular volume Imbalances have been connected to that may affect hemodynamic stability in a donor include diabetes insipidus attributable to ischemia progress- ing to the pituitary, sepsis resulting in Table 1. Typical Maintenance Fluids for Organ Donors After Brain Death12 inflammation and capillary leakage, Intravascular metabolic acidosis, and pulmonary Infused Volume edema.6,9 Osmolarity, Volume, Expansion, Hemodynamic instability may lead Maintenance Fluid mOsm/L mL mL to reduced oxygen supply and ischemia Crystalloids in the donated organ. Proper manage- 0.9% Sodium chloride injection 287 1000 250 ment of donor hemodynamics is cru- 5% Dextrose injection 278 1000 100 cial to avoid dysfunction of the organs Colloids planned for donation.5 Short-acting i.v. antihypertensives have been used Albumin 5% ~280 500 500 to control hypertension during auto- Albumin 25% ~280 100 500 nomic storm. By controlling hyper- Hetastarch 6% 310 500 500 tension during autonomic storm with

AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 1831 CLINICAL REVIEW MANAGEMENT OF ORGAN DONORS

Table 2. Electrolyte Goals for Organ Donors After Brain Death6,9,13 Serum Concentration Goal Before Replacement Maximum Rate of Electrolyte Concentration Therapy Dose to Administer Administration Sodium 135–150 meq/dL Serum osmolality and . . .a . . .a volume status should be assessed before initiating replacement therapy Potassiumb 4–6 meq/L 2.5–3.4 meq/L 20–40 meq i.v. 40 meq/hr <2.5 meq/L 40–80 meq i.v. Magnesiumb 1.7–2.3 mg/dL 1–1.5 mg/dL Magnesium sulfate Magnesium sulfate 1 1–4 g g/hr <1 mg/dL Magnesium sulfate 4–8 g Calcium (ionized) >1.1 mmol/L <0.9 mmol/L Calcium gluconate 3 g May be given over 10 or calcium chloride min if symptomatic 1 g (tetany, CNS and cardiovascular symptoms) Phosphorusb,c 3–4.5 mg/dL 2.3–2.7 mg/dL 0.08–0.16 mmol/kg Phosphate 7 mmol/hr 1.5–2.2 mg/dL 0.16–0.32 mmol/kg <1.5 mg/dL 0.32–0.64 mmol/kg aManagement of sodium disorders is complex and beyond the scope of this article. CNS = central nervous system. bPatients with renal insufficiency should receive 50% of the normal dose. cReplacement dose based on phosphate component. May be given as sodium phosphate or potassium phosphate.

poor outcomes, such as graft loss after the amount of elemental calcium The use of PRBCs also increases sys- liver transplantation in patients with when compared with calcium gluco- temic vascular resistance.2,3 hypernatremia.3 nate. Regardless, calcium should be Hydroxyethyl starch produces vol- These imbalances should be man- replaced when serum calcium con- ume expansion by increasing the on- aged through electrolyte replacement centrations drop below 0.9 mmol/L cotic pressure within the intravascular and fluid management. Electrolyte with either 3 g of calcium gluconate or space. Published literature guiding goals are included in Table 2. Potas- 1 g of calcium chloride. Finally, phos- fluid resuscitation in organ donors sium should be replaced intrave- phorus may be replaced with products studied 16 brain-dead multiorgan nously at a dose of 20–40 meq when containing either sodium phosphate donors randomized to receive a com- the serum concentration is 2.5–3.4 or potassium phosphate. The provider bination of hydroxyethyl starch and meq/L. Higher doses (40–80 meq) should assess the electrolyte status of electrolyte solution or crystalloid fluid should be used when the serum con- the donor when choosing a product. therapy alone.15 Hemodynamic val- centration is less than 2.5 meq/L. Replacement is weight based depend- ues were maintained in each group. A Potassium should be administered ing on the current serum phosphorus smaller infused volume was necessary no faster than 40 meq/hr. Similarly, level and can be referenced in Table 2. in the group receiving hydroxyethyl magnesium, calcium, and phospho- starch plus electrolyte solution; how- rus are also replaced based on serum Colloids, blood products, and ever, hydroxyethyl starch increases concentrations. For example, serum vasopressors the risk of acute kidney injury and the magnesium concentrations of <1 mg/ Colloids such as 5% albumin (12.5– need for renal replacement therapy. dL should be replaced with 4–8 g mag- 25 g given as needed) and packed red This risk may translate to an increased nesium sulfate, while serum concen- blood cells (PRBCs) serve an additional risk of impairment in recipient renal trations of 1–1.5 mg/dL only require purpose when used for hemodynamic function when the donor receives hy- 1–4 g of magnesium sulfate. The rate stabilization. If the donor is requir- droxyethyl starch.12,16 of administration should be limited ing large amounts of crystalloids, col- Once adequate fluid resuscitation to 1 g/hr. Two different products may loids may be used to avoid fluid over- has occurred, vasoactive drugs may be be used for calcium replacement: cal- load and tissue edema.2,14 In addition, initiated for persistent hypotension. cium gluconate and calcium chloride. PRBCs can be used to correct anemia Pharmacologic properties should be The dosing differs for these agents, as to a goal hematocrit value above 30% taken into consideration before ini- calcium chloride contains three times to maintain adequate oxygen delivery. tiating therapy, as there is no current

