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
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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