ON-LINE SUPPLEMENT I: SUPPLEMENTAL TEXT

METHODS

The development of this document was the end result of a collaborative effort

initiated by the Board of Regents of the American College of Critical Care Medicine (an

official body of the SCCM) and the Transplant Network of the ACCP. Chairs of the

Task Force were appointed by the respective societies (SB and GJF for SCCM and RMK

for ACCP) and were charged with selection of task force members, who were identified

by national reputation, specific expertise, and/or active participation in SCCM or ACCP

committees relevant to the mission of the Task Force. Ultimately, a multidisciplinary,

multi-institutional committee of 44 members, incorporating expertise in critical care

medicine, organ donor management, and transplantation was assembled and approved by

the Task Force chairs. Special effort was made to ensure that all relevant subspecialty

groups were represented, including medical, surgical, pediatric, and anesthesia critical

care; neurology; medical and surgical transplantation, and healthcare organizations

involved in organ procurement and transplantation. While the intent of the task force was

to generate recommendations that are universally applicable, we recognize that the

exclusive use of physicians based in the United States may result in some variances with

international practices, particularly with respect to legal aspects of brain death

declaration, the practice of donation after cardiac death, and the organization and role of

the organ procurement organizations. Task force members collaborated over a 5-year

period in person, via teleconferences, and by email to develop the document. Members of

the task force were divided into 13 subcommittees, each focused on one of the following

general or organ-specific areas: death determination using neurological criteria, donation

after circulatory death determination, authorization (formerly known as consent) process,

general contraindications to donation, hemodynamic management, endocrine dysfunction

and hormone replacement therapy, pediatric donor management, cardiac donation, lung

donation, liver donation, kidney donation, small bowel donation, and pancreas donation.

Subcommittees were first charged with the task of performing comprehensive PubMed

searches of English-only publications related to their assigned areas. The reference lists

of key articles were also scanned to identify additional publications. Each subcommittee

was asked to generate a spread sheet classifying all articles into one of the following

categories:

a. Randomized, controlled trial without important limitations

b. Randomized, controlled trial with important limitations

c. Observational study with exceptionally strong evidence

d. Observational study of unexceptional quality

e. Case series/case report

f. Review article/editorial

It became clear from this process that the available literature was overwhelmingly

comprised of observational studies of categories d and e, representing low quality

evidence, with a notable scarcity of categories a and b. For this reason, a decision was

made by the co-chairs that the document would assume the form of a consensus statement

rather than an evidence-based (and formally graded) guideline. As defined by the ACCP,

a consensus statement is “a written document that represents the collective opinions of a

convened expert panel. The opinions expressed in the consensus statement are derived

by a systematic approach and traditional literature review where randomized trials do not

commonly exist(1).”

After reviewing the literature, subcommittees were charged with generating a

series of management-related questions that were reviewed and approved by the task

force co-chairs. For each question, subcommittees provided a summary of relevant

literature and specific recommendations. The specific recommendations were approved

by all members of the subcommittee and then assembled into a complete document. The

complete document was then sent to all subcommittee chairs for feedback and, once

approved, sent to all members of the task force for feedback and final approval. In the

process of revising the draft document, relevant articles through December 2012 were

added. The document was then vetted by reviewers chosen by SCCM, ACCP, the

American Thoracic Society, and the Association of Organ Procurement Organizations

(AOPO), who provided the Task Force chairs with detailed comments and suggested

revisions. This process took over one year to complete and resulted in a final document

that was then officially endorsed by three of the organizations: SCCM, ACCP, and

AOPO.

DEATH DETERMINATION USING NEUROLOGICAL CRITERIA

The specific neurological criteria needed to establish death have been debated

since an ad hoc committee at Harvard Medical School proposed the diagnosis of brain

death and a list of appropriate criteria in 1968(2). In spite of the controversy, these have

become the basis for most accepted definitions. The committee defined brain death as

unresponsiveness and lack of receptivity, an absence of breathing and movement, and an

absence of brainstem reflexes with a flat electroencephalogram as a confirmatory test.

