Circulation

AHA SCIENTIFIC STATEMENT

Standards for Studies of Neurological

Prognostication in Comatose Survivors of
Cardiac Arrest
A Scientific Statement From the American Heart Association
ABSTRACT: Significant improvements have been achieved in cardiac Romergryko G. Geocadin,
arrest resuscitation and postarrest resuscitation care, but mortality MD, Chair
remains high. Most of the poor outcomes and deaths of cardiac arrest Clifton W. Callaway, MD,
survivors have been attributed to widespread brain injury. This brain injury, PhD, FAHA
commonly manifested as a comatose state, is a marker of poor outcome Ericka L. Fink, MD, MS
and a major basis for unfavorable neurological prognostication. Accurate Eyal Golan, MD
prognostication is important to avoid pursuing futile treatments when David M. Greer, MD, MA,
poor outcome is inevitable but also to avoid an inappropriate withdrawal FAHA
Nerissa U. Ko, MD, MAS
of life-sustaining treatment in patients who may otherwise have a chance
Eddy Lang, MD
of achieving meaningful neurological recovery. Inaccurate neurological
Daniel J. Licht, MD
prognostication leading to withdrawal of life-sustaining treatment and Bradley S. Marino, MD,
deaths may significantly bias clinical studies, leading to failure in detecting MPP, MSCE, FAHA
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the true study outcomes. The American Heart Association Emergency Norma D. McNair, PhD,
Cardiovascular Care Science Subcommittee organized a writing group RN, FAHA
composed of adult and pediatric experts from neurology, cardiology, Mary Ann Peberdy, MD,
emergency medicine, intensive care medicine, and nursing to review FAHA
existing neurological prognostication studies, the practice of neurological Sarah M. Perman, MD,
prognostication, and withdrawal of life-sustaining treatment. The MSCE, FAHA
writing group determined that the overall quality of existing neurological Daniel B. Sims, MD, FAHA
prognostication studies is low. As a consequence, the degree of Jasmeet Soar, MA, MB,
BChir
confidence in the predictors and the subsequent outcomes is also low.
Claudio Sandroni, MD,
Therefore, the writing group suggests that neurological prognostication
Vice Chair
parameters need to be approached as index tests based on relevant On behalf of the
neurological functions that are directly related to the functional outcome American Heart
and contribute to the quality of life of cardiac arrest survivors. Suggestions Association Emergency
to improve the quality of adult and pediatric neurological prognostication Cardiovascular Care
studies are provided. Committee

Key Words:  AHA Scientific Statements

◼ cardiac arrest ◼ coma ◼ hypoxic-
ischemic encephalopathy ◼ outcome
◼ prediction ◼ prognosis

© 2019 American Heart Association, Inc.