1832 AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 MANAGEMENT OF ORGAN DONORS CLINICAL REVIEW

Table 3. Vasopressors for Use in Organ Donors After Brain Death9,12 Agent Starting Dose Target Receptors Monitoring Required Place in Therapy Dopamine 3–10 mg/kg/min 3–5 mg/kg/min: Heart rate, blood pressure, Typically first line dopamine electrocardiogram, renal

5–10 mg/kg/min: b1 function 10–20 mg/kg/min: a1

Epinephrine 0.05–0.5 mg/kg/ b1, b2, a1 Heart rate, blood pressure Second line min

Norepinephrine 0.1–2 mg/kg/ b1, a1 Heart rate, blood pressure Second line min

Phenylephrine 0.1–1 mg/kg/ a1 Heart rate, blood pressure Avoid as sole agent due min to potent a-adrenergic effects

Isoproterenol 2–10 mg/min b1, b2 Heart rate, blood pressure, May be used for electrocardiogram, bradyarrhythmia due to respiratory rate, serum vagus nerve disruption glucose, potassium, in brainstem (typically magnesium not responsive to atropine)

Vasopressin 0.03 units/min V1 Heart rate, blood pressure, First line; may allow for serum and urine dose de-escalation of sodium, fluid input and other vasopressors output

consensus on the ideal combination be an ideal agent to use in donors with tion and the use of vasopressors do of vasopressors for this population uncorrected tachyarrhythmias. not achieve adequate hemodynamic (Table 3).3 Dopamine is typically the Vasopressin is used as an alterna- stability, the use of hormone replace- vasopressor selected to manage organ tive to dopamine for first-line therapy ment is often considered. Data sup- donors with hemodynamic instability.3 for managing hemodynamic instabili- port the theory that in brain death, Dopamine exerts its ability to protect ty because it augments catecholamine malfunction of the hypothalamic– endothelial cells via induction of pro- stimulation, triggers peripheral vaso- pituitary–adrenal axis results in low tective enzymes, which is thought to constriction, and treats diabetes in- levels of cortisol and thyroid hor- lead to beneficial outcomes in organ sipidus.3,6 Its role in diabetes insipidus mones, which can contribute to hy- recipients.17,18 One randomized con- and hemodynamic stability has been potension and subsequent organ trolled trial studied the use of dopa- reviewed extensively in hormonal deterioration. The administration of mine as pretreatment versus placebo therapy. exogenous hormones has been found in 300 brain-dead donors to identify Norepinephrine has also been to increase hemodynamic stability, the impact of pretreatment on early used as an option for blood pressure decrease requirements for vasoactive graft function after renal transplan- support in donor management. Data therapy, and increase the total num- tation.17 Dopamine was initiated at 4 are conflicting regarding the impact ber of organs transplanted.3 mg/kg/min and continued through on recipient survival after norepi- Currently, exogenous hormone cross-clamp of the aorta during pro- nephrine use in donors.19,20 In heart therapy can include the adminis- curement. The investigators found transplant recipients, a retrospective tration of four separate hormones: pretreatment with dopamine reduced study found no difference in recipient thyroid hormone (triiodothyronine the need for dialysis after kidney trans- survival during follow-up when do- or thyroxine), corticosteroids, antidi- plantation. If hemodynamic support is nors were pretreated with either nor- uretic hormone (vasopressin or des- needed beyond dopamine 10 mg/kg/ epinephrine or dopamine. However, mopressin), and insulin. These can min, another vasoactive drug should a subgroup analysis of patients who be given alone or in combination be added, preferably one that does not were followed for five years revealed with each other, though the optimal exert primary a-adrenergic vasocon- that norepinephrine pretreatment im- regimen of these hormones remains strictor effects.6 Excessive a-adrenergic proved long-term survival.19 unknown.21 stimulation may lead to pulmonary Decreased circulating levels of thy- edema by increasing pulmonary capil- Hormone replacement therapy roid hormones have been observed in lary permeability.6 Dopamine may not When aggressive volume reple- donors after brain death. Low levels of

AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 1833 CLINICAL REVIEW MANAGEMENT OF ORGAN DONORS triiodothyronine and thyroxine may led to a mean of 3.31 organs per donor, Desmopressin, a synthetic vaso- contribute to hemodynamic instabil- while no therapy led to 2.87 organs per pressin analog, has a longer duration ity in these donors by causing a de- donor. Overall, therapy with triiodo- of action and a decreased vasocon- crease in available adenosine triphos- thyronine/thyroxine was associated strictor effect compared with vaso- phate, reduced myocardial energy with the procurement of significantly pressin. Desmopressin can be given stores, and a transition from aerobic more hearts, lungs, kidneys, pancre- at a rate of 0.5–2.0 mg/hr every two to anaerobic metabolism.22 In order ases, and intestines, but no significant to three hours adjusted to achieve a to avoid these negative effects, UNOS difference in the number of livers pro- urine output goal of 1–3 mL/kg/hr. recommends the use of triiodothyro- cured was found. In addition, donor Guesde and colleagues32 assessed the nine in the management of cardio- therapy with triiodothyronine/thy- effects of desmopressin in brain-dead thoracic donors.23 Triiodothyronine roxine was associated with improved donors on both early and long-term has a shorter half-life than thyroxine posttransplantation graft survival graft function in kidney transplant re- and is more potent and thus preferred or no difference in survival, except cipients. Patients were randomized to for donor management.24 Liothyro- for pancreas recipient survival at 12 receive either desmopressin as a 1-mg nine sodium (the sodium salt of the months in one study group.26 However, i.v. bolus injection every two hours l-isomer of 3,3´′,5-triiodothyronine despite the positive outcomes of some when urine output exceeded 300 mL/ [(l-triiodothyronine]) can be admin- studies, additional studies have found hr or no desmopressin. Kidney trans- istered intravenously as a 4-mg (of lio- mixed results, and a beneficial effect plant recipients were assessed during thyronine) bolus injection, followed on hemodynamic status has not been the first two weeks after transplanta- by a 3-mg/hr continuous infusion.12 proven.27-30 Randomized, prospective tion, as well as long-term. The admin- The use of i.v. levothyroxine (sodi- trials are needed to determine the in- istration of desmopressin decreased um salt of the l-isomer of thyroxine fluence of triiodothyronine/thyroxine diuresis in donors and did not appear [thyroxine]) may also be effective, therapy in donor management. to influence serum creatinine concen- as it is converted into active triiodo- The dysfunction of the hypotha- tration, the need for dialysis during the thyronine in the body. However, this lamic–pituitary–adrenal axis also leads first two weeks after transplantation, conversion process may occur with- to depletion of antidiuretic hormone or long-term survival of renal trans- in several hours of administration, and can cause central diabetes insipi- plant recipients. Both vasopressin and which could delay the cardiac ef- dus in up to 90% of brain-dead donors. desmopressin are known to control fects.25 Levothyroxine sodium can be Dehydration, hemodynamic instabil- diuresis and decrease inotropic re- administered as a 20-mg bolus injec- ity, and hypernatremia have been de- quirements.32-34 Retrospective database tion followed by a continuous infu- scribed in untreated donors. Vasopres- reviews have found that desmopressin sion of 10 mg/hr. This can be adjusted sin, an exogenous form of antidiuretic and vasopressin can improve the num- to maintain a systolic blood pressure hormone, is used to prevent or control ber and quality of organs recovered of >100 mm Hg. Adverse effects in- polyuria, polydipsia, and dehydration from brain-dead donors.35-38 clude tachycardia, tremors, fever, and in donors with central diabetes insipi- After the diagnosis of brain arrhythmias. dus. The use of vasopressin to replete death, corticosteroids are adminis- A retrospective review of 63,593 levels of circulating antidiuretic hor- tered to moderate the inflammatory brain-dead donors evaluated the use mone has been shown to improve the response by inhibiting the release of of triiodothyronine/thyroxine admin- probability of organ transplantation in proinflammatory cytokines and stabi- istration and posttransplantation kidney, heart, liver, lung, and pancreas lizing cell membranes. The use of cor- organ graft survival in the recipients donors.25 It may also help contribute ticosteroids in organ donors has been at 1 and 12 months. In study 1, full to improved hemodynamic stability associated with a decrease in early documentation of triiodothyronine/ and enhance the donor’s response to graft failure and rejection episodes thyroxine administration was avail- catecholamines.31 In donors with dia- in transplant recipients.23,39,40 Meth- able, but information regarding cor- betes insipidus who are at high risk of ylprednisolone may help to decrease ticosteroids, antidiuretic hormone, developing hypovolemia or continue pulmonary edema and stabilize lung and insulin were not fully recorded. In to be hypotensive despite crystalloid function.41 However, the influence on study 2, full documentation of the ad- repletion, vasopressin can be initi- recipient allograft outcomes remains ministration of all four hormones was ated with a bolus of 1 unit followed by controversial. One prospective study available. In study 1, triiodothyronine/ a continuous infusion of 0.5–4 units/ randomized 100 donors to receive thyroxine therapy led to a mean hr. Because of its potent effects on methylprednisolone or control.42 Re- of 3.35 organs donated per donor, vasoconstriction, vasopressin can de- cipients of liver transplants from do- while no therapy led to a mean of crease renal blood flow, which may nors who received corticosteroids had 2.97 organs per donor. In study 2, lead to ischemic injury of the donor a decreased rate of acute rejection triiodothyronine/thyroxine therapy kidneys.32 within the first six months after trans-