These findings had to be present at repeat examination 24 hours later, in the absence of

central nervous system depressants and with a body temperature greater than 90oF

(32.2oC). A suggestion to use irreversible loss of brainstem function alone, rather than

loss of whole brain function, as the basis for brain death came out of the Conference of

Royal Colleges and Their Faculties in the United Kingdom in 1976, but this has not been

utilized in many countries, including the United States(3).

In 1981, two key events advanced the notion of death determination using

neurological criteria. First, the President’s Commission for the Study of Ethical Problems

in Medicine and Biomedical and Behavioral Research published its recommendations(4).

Second, the Uniform Determination of Death Act (UDDA) was created by the National

Conference of Commissioners on Uniform State Laws(5). The UDDA set a national

standard for death determination by neurological criteria and the more common

circulatory-respiratory criteria that could be similarly applied to all states. This model

legislation, which was enacted by all 50 states, asserts that “[an] individual who has

sustained either irreversible cessation of circulatory and respiratory functions, or

irreversible cessation of all functions of the entire brain, including the brainstem, is

dead.” The UDDA does not set a medical standard of practice but stipulates that

“determination of death must be made in accordance with accepted medical standards.”

Thus, the law does not intrude upon medical diagnostics, but rather enables a legal basis

for medical practice. Perhaps as a result, there is variation in clinical practice in how

death is determined using neurological criteria.

The general findings of the National Conference of Commissioners on Uniform

State Laws were most recently supported in a white paper by the President’s Council on

Bioethics, with the recommendation that “the current neurological standard for declaring

death, grounded in a careful diagnosis of total brain failure, is biologically and

philosophically defensible”; however, the authors did cite a minority opinion that did not

recognize “total brain failure” as a valid criterion for establishing death(6). The

President’s Council also endorsed a key element requiring “that any statutory ‘definition’

should be kept separate and distinct from provisions governing the donation of cadaveric

organs and from any legal rules on decisions to terminate life-sustaining treatment(6).”

Finally, the council endorsed the UDDA.

DONATION AFTER CIRCULATORY DETERMINATION OF DEATH (DCDD)

The majority of transplanted organs are derived from donation after neurological

determination of death (DNDD). The unmet need for donor organs has prompted the

utilization of organs from an alternative donor pool, those declared dead on the basis of

circulatory, rather than neurological, criteria(7-16). Over the last 20 years, supported by

recommendations from the Institute of Medicine, an increased number of organs have

been obtained from patients declared dead following the cessation of circulatory

function(17,18). This option has been used when a patient or the patient’s surrogate

desires to withdraw life support but would like to donate organs. Following the

withdrawal of life support and resuscitative interventions, the patient is declared dead

after permanent circulatory arrest has occurred. After cessation of circulation occurs,

there is an observation period, commonly for a period of 5 minutes but a minimum of 2

minutes before the surgical recovery of organs begins. This observation period is to

ensure that circulation will not restart on its own. This donation process had been termed

non-heart- beating organ donation, donation after cardiac death, and more recently

donation after circulatory determination of death (DCDD).

DCDD can occur in a variety of clinical scenarios, which have been classified into

five categories known as the Maastricht classification(19,20): I, dead on arrival; II,

unsuccessful resuscitation; III, awaiting cardiac arrest following withdrawal of life

support measures; IV, cardiac arrest after brain death; V, unexpected cardiac arrest in a

hospital setting. According to the OPTN, most DCDD transplants in the United States

occur following planned withdrawal of support (Maastricht III), whereas those following

unplanned (uncontrolled) DCDD are uncommon (216 of 2,136 DCDD donors)(21). The

applicability of, and outcomes following, uncontrolled DCDD continue to be evaluated.

One study of uncontrolled DCDD in kidney transplantation demonstrated similar

outcomes compared to planned withdrawal, despite longer warm ischemic times(22).