https://www.ahajournals.org/journal/circ

Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702 August 27, 2019 e517

 Geocadin et al
S WHY IS NEUROLOGICAL
ignificant improvements have been achieved
CLINICAL STATEMENTS
in both resuscitation for cardiac arrest and
AND GUIDELINES
postresuscitation care, but mortality remains
high. According to the American Heart Association’s
“Heart Disease and Stroke Statistics—2019 Update,”1
there are ≈356 000 cases of out-of-hospital cardiac ar-
rest (OHCA) and 209 000 cases of in-hospital cardiac
arrest (IHCA) in the United States. The survival to hos-
pital discharge was 12% for OHCA and 25% for IHCA.
For OHCA, survival with good neurological outcome
is 8%.1 The vast majority of patients successfully re-
suscitated from cardiac arrest present in coma or with
an altered level of consciousness caused by the wide-
spread nature of brain injury after cardiac arrest. Al-
though most of the deaths in patients initially resusci-
tated from cardiac arrest are attributed to brain injury,
only ≈10% of these deaths meet the clinical criteria
for brain death.2,3 Instead, most deaths associated with
brain injury after cardiac arrest result from active with-
drawal of life-sustaining treatment (WLST) because a
poor neurological outcome is predicted. For this rea-
son, accurate neurological prognostication in coma-
tose cardiac arrest survivors is of utmost importance
to avoid both pursuing futile treatments in patients
destined for a poor outcome and making an inappro-
priate WLST in patients who may have a chance for
neurological recovery.
Unfortunately, the overall certainty in the evidence in
neurological prognostication studies is low. As a conse-
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quence, our degree of confidence that there is a correct
association between the predictors described in these
studies and the subsequent outcomes is also low. This
results from a series of biases that limit the internal va-
lidity of these studies. These biases have only recently
been highlighted in systematic reviews4–6 and are men-
tioned later in this document.
The overall aims of this scientific statement include
the following:
1. To examine the characteristics of neurological
prognostication studies of comatose adult and
pediatric survivors of cardiac arrest and to illus-
trate how biases affect these studies;
2. To provide quality standards and reporting
requirements for neurological prognostication
studies of comatose adult and pediatric survivors
of cardiac arrest on the basis of existing standards
for prognosis research;
3. To provide insights into the clinical elements cur-
rently used in neurological prognostication stud-
ies of comatose adult and pediatric survivors of
cardiac arrest to improve their relevance to clinical
practice; and
4. To provide suggestions to improve the scientific
quality of neurological prognostication studies
in comatose adult and pediatric survivors of
cardiac arrest.
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
PROGNOSTICATION IMPORTANT?
Determining prognosis after successful resuscitation is
a central component of post–cardiac arrest care. First,
families or surrogate decision-makers must develop
realistic expectations and make plans about ongoing
intensive care. Second, prognosis determines the ex-
tent to which resources are mobilized or withheld for
individual patients; indeed, WLST remains the most
common cause of in-hospital death for patients resus-
citated from both IHCA2 and OHCA.7 Third, prognostic
tests can potentially be used for early risk stratification
to identify the most appropriate population for clinical
trials so that the accuracy of prognostication may affect
research findings. Fourth, prognostic tests are used in
clinical intervention trials in which decisions to perform
WLST lead to death before the effect of specific inter-
ventions studied can be fully appreciated, which may
bias research findings. In infants and children, prognos-
tication is even more challenging because long-term
outcomes are measured in years, not months, and de-
pend on many nonmedical factors such as the age or
development of the child and socioeconomic factors.
Accurate neurological prognostication in children is still
crucial for all these factors and to help families prepare
for potentially significant changes in their lives.
Premature WLST based on poor prognosis can result
in death for patients who can potentially recover. This
clinical practice may present an immediate threat to pa-
tient safety.
In a clinical trial network that prospectively collect-
ed the mode of death for 4265 subjects hospitalized
after OHCA, about one-third had WLST in <72 hours
after admission because of perceived poor neurologi-
cal prognosis.8 The authors suggested that WLST for
neurological reasons within 72 hours may be associ-
ated with mortality in ≈2300 Americans each year, of
whom nearly 1500 (65%) might have had a functional
recovery if allowed to live longer. The observation of de-
layed awakening of comatose patients >72 hours after
hospital admission is increasing.3,9,10 One study included
both IHCA and OHCA, with ≈40% of the cohort expe-
riencing an IHCA. Of patients with early WLST (defined
as within 48 hours of return of spontaneous circula-
tion [ROSC]), 48% had an OHCA, and 52% had an
IHCA. The reasoning behind the establishment of WLST
is not defined from this retrospective study.11 Although
WLST is undertaken in IHCA, it is not as well described
as OHCA. In the Get With The Guidelines–Resuscita-
tion registry that focused on IHCA, WLST is a variable in
the registry, but it is optional information and has not
been consistently reported by Get With The Guidelines–
Resuscitation investigators.
Learning whether a patient will recover and, if so,
with what deficits is important to families, caregivers,
Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702
 Geocadin et al
and patients. False optimism can worsen the psycho-
logical trauma of a poor outcome. Symptoms of post-
traumatic stress or depression occur in ≥15% of family
members of patients who experience chronic critical ill-
ness,12 and these symptoms may be aggravated by poor
communication or engagement in decision-making
with providers.13,14 Clinical care teams and surrogate
decision-makers are often divergent in their estimation
of a patient’s prognosis in critical care units, which can
contribute to communication problems.
In pediatric patients, this communication gap is ag-
gravated by a lack of clarity about long-term (>10 years)
outcomes and an inability to quantify neuronal plasticity
in the individual patient. In addition, both patients and
their surrogates may have preexisting values and prefer-
ences that inform their tolerance and desire for critical
care. Some patients may have expressed a desire not to
receive aggressive critical care or prolonged support if
permanent disabilities are anticipated. The sooner that
the risk of impaired survival can be determined, the less
exposure such a patient will have to unwanted interven-
tions. The goal is to have an accurate, precise, and clini-
cally applicable test for most patients after cardiac arrest
that can be reliably applied as early as possible after re-
suscitation. In the era of targeted temperature manage-
ment (TTM), neurological prognostication testing may
not be accurately applied until several days after ROSC.
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NEUROLOGICAL BASIS OF
PROGNOSTICATION
Brain injury is the main determinant of functional out-
comes in patients with critical illness.15 Neurological as-
sessments in comatose survivors of cardiac arrest are
the basis for neurological prognostication.16–19 As an
organ sensitive to ischemia and hypoxia, the brain is
injured directly as a result of loss of blood flow during
arrest (no-flow time) and the suboptimal flow that de-
pends on the quality of cardiopulmonary resuscitation
(CPR). Secondary neurological injury has also been de-
scribed as a consequence of reperfusion after success-
ful resuscitation. The neuronal injury cascade leading
to cell death involves many steps, including excitotoxic-
ity, disrupted calcium homeostasis, free radical forma-
tion, pathological protease cascades, and activation of
cell death signaling pathways.20,21 The extent of isch-
emic and reperfusion injury and the temporal profile
of brain injury, its recovery, and its impact on clinical
manifestations that span hours to several days are very
important parameters to consider in the design of neu-
rological prognostication studies.22 In pediatric patients,
neuronal plasticity and capacity to recover function are
poorly understood and add to the complexity of care.
The spectrum of recovery in children is broader and is
modifiable by the socioeconomic status of the family.
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
Coma and Spatial Distribution of Brain
CLINICAL STATEMENTS
Injury
AND GUIDELINES
As the brain is subjected to global hypoxia/ischemia
with cardiac arrest, the injury pattern manifested is not
homogeneous and is determined by the selectively vul-
nerable neuron subpopulations. The clinical spectrum
of post–cardiac arrest neurological disorders correlates
well with the selective vulnerability of the cortex, arousal
systems, thalamus, cerebellum, and brainstem to global
hypoxia/ischemia. During the immediate postresuscita-
tion period, coma and varying manifestations of disor-
ders of consciousness (coma, stupor, vegetative state/
unresponsive wakefulness syndrome, minimally con-
scious state, encephalopathy) are the most common
neurological manifestations of hypoxic/ischemic brain
injury. Coma is defined as unresponsiveness to inter-
nal and external stimuli with a complete absence of
arousal.23,24 Clinically, it is the complete failure of the
arousal system with no spontaneous eye opening and
the inability to be awakened by application of vigorous
sensory stimulation.23 Coma has been used as the cor-
nerstone in neurological prognostication because the
irreversibility of coma precludes a favorable outcome
and represents extensive injury to the brain.
Assessing Brain Injury and Prognosis
Neuroanatomy, neurophysiology, and developmental
biology provide the clinical basis for determining brain
injury and its clinical manifestation and outcome across
ages. The most vulnerable area is the cerebral cortex,
followed by subcortical structures such as the thalamus,
basal ganglia, and cerebellum. The least vulnerable is
the brainstem. Different patterns of injury may appear
in pediatric populations, in whom subcortical structures
seem to play a larger role in neurological prognostica-
tion, and injury may inhibit plasticity and recovery.25,26
Consciousness requires the function of a complex
system that includes the cerebral cortex, subcortical
structures, thalamus, hypothalamus, midbrain, and
portions of the brainstem.27 The degree of injury to
the components of the brain arousal system (previ-
ously known as the ascending reticular activating sys-
tem) such as subcortical projections, the thalamus, and
midbrain is key in determining poor prognosis. These
areas can be assessed by use of short-latency somato-
sensory evoked potential (SSEP), in which the N20 wave
represents the thalamocortical connectivity and, more
recently, electroencephalography (EEG) patterns. SSEP
has not been studied sufficiently in children to under-
stand its prognostic value.
The involvement of the brainstem in coma is assessed
by evaluating key brainstem areas such as the cranial
nerve (Cn) III nucleus in the midbrain, resulting in the ab-