1834 AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 MANAGEMENT OF ORGAN DONORS CLINICAL REVIEW plantation compared with the control hyperglycemia can damage the pan- salvage the organ and support better group. creatic b cells, which may lead to graft outcomes for the organ recipient. In- In a prospective multicenter clus- dysfunction in the pancreas transplant fected donors should ideally receive ter study (n = 259), brain-dead donors recipient.4 Intravenous insulin infu- antimicrobial therapy for at least received either low-dose hydrocor- sions administered at a minimum rate 24–48 hours. Optimally, a clinical re- tisone or no corticosteroids (control of 1 unit/hr adjusted to achieve goal sponse to therapy (improved white group).43 Norepinephrine weaning blood glucose levels of 120–180 mg/dL blood cell count and improved hemo- was improved in donors treated with may be used, especially in pancreas dynamics) should also be demonstrat- low-dose hydrocortisone, but no sig- donors, to help minimize this risk.2 In ed before procurement. nificant difference in primary function one study, prospective data were col- Antimicrobial selection should be recovery of transplanted allografts lected for organ donors after neuro- guided by multiple factors, including was found between groups. Similar logic determination of death from active infectious diagnosis, length of results were seen in a trial of 50 do- UNOS (Region 5 from 2010 to 2012, stay, and risk factors for multidrug- nors who either received pretreatment n = 1611).46 Hyperglycemia was asso- resistant organisms (e.g., chronic dialy- with methylprednisolone or no pre- ciated with lower organ transplanta- sis, previous use of antibiotics, previous treatment before organ harvesting.44 tion rates and worse graft outcomes. hospitalization).48 Donors with these Three-month kidney allograft survival Targeting a glucose concentration of risk factors should receive treatment times were similar between groups. ≤180 mg/dL seems to preserve out- with a broad-spectrum antimicrobial Dhar et al.45 conducted a study of comes and is consistent with general such as piperacillin–tazobactam, van- 132 consecutive brain-dead donors critical care guidelines. comycin, cefepime, or meropenem. managed with either a high-dose The use of concomitant hormone However, organ donors may not re- (methylprednisolone 15 mg/kg) or therapies has also been studied in ceive antimicrobials until the time a low-dose (300 mg hydrocortisone) organ donors after brain death. A of transplantation if no active in- corticosteroid regimen. The oxygen- retrospective, multivariate analysis fectious diagnosis is present at the ation rate of transplanted organs was of brain-dead donors (n = 10,292) time of death. Donors may receive similar in both groups, though insulin revealed that hormone replacement prophylactic therapy such as cefa- requirements and glycemic control (methylprednisolone i.v. bolus injec- zolin at the time of transplantation, were improved in the hydrocortisone tion and infusions of vasopressin and according to ASHP’s “Clinical Prac- group. The authors concluded that the either triiodothyronine or thyroxine) tice Guidelines for Antimicrobial low-dose corticosteroid regimen did was associated with a significantly in- Prophylaxis in Surgery.”47 A detailed not result in worsened donor pulmo- creased probability of an organ being discussion of blood-borne infectious nary or cardiac function when compa- transplanted from a donor.30 disease and prophylaxis is outside rable organs were transplanted in the the scope of this article. Readers group receiving methylprednisolone Antiinfectives should refer to their local OPO for 15 mg/kg. According to both the Soci- The presence of an active infec- more information. ety of Critical Care Medicine (SCCM) tion can be detrimental to the organ consensus statement and the UNOS recipient, and all organ donors should Heparin recommendations for cardiothoracic be screened for infectious processes.47 One of the major factors affect- donors, methylprednisolone 15 mg/ Per OPTN policy, blood and urine cul- ing the survival of a donated organ is kg i.v. can be used to reduce the in- tures should be collected on all poten- blood circulation to the organ after flammatory cascade that occurs after tial organ donors, and donors should reperfusion. Thrombosis is a concern brain death.2,6 The SCCM consensus be screened for multiple infectious once circulation is temporarily lost statement also gives equal weight to risks including but not limited to hu- during the organ procurement proc- methylprednisolone 1000 mg i.v. or a man immunodeficiency virus, hepa- ess.49 Common practice includes ad- 250-mg bolus injection followed by an titis, cytomegalovirus, Epstein-Barr ministering heparin i.v. before aortic i.v. infusion at a rate of 100 mg/hr. No virus, and syphilis.2 Depending on the cross-clamping to avoid thrombotic recommendation was made regarding donated organ, additional tests may complications.49,50 the dosing of hydrocortisone in either be required such as a sputum Gram’s Heparin acts as a potent antico- guidance document.2,6 stain for potential lung donors. agulant by inactivating thrombin and Hyperglycemia is a common find- Typically, donor organs are not activated factor X.51 While no stan- ing in brain-dead donors due to the used in the presence of gram-negative dard dosing regimen currently exists, physical stress of their injury, infu- bacteremia or an invasive fungal infec- a heparin dose of 30,000–40,000 units sion of dextrose-containing solutions, tion.47 However, antimicrobials may i.v. administered after the declara- changes in carbohydrate metabolism, be used in the donor and the recipient tion of brain death has been widely and peripheral insulin resistance. This to manage such infections in order to accepted.50

AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 1835 CLINICAL REVIEW MANAGEMENT OF ORGAN DONORS

Evidence regarding the use of argatroban 200 mg over 15 minutes eral motor nerves are electrically stim- thromboprophylaxis in organ donors before aortic cross-clamping. Organs ulated with four sequential stimuli is limited; however, the percentage were donated to seven recipients, and over a two-second period. Providers of pulmonary emboli found during no thrombotic events or complica- adjust the dose of the paralytic agent organ procurement is high, possibly tions related to HIT were reported in in response to the muscle innervated due to the mechanism of donor in- organ recipients after transplantation. by the stimulated nerve. The number jury.49 Thus, it is reasonable to con- of muscle twitches, which can range tinue thromboprophylaxis to pre- Paralytics from zero to four, is recorded. If the vent the occurrence of pulmonary Donors determined to be brain- donor responds with four twitches, emboli. In some cases, donors may dead are considered to have an irre- the paralytic dose may be increased. have heparin-induced thrombocyto- versible loss of brain function. While Alternatively, zero twitches may indi- penia (HIT), which precludes the use this occurs, it is possible for the donor cate the need to decrease the dose. An of heparin for thromboprophylaxis. to continue to exhibit reflex move- acceptable TOF goal in organ donors If heparin were administered to an ments due to the continued function is one or two twitches.54 organ donor at the time of organ re- of spinal reflexes.53 Examples of re- No specific neuromuscular block- covery, an acute thrombotic reaction flex movements include periodic leg er has been identified as the preferred could occur. While data assessing this movement, raising of upper extremi- agent for use in organ donors after issue in the organ donor population ties, and triple flexion. brain death; however, the donor’s are limited, it is clear that thrombosis It is important that the donor not renal, hepatic, and cardiovascular in the donated organ can result in po- receive paralytic agents or sedatives statuses should be considered when tential early allograft dysfunction. before the determination of brain selecting an agent (Table 4). Nondepo- Argatroban (a direct thrombin in- death in order to ensure an accurate larizing neuromuscular blockers act hibitor) may be used for prophylaxis neurologic assessment. However, once by antagonizing the action of acetyl- and treatment of thrombosis in do- the diagnosis is confirmed, represen- choline at the postsynaptic nicotinic nors diagnosed with HIT. Bleeding is tatives from OPOs may request the use receptor.55 In contrast to depolarizing a complication of argatroban use, but of paralytic agents to manage move- neuromuscular blockers, such as suc- the benefit of thrombosis prevention ments due to spinal reflexes. When cinylcholine, nondepolarizing agents is thought to outweigh this risk. Two monitoring the use of these agents do not cause a change in the receptor case studies have described the use of in neuromuscular blockade, provid- but a gradual reduction in end-plate argatroban in multiorgan donors (livers may use the train-of-four (TOF) potential.56 er, kidneys, and heart) after a confir- method to determine the degree of Rocuronium, vecuronium, and mation of HIT.52 The donors received paralysis. With this method, periph- pancuronium may be preferred in

Table 4. Comparison of Neuromuscular Blockers Used in Organ Donors After Brain Death55,56 Variable Pancuronium Vecuronium Rocuronium Atracurium Cisatracurium Loading dosea 0.08 mg/kg 0.1 mg/kg 0.6 mg/kgb 0.4 mg/kg 0.1 mg/kg Maintenance dose 0.02–0.04 mg/ 0.02–0.04 mg/ 0.01–0.012 mg/ 0.4 mg/kg/hr 2–10 mg/kg/min kg/hr kg/hr kg/min Prolonged elimination in renal failure Yes Yes Yes No No Onset of action 2–3 min 3–5 min 1–2 min 2–3 min 2–3 min Half-life 110 min 65–75 min 66–144 min 20 min 22–29 min Prolonged elimination in hepatic failure Yes Yes Yes No No Adverse reactions Tachycardia, Bradycardia, Tachycardia, Histamine Bradycardia, hypotension flushing hypertension release, hypotension flushing aBased on actual body weight unless otherwise noted. bMay use ideal body weight if patient is morbidly obese.