DCDD has increased the supply of organs available for transplantation and now

accounts for about 12% of deceased organ donors in the US(23,24). Kidney

transplantation has experienced the most rapid increase with the increase in DCDD

donors(16-26). Universal identification of DCDD could lead to a 20% improvement in

the organ supply from deceased donors(27). Although the volume of DCDD literature is

expanding, no large prospective randomized human DCDD trials have been reported.

HEMODYNAMIC MANAGEMENT

Hemodynamic alterations associated with brain death relate to pathophysiologic

processes occurring during ischemic rostrocaudal brainstem injury (most often due to

raised intracranial pressure [ICP] leading to cerebral herniation through the tentorium)

and subsequent effects mediated after complete loss of brainstem function. A complex

interplay of neurohumoral, hormonal, and proinflammatory phenomena contributes to the

cardiovascular response to brain death. Clinically manifested hemodynamic changes can

be observed in two distinct phases of the brain death event: progressive ischemia phase

and brainstem death completion phase.

Early in the progressive ischemia phase, impaired cerebral perfusion pressure due

to rising ICP leads to a compensatory rise in mean arterial pressure. Involvement of the

pons leads to sympathetic stimulation and a hypertensive response (Cushing reflex). This

catecholamine or autonomic storm, in conjunction with the ischemic insult to the vagal

cardiomotor nucleus in the medulla oblongata, results in unopposed massive sympathetic

stimulation and loss of baroreceptor control(28,29).

The surge in circulating catecholamine levels has been repeatedly demonstrated in

animal models and in human series where serum dopamine, norepinephrine, and

epinephrine concentrations are increased several-fold from baseline values, causing acute

severe vasoconstriction and a rise in systemic vascular resistance(30-32). Clinical

manifestations are hypertension, tachycardia (often with arrhythmias), and acute

myocardial dysfunction. A Takotsubo cardiomyopathy-like pattern may be seen due to

catecholamine toxicity. Myocyte necrosis is consequent to catecholamine-induced cyclic

adenosine monophosphate-mediated calcium flux and phosphorylation of ryanodine

receptors(33-40). Oxygen-derived free radical formation, causing cardiac myocyte

injury, may also result from catecholamines. Other implicated mechanisms include

dysregulated adrenergic receptor signaling and high-energy phosphate metabolic

activity(41,42). Similar phenomena have been observed in stress cardiomyopathies

associated with subarachnoid hemorrhage, pheochromocytoma, severe emotional stress,

and IV catecholamine infusions. Myocardial damage may be perpetuated by

catecholamine-mediated intense coronary vasoconstriction against the background of

increased oxygen demands causing subendocardial ischemia, which predominantly

occurs in the left ventricle Left and right ventricle dysfunction and failure are reported

with a resultant fall in cardiac output, rise in left atrial pressure and acute transient mitral

regurgitation(43).

The second phase is the brainstem death completion phase. Controlled models of

brain death in dogs demonstrate spinal cord ischemia coinciding with terminal

herniation(35). This leads to deactivation of the sympathetic system, causing loss of

vasomotor tone, a decrease in serum catecholamine levels, and a fall in cardiac

stimulation. The result is a state of profound vasodilation, frequently associated with

relative hypovolemia, causing a further fall in preload against the background of cardiac

dysfunction and loss of afterload.

The donor’s hemodynamic status is also influenced by coexisting factors that

affect the heart’s effectiveness. The venous volume reservoir that determines preload is

frequently diminished due to hypovolemia. In addition to venous pooling and increased

capacitance resulting from venous vasodilation, an absolute fluid volume loss is

commonly caused by other factors: diabetes insipidus from pituitary ischemia and initial

brain injury; stimulation of the inflammatory cascade due to upregulation of cytokines

(interleukin [IL]-6, IL-1β, IL-8, IL-2R, tumor necrosis factor-α) that mediate

inflammation and capillary leakage into the interstitial space(44); and hyperosmolar

therapy for managing elevated ICP. Additional abnormalities, such as acidosis, anemia,

hypothermia, hypoxia, electrolyte imbalance, relative adrenal insufficiency, and

concomitant sepsis, are frequently present and affect the hemodynamic profile(45).