sence of pupillary light reflex, and the trigeminal nerve
August 27, 2019 e519
 Geocadin et al
nucleus, injury to which leads to the loss of the corneal
CLINICAL STATEMENTS
reflex. In preterm infants, the lack of pupillary reflexes
AND GUIDELINES
may be developmental and should not be used for prog-
nosis. In those with widespread cerebral cortical injury
but with preservation of the brainstem, the patient may
at best achieve an unresponsive wakefulness syndrome
(formerly known as the vegetative state). These patients
remain unresponsive but with preserved brainstem re-
flexes. Patients with some injury to the cerebral cortex
but with preservation of subcortical and brainstem areas
may present with varying cognitive and motor deficits.
In the very young, cortical plasticity is mediated by sur-
viving subplate neurons, and injury to subcortical areas
may inhibit recovery through plasticity and cortical reas-
signment.28 Neuroimaging is an evolving modality that
may be able to identify the location and extent of brain
injury but fails to identify function or loss thereof. The
high susceptibility of the cerebral cortex results in a high
incidence of seizures in this population and watershed
ischemic injury. Because neurological function is defined
by cell location and not necessarily by cell type, serologi-
cal and cerebrospinal fluid (CSF) chemical biomarkers
that measure injury by cell types (neuron, astroglia, and
cytoskeletal markers) continue to have significant chal-
lenges and limitations as reliable prognostic markers of
brain injury after cardiac arrest.
Neurological prognostication of unfavorable outcome
is based on the absence or limitations of function of a
particular injured area of the brain as determined by clini-
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cal assessment or diagnostic testing. This determination is
susceptible to errors caused by any one or a combination
of the following: (1) clinical confounders that may unduly
suppress that particular brain function (ie, hypotension,
hypothermia, concurrent metabolic derangement); (2)
drugs (ie, paralytics, sedatives); (3) inappropriate timing
(ie, testing done before the peak of blood or CSF-based
biomarker); (4) lack of expertise in testing; (5) lack of ex-
perience in interpretation; and (6) the developmental age
or baseline neurological capacity of the patient.
DESIGN OF NEUROLOGICAL
PROGNOSTICATION STUDIES
Prognostic Accuracy Studies
The vast majority of studies on prognostication after
cardiac arrest are prognostic accuracy studies that as-
sess the ability of the test under investigation (index
test) to predict the occurrence of a target condition in
a given population. For a test with a binary outcome,
its accuracy comprises both sensitivity and specificity,
which measure how well the test correctly identifies pa-
tients who will subsequently develop or not develop the
target condition, respectively.
Prognostic accuracy studies differ from diagnostic
accuracy studies in which the index test is evaluated
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
against a clinical reference standard (or gold standard).
Prognostic accuracy studies evaluate the index test
against the development of the predicted target condi-
tion over the time interval from the moment when the
index test is recorded until the end of observation.
Most neurological prognostication index tests re-
ported in the cardiac arrest literature indirectly measure
the severity of brain injury after cardiac arrest.4,29 In a
patient who is comatose after cardiac arrest, a positive
result of one of these tests indicates that the outcome
of that patient will be poor (death or severe neurologi-
cal disability). If this occurs, the prediction is correct,
and the test result is a true positive.
In patients with brain injury after cardiac arrest,
avoiding a falsely pessimistic prediction is essential be-
cause treatment limitations are based mainly on predic-
tion of a poor neurological outcome.30 In this context,
the false-positive rate (FPR) of a neuroprognostic test
is the proportion of patients with good outcome who
are assigned a falsely pessimistic prediction, that is, the
number of false positives divided by the total number of
patients with a good outcome. The FPR is the comple-
ment of specificity (ie, FPR=1−specificity). Therefore,
when specificity is 100%, the FPR is 0%.
When results of neuroprognostic studies are re-
ported, positive predictive values and negative predic-
tive values, or sensitivity and specificity, are equally ac-
ceptable, provided that the contingency table (ie, the
number of true- and false-positive and true- and false-
negative test results) is also provided.
Predictive Tests as Categorical or
Continuous Variables
Although the predictor variables of some neuroprog-
nostic tests are dichotomous (eg, presence or absence
of a motor response), those of other tests are continu-
ous variables (eg, the blood level values of a biomarker)
or are expressed on an ordinal scale (eg, the motor
score of the Glasgow Coma Scale). However, to calcu-
late the sensitivity and specificity of these tests, results
are usually dichotomized by establishing a threshold
that divides positive from negative results. In this case,
test sensitivity and specificity depend on the threshold:
A high threshold increases the specificity of the test and
decreases the sensitivity, and vice versa. This interde-
pendence is expressed by the receiver-operating char-
acteristics curve and its relevant area under the curve.
However, this curve does provide sufficient information
on the distribution of individual test results, for which
boxplots are more appropriate.
Precision
Although achieving high test accuracy is desirable, this
result has little clinical value when the precision of its
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 Geocadin et al