1836 AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 MANAGEMENT OF ORGAN DONORS CLINICAL REVIEW donors with normal renal and he- Preservation solutions can be cate- pharmacotherapy for each potential patic functions who are not receiv- gorized as intracellular or extracellular organ donor to ensure organ recovery ing corticosteroids. Corticosteroids solutions based on their overall sodium and donation. Typical medications may be used after the diagnosis of and potassium concentrations. Intra- used in organ donors include agents brain death to moderate the inflam- cellular solutions have high concen- for blood pressure management and matory response. Adverse cardiovas- trations of potassium and low concen- fluid resuscitation, medications nec- cular effects, such as hypotension, as- trations of sodium in order to mimic essary for electrolyte management, sociated with neuromuscular blockers the cellular milieu and minimize con- blood products, vasopressors, hor- are related to stimulation or blockade centration gradients across cellular mone replacement therapy, antiinfec- of the autonomic nervous system and membranes that could favor the efflux tives, anticoagulants, paralytics, and vasodilation due to histamine release. of potassium from the donor organ organ preservation solutions. Anaphylaxis is extremely rare. Pan- cells. These solutions include the curonium may be the drug of choice Euro Collins solution and the Univer- Disclosures in donors with normal renal and he- sity of Wisconsin solution. However, The authors have declared no potential patic functions due to the low cost of concerns have been raised that high- conflicts of interest. the drug. However, the possibility of potassium concentrations may lead References hypotension due to pancuronium- to vasoconstriction within the do- 1. Organ Procurement and Transplanta- induced histamine release should be nor organ, particularly in the pulmo- tion Network. Data. https://optm. considered when choosing an agent. nary vasculature. These concerns led transplant.hrsa.gov/data (accessed In donors with renal or hepatic in- to the development of extracellular 2016 Aug 15). sufficiency, atracurium or cisatracu- (low-potassium concentration) solu- 2. United Network for Organ Sharing. rium may be preferred because of the tions such as histidine–tryptophan– Critical pathway for the organ donor. www.unos.org/docs/Critical_Path- drugs’ spontaneous degradation via ketoglutarate and Celsior flushing and way.pdf (accessed 2015 Jan 1). Hofmann elimination.55 cold storage solution (Sanofi, Bridge- 3. Wood K, Becker B, McCartney J et al. water, NJ). To date, no consensus has Care of the potential organ donor. Organ preservation solutions been reached regarding the equiva- N Engl J Med. 2004; 351:2730-9. Graft preservation remains one of lence of intracellular and extracellular 4. Organ Procurement and Transplanta- tion Network. Policies. https://optn. 57 the most important aspects of trans- preservation solutions. transplant.hrsa.gov/governance/poli- plantation, as it determines graft sur- Although a full review of preser- cies (accessed 2016 Aug 15). vival and overall patient outcomes. vation solutions is outside the scope 5. Boyd G, Phillips M, Henry M. Hypothermia is commonly used to of this article, recent articles have re- Cadaver donor management. In: decrease organ metabolic activity and viewed these solutions in-depth.57-59 Phillips MG, ed. Organ procurement, preservation and distribution in cellular degradation during the ex vivo Discussion transplantation, 2nd ed. Richmond, period; however, it may not prevent all VA: United Network for Organ Shar- cellular damage that can occur. Pres- The care given to one organ do- ing; 1996. ervation solutions have been devel- nor is tantamount to the care of sev- 6. Kotloff R, Blosser S, Fulda G et al. oped to be used in conjunction with eral transplant recipients. Aggressive Management of the potential organ donor in the ICU: Society of Critical hypothermia for additional cellular donor management ensures that the Care Medicine/American College protection. largest number of organs can be suc- of Chest Physicians/Association of These solutions are commonly cessfully procured and improves the Organ Procurement Organizations formulated with three general com- organs’ overall quality. Together, the consensus statement. Crit Care Med. ponents: colloids, buffers, and anti- interventions outlined in this article 2015; 43:1291-325. 7. Wijdicks EF, Varelas PN, Gronseth oxidants. Colloids are used to combat contribute to the stability of the donor, GS et al. Evidence-based guideline tissue edema by promoting water as well as the eventual outcomes for or- update: determining brain death in retention in the extravascular space, gan transplant recipients. By fostering adults: report of the quality standards rather than moving into the graft cells a greater understanding of these medi- subcommittee of the American Acad- and creating cellular edema. Buf- cations and the literature surrounding emy of Neurology. Neurology. 2010; 75:77-83. fers combat the negative effects of their use, pharmacists in a wide variety 8. Reich DJ, Mulligan DC, Abt PL et al. acidosis as the organ transitions from of hospital settings will be better pre- ASTS recommended practice guide- aerobic to anaerobic metabolism at- pared to provide for these donors and lines for controlled donation after tributable to ischemia. Antioxidants ultimately contribute to the donor’s cardiac death organ procurement are used to counteract the effects of ability to provide their final gift. and transplantation. Am J Transplant. 2009; 9:2001-11. reactive oxygen species created dur- Conclusion 9. Ullah S, Zabala L, Watkins B et al. ing ischemia, which can cause tissue Cardiac organ donor management. damage.57 It is essential to provide optimal Perfusion. 2006; 21:93-8.

AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 1837 CLINICAL REVIEW MANAGEMENT OF ORGAN DONORS

10. Audibert G, Charpentier C, Seguin- 23. Ranasinghe AM, Bonser RS. Endo- increases the rate of successful organ Devaux C et al. Improvement of crine changes in brain death and procurement in potential donors. Am donor myocardial function after transplantation. Best Pract Res Clin J Surg. 2012; 204:856-61. treatment of autonomic storm during Endocrinol Metab. 2011; 25:799-812. 36. Callahan D, Neville A, Bricker S et al. brain death. Transplantation. 2006; 24. Zaroff JG, Rosengard BR, Armstrong The effect of arginine vasopressin on 82:1031-6. WF et al. Consensus conference organ donor procurement and lung 11. Brevibloc (esmolol hydrochloride) report: maximizing use of organs function. J Surg Res. 2014; 186:452-7. intravenous injection prescribing recovered from the cadaver donor: 37. Bloom MB, Raza S, Bhakta A et al. information. Deerfield, IL: Baxter cardiac recommendations, March 28- Impact of deceased organ donor Healthcare Corporation; 2012. 29, 2001, Crystal City, Va. Circulation. demographics and critical care end 12. Randell T, Orko R, Hockerstedt K. 2002; 13:836-41. points on liver transplantation and Perioperative fluid management of 25. Rosendale JD, Kauffman HM, graft survival rates. J Am Coll Surg. the brain-dead multiorgan donor. McBride MA et al. Aggressive 2015; 220:38-47. Acta Anaesthesiol Scand. 1990; 34:592. pharmacologic donor management 38. Nozary Heshmati B, Ahmadi F, Azimi 13. Mutter TC, Ruth CA, Dart AB. Hy- results in more transplanted organs. P et al. Hemodynamic factors af- droxyethyl starch (HES) versus other Transplantation. 2003; 75:482-7. fecting the suitability of the donated fluid therapies: effects on kidney 26. Novitzky D, Mi Z, Sun Q et al. Thyroid heart and kidney for transplantation. function. Cochrane Database Syst Rev. hormone therapy in the management Int J Organ Transplant Med. 2013; 2013; 23:CD007594. of 63,593 brain-dead organ donors: a 4:150-4. 14. Cittanova ML, Leblanc I, Legendre C retrospective analysis. Transplanta- 39. Kuecuek O, Mantouvalou L, Klemz R et al. Effect of hydroxyethyl starch in tion. 2014; 98:1119-27. et al. Significant reduction of proin- brain-dead kidney donors on renal 27. Goarin JP, Cohen S, Riou B et al. The flammatory cytokines by treatment function in kidney-transplant recipi- effects of triiodothyronine on hemo- of the brain-dead donor. Transplant ents. Lancet. 1996; 348:1620. dynamic status and cardiac function Proc. 2005; 37:387-8. 15. Hamilton L. Fluids, electrolytes, and in potential heart donors. Anesth 40. McBride MA, Peters TG, Henderson nutrition. In: ACCP 2015 pharmaco- Analg. 1996; 83:41-7. JM et al. Expanded donor study. In: therapy preparatory review course. 28. Perez-Blanco A, Caturla-Such J, UNOS report to the Health Resources Lenexa, KS: American College of Canovas-Robles J et al. Efficiency of & Services Administration. Rich- Clinical Pharmacy; 2015:3-49. triiodothyronine treatment on organ mond, VA: United Network for Organ 16. Schnuelle P, Gottmann U, Hoeger S donor hemodynamic management Sharing; 1997. et al. Effects of donor pretreatment and adenine nucleotide concen- 41. Venkateswaran RV, Patchell VB, with dopamine on graft function after tration. Intensive Care Med. 2005; Wilson IC et al. Early donor manage- kidney transplantation. JAMA. 2009; 31:943-8. ment increases the retrieval rate of 302:1067-75. 29. Venkateswaran RV, Steeds RP, Quinn lungs for transplantation. Ann Thorac 17. De Vries DK, Wijermars LG, Reinders DW et al. The haemodynamic effects Surg. 2008; 85:278-86. ME et al. Donor pre-treatment in of adjunctive hormone therapy in 42. Kotsch K, Ulrich F, Reutzel-Selke A clinical kidney transplantation: a potential heart donors: a prospective et al. Methylprednisolone therapy in critical appraisal. Clin Transplant. randomized double-blind factorially deceased donors reduces inflamma- 2013; 27:799-808. designed controlled trial. Eur Heart J. tion in the donor liver and improves 18. Von Ziegler F, Helbig S, Kreissl N et 2009; 30:1771-80. outcome after liver transplantation: al. Norepinephrine versus dopa- 30. Macdonald PS, Aneman A, Bhonagiri a prospective randomized controlled mine pretreatment of potential D et al. A systematic review and meta- trial. Ann Surg. 2008; 248:1042-50. heart donors—impact on long-term analysis of clinical trials of thyroid 43. Pinsard M, Ragot S, Mertes PM et al. outcome. Ann Transplant. 2013; hormone administration to brain Interest of low-dose hydrocortisone 18:320-6. dead potential organ donors. Crit therapy during brain-dead organ 19. Stoica SC, Satchithananda DK, White Care Med. 2012; 40:1635-44. donor resuscitation: the CORTICOME PA et al. Noradrenaline use in the 31. Dare AJ, Bartlett AS, Fraser JF. Critical study. Crit Care. 2014; 18:R158. human donor and relationship with care of the potential organ donor. Curr 44. Chatterjee SN, Terasaki PI, Fine S et load-independent right ventricular Neurol Neurosci Rep. 2012; 12:456-65. al. Pretreatment of cadaver donors contractility. Transplantation. 2004; 32. Guesde R, Barrou B, Leblanc I et al. with methylprednisolone in human 78:1193-7. Administration of desmopressin in renal allografts. Surg Gynecol Obstet. 20. Kraft M, Btaiche I, Sacks G et al. brain-dead donors and renal function 1977; 145:729-32. Treatment of electrolyte disorders in in kidney recipients. Lancet. 1998; 45. Dhar R, Cotton C, Coleman J et al. adult patients in the intensive care 352:1178-81. Comparison of high- and low-dose unit. Am J Health-Syst Pharm. 2005; 33. Pennefather SH, Bullock RE, Mantle corticosteroid regimens for organ 62:1663-82. D, Dark JH. Use of low dose arginine donor management. J Crit Care. 2013; 21. Mi Z, Novitsky D, Collins JF, Cooper vasopressin to support brain-dead 28:111.e1-7. DK. The optimal hormone replace- organ donors. Transplantation. 1995; 46. Sally MB, Ewing T, Crutchfield M et ment modality selection for multiple 59:58-62. al., for United Network for Organ organ procurement from brain-dead 34. Kinoshita Y, Yahata K, Yoshioka T et Sharing (UNOS) Region 5 Donor organ donors. Clin Epidemiol. 2015; al. Long-term renal preservation after Management Goals (DMG) Work- 7:17-27. brain death maintained with vaso- group. Determining optimal thresh- 22. Salim A, Vassiliu P, Velmahos GC et al. pressin and epinephrine. Transpl Int. old for glucose control in organ do- The role of thyroid hormone admin- 1990; 3:15-8. nors after neurologic determination istration in potential organ donors. 35. Plurad D, Bricker S, Neville A et al. of death: a United Network for Organ Arch Surg. 2001; 136:1377-80. Arginine vasopressin significantly Sharing Region 5 Donor Manage-