PEDIATRIC DONOR MANAGEMENT ISSUES

The demand for organs and tissues for transplantation continues to increase with

a widening gap between donors and recipients(46). Despite this increasing demand, the

number of children on the national transplant waiting list (approximately 1.5%)(46) is

slowly declining. Although the composition of the pediatric waiting list changes

frequently, mortality among children on solid organ transplant wait lists remains a

significant problem with the highest rate in children younger than 1 year. In 2011, more

than 90 children died on wait lists in the U.S. and approximately 60 more were removed

from the waiting list because transplantation was no longer an option(46).

The pediatric donor pool continues to decline for many reasons. Improved

medical and surgical treatments, vaccinations that have eradicated life-threatening

diseases, safety restraints, education and awareness about child health hazards, and the

involvement of pediatric critical care specialists have all reduced morbidity and mortality

in children over the past 25 years. Missed opportunities for organ donation continue to

occur in many medical institutions nationally. Families may not be given the opportunity

or may decline the option of donation, potential organs for transplantation may be lost

due to hemodynamic instability and inappropriate donor management, and opportunities

for donation may be inappropriately denied by medical examiners in cases of abusive

trauma.

CARDIAC DONORS

Are There Any Unique Inclusion/Exclusion Criteria Regarding the Cardiac Donor?

Age: Clinical issues that led to the traditional age limit of 40 years include: 1)

incidence of undetected coronary artery disease; 2) the natural decline in cardiomyocytes

and muscle mass with age; and 3) suggestion of an enhanced rate of cellular rejection and

allograft vasculopathy(47,48,49). The relative ease with which coronary angiography can

be obtained has permitted the thorough evaluation of the coronary vasculature in patients

older than age 40 and in those with known risk factors for coronary artery disease(50).

Improvements in immunosuppressive drug regimens have led to steady gains in survival

rates across all follow-up intervals; mean duration of graft viability is 14.5 years. Most

transplant institutions now demonstrate similar survival rates among older and younger

donor hearts(51). Additionally, a study using intravascular ultrasound demonstrated that

donor coronary artery disease did not accelerate the development of recipient

vasculopathy(52). These insights and experiences have led to consideration of donors as

old as age 65, a practice supported by a single-center case series(53) and now

incorporated into guidelines published by the Clinical Practice Committee of the

American Society of Transplantation(54). However, international registry data reveal that

organs from donors older than 55 yield a 1.75 1-year odds ratio of recipient death, thus

highlighting the continued influence of age on outcomes(55).

Left ventricular hypertrophy (LVH): Initial reports evaluating the use of hearts

with LVH demonstrated a substantial incidence of graft dysfunction in the first 30 days

and consequently worse survival. Subsequent studies with larger patient populations

found equivalent survival data for patients with mild LVH (left ventricle wall thickness

<1.4 cm) compared to those without LVH(56,57). Data relating to moderate LVH are

conflicting, and the populations with severe LVH are too small to draw clear conclusions.

The degree of LVH regresses in transplanted hearts over the first few months

postoperatively(56-58). Donor hearts with LVH should be used with caution when the

recipient has an extensive history of hypertension or is receiving perioperative

mechanical circulatory supports(57).

Cardiac arrest: Cardiac arrest is not uncommon as a consequence of a severe

traumatic head injury or catastrophic intracranial events. In a study examining this issue,

the mean duration of cardiac arrest was 15 minutes and donors with an arrest were

typically younger than those without(59). The recipients of these hearts did not require

greater perioperative resource use, did not experience greater postoperative

complications, and did not exhibit different 30-day, 1-year, or 5-year survival rate.

Donor/recipient size matching: Generally a 70- to 75-kg male donor heart

suffices for all situations(60). When a female donor heart is used, an effort should be

made to reasonably match body sizes, as a woman's left ventricular weight index remains

smaller than that of a man, even accounting for age and blood pressure

differences(48,57). The traditional advice has been to avoid body mass index (BMI)

mismatches >20%(61). More recent data, however, question whether tight adherence to

this guideline is necessary, except when recipient pulmonary hypertension is

prominent(62).

Thoracic trauma: One center in Germany has described the use of hearts from

patients with “severe chest trauma,” including pneumothorax, hemothorax, bilateral rib

fractures, pulmonary contusions, and aortic hematoma, and found no substantive effect

on postoperative graft function(63). Occult injuries undetected by echocardiography and

angiography have been found at cardiac explantation, leading to subsequent cancellation

of transplantation(64,65). The literature lacks clear definition as to what degree of injury

might preclude consideration for transplantation.

KIDNEY DONORS

Are There Any Unique Inclusion/Exclusion Criteria Regarding the Kidney Donor?

Although concerns exist regarding the suitability of kidney grafts from potential

donors with the characteristics below, evidence suggests that they may, in fact, be

considered for transplantation:

Resolving acute kidney injury in otherwise healthy donors(66-69)

Donors positive for hepatitis B core antibody in the absence of surface antigen

if recipients are appropriately immunized(70)

Hepatitis C seropositive donors with no chronic kidney disease if recipient is

hepatitis C seropositive and depending on the genotypes of both donor and

recipient(71,72)

Pediatric donors weighing <20 kg. For extremely small donors (i.e., <12 kg),

en block double kidney transplantation has been the procedure of choice and

is associated with superior 1-year outcomes. Single kidney transplant from

larger donors (12-20 kg) is an acceptable alternative and, at experienced

centers, has yielded excellent results even from donors below this weight

range(73,74).

Donors with kidney stones in the absence of chronic kidney damage(75)

Donation after DCDD(76)

Patients with the following are generally not considered as potential kidney donors but

such cases should still be discussed with the OPO representative:

Untreated renal abscess and pyelonephritis

Hepatitis B surface antigen positivity

HIV-positive status

Chronic kidney disease, including significant reduction in glomerular

filtration rate and proteinuria(77)

Acute renal failure requiring renal replacement therapy(78,79)

Severe glomerulosclerosis (>30%), interstitial fibrosis, and

arteriosclerosis(80,81)

Age >70 years(82)

LIVER DONORS

Are There Any Unique Inclusion/Exclusion Criteria Regarding the Liver Donor?

Liver allografts have been successfully utilized from donors of advanced age (>70

years)(83,84), although grafts taken from these donors may not fare as well when

transplanted into recipients with hepatitis C(85). Livers from donors with hepatitis C

have been successfully transplanted. Additionally, those who underwent

cardiopulmonary resuscitation are now considered potential donors; in fact, there may

even be some benefit in this period of “ischemic preconditioning(86).” Potentially

suitable livers may come from donors on vasopressors, donors with active infections,

hypernatremic donors, morbidly obese donors, individuals with significant alcohol use,

high-risk donors (per Centers for Disease Control and Prevention), those with brain

tumors and malignancies, and after circulatory determination of death. Even prior liver

transplantation does not preclude organ donation; such re-use of liver allografts has been

conducted in several transplant centers(87,88).

Although liver donor criteria have been liberalized, a number of factors correlate

with inferior outcomes: advanced donor age,(83,89) duration of ICU stay,(90)

macrovesicular hepatic steatosis greater than 30%(91,92), hypernatremia(93), elevated

base deficit(94), hypotension, death from causes other than trauma, donation after

circulatory death, and race(95). Morbid obesity contributes to macrovesicular steatosis,

which can reduce graft function. A history of significant alcohol consumption in the

organ donor may increase the risk of transplanted organ dysfunction, but this has been

difficult to study. Livers from donors with a known history of significant alcohol use

have been used successfully for transplantation, and one small series reported similar

outcomes in a comparison of livers from donors who consumed >30 g alcohol daily for

over 10 years and livers from those without any identifiable risk factors(96). Markedly

elevated liver enzymes that continue to trend upwards likely increase the risk of a poor

outcome(90). Organs have been successfully procured from high-risk donors, so many

individual risk factors do not contraindicate organ donation(97-101). Scoring systems

have been developed to identify high-risk liver donors(95,102,103).

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