1838 AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 MANAGEMENT OF ORGAN DONORS CLINICAL REVIEW

ment Goals Workgroup prospective analysis. J Trauma Acute Care Surg. 2014; 76:62-8. 47. American Society of Health-System Pharmacists. Clinical practice guidelines for antimicrobial prophylaxis in surgery. www.ashp.org/surgicalguide- lines (accessed 2015 Mar 1). 48. Ison MG, Grossi P; for the AST Infectious Diseases Community of Practice. Donor-derived infections in solid organ transplantation. Am J Transplant. 2013; 13(suppl 4):22-30. 49. McKeown DW, Bonser RS, Kellum JA. Management of the heartbeating brain-dead organ donor. Br J Anaesth. 2012; 108(suppl 1):i96-107. 50. Motta E. The ethics of heparin administration to the potential non- heart beating organ donor. J Prof Nurs. 2005; 21:97-102. 51. Hirsh J, Anand S, Halperin J et al. Mechanism of action and pharma- cology of unfractionated heparin. Arterioscler Thromb Vasc Biol. 2001; 21:1094-6. 52. Aloia T, Goss J. A report of outcomes after orthotopic liver transplant with allografts from heparin antibody- positive donors. Exp Clin Transplant. 2009; 1:13-7. 53. Han S, Kim G, Lee K et al. Reflex movements in patients with brain death: a prospective study in a tertiary medical center. J Korean Med Sci. 2006; 21:588-90. 54. McManus C. Neuromuscular blockers in surgery and intensive care, part 2. Am J Health-Syst Pharm. 2001; 58:2381-95. 55. Appiah-Ankam J, Hunter J. Pharma- cology of neuromuscular blockers. Continuing education in anaesthe- sia. Crit Care Pain. 2004; 4:1-7. 56. Lexicomp. Non-depolarizing neuromuscular blockers. In: Lexicomp Online [online database]. Hudson, OH: Lexi-Comp (accessed 2015 Nov 1). 57. Latchana N, Peck JR, Whitson B, Black SM. Preservation solutions for cardiac and pulmonary donor grafts: a review of the current literature. J Thorac Dis. 2014; 6:1143-9. 58. Cameron AM, Barandiaran Cornejo JF. Organ preservation review: histo- ry of organ preservation. Curr Opin Organ Transplant. 2015; 20:146-51. 59. Latchana N, Peck JR, Whitson BA et al. Preservation solutions used during abdominal transplantation: current status and outcomes. World J Transplant. 2015; 5:154-64.

AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 22 | NOVEMBER 15, 2016 1839 Copyright of American Journal of Health-System Pharmacy is the property of American Society of Health System Pharmacists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.