e­ stimate is low (ie, when the CI around that estimate is
large). As for other clinical tests, precision essentially de-
pends on the sample size of the study. The STARD accu-
racy studies (Standards for Reporting Diagnostic)31 require
reporting the intended sample size of the study, along
with the methods used for its calculation. Calculating
sample size in the planning phase of prognostic accuracy
studies may help the investigators obtain the degree of
precision that is considered clinically acceptable for the
test (eg, an upper bound of 95% CI of the FPR estimate
not higher than 5%). This can be based on the hypoth-
esized values of sensitivity and specificity and the estimat-
ed prevalence of the target condition in the population.32
Unfortunately, preliminary sample size calculation is
uncommon in accuracy studies.33 As far as neurologi-
cal prognostication after cardiac arrest is concerned,
among a total of 87 studies included in 2 systematic re-
views published in 2013,5,6 no study reported a sample
size calculation. This gap in the literature probably re-
sults because most studies are based on a convenience
sample of all available patients.
Multivariable Models
Index tests can be combined with other tests or ex-
planatory variables in a multivariable model, with the
aim of achieving a more accurate prediction or to in-
vestigate the interaction between the index test and
these variables. In this case, the likelihood of identifying
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the target condition on the basis of the presence of a
given predictor is reported with an odds ratio or risk
ratio. Compared with the univariable prognostic accu-
racy study design, multivariable models are more com-
plex and generally require the inclusion of large sepa-
rate data sets for model development and subsequent
model validation. Multivariable models are rarely used
for neurological prognostication. An example is rep-
resented by the Good Outcome Following Attempted
Resuscitation score, developed from the Get With The
Guidelines–Resuscitation registry and aimed to predict
neurologically intact survival after in-hospital CPR.34
Methods for sample size calculation for studies based
on multivariable models35 differ from those of univari-
able prognostic accuracy studies.
One important role for multivariable models is test-
ing whether a prognostic test offers independent infor-
mation in addition to other data available about a pa-
tient. If a second test is associated with outcome even
when adjusted for a first prognostic test, there may be
clinical merit in obtaining both tests. For example, EEG
is independently associated with outcome even when
adjusted for the baseline neurological examination of a
patient.36 Improvement in diagnostic accuracy is some-
times reported as increases in area under the curve of
receiver-operating characteristics curves for multivari-
able models compared with univariable models.
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
One of the most important messages to emerge
CLINICAL STATEMENTS
from the neurological prognostication literature is that
AND GUIDELINES
the relationships between predictor variables and out-
comes are not linear, nor are they likely to be restricted
to a single approach for optimizing the prediction of
outcome. Information that informs outcome prediction
can arise from a number of modalities, including clini-
cal assessment, imaging, biomarkers, and EEG monitor-
ing. All these factors are likely to contribute to predic-
tion to some degree, but none is likely to stand as a
stand-alone tool. Given these circumstances, it would
be important to quantify the relative contribution of
each modality and to ascertain how they contribute to
neurological prognostication in combination with the
findings from each modality increasing or decreasing
the likelihood of neurologically intact survival.
To achieve this requires the contribution of multi-
modal modeling analyses that integrate multiple di-
agnostic and predictive strategies and that can yield
a composite estimate of prognosis with estimates of
precision reported as CIs. A number of modeling and
analytic strategies can be considered and would cer-
tainly merit from both biostatistical input and evidence
syntheses to inform model development. The applica-
tion of multimodal modeling can be envisioned as a
web or smartphone application that clinicians can ap-
ply at the bedside and that would generate prognostic
estimates based on the inputted results of multiple as-
sessment modalities.
Current Measures of Neurological
Outcome
Clinician-reported measures of neurological function
after cardiac arrest include the modified Rankin Scale
(mRS),37 the Cerebral Performance Categories (CPC),38
the CPC-Extended,39 and the Glasgow Outcome Scale–
Extended.40 However, to date, only the CPC and mRS
have been used extensively in patients with cardiac ar-
rest. The CPC includes 5 categories, from 1 (no or mi-
nor disabilities) to 5 (dead), and was adapted from the
Glasgow Outcome Scale, developed for traumatic head
injury. The mRS includes 7 scores, from 0 (no symptoms)
to 6 (dead), and was originally developed for stroke.
In children, the clinician-reported measure of neu-
rological function after cardiac arrest is a comple-
ment of the Pediatric Cerebral Performance Category
(PCPC),41,42 the King’s Outcome Scale for Childhood
Head Injury (KOSCHI),43 and the Pediatric Stroke Out-
come Measure (PSOM).44 The KOSCHI (5-point ordinal
scale: 1=death to 5=good recovery) and PSOM (3-point
ordinal scale: 0=no deficit to 2=severe deficit) are com-
mon outcome scales originally developed for traumatic
brain injury and stroke, respectively. The Functional
Systems Score assesses 6 domains of function (men-
tal status, sensory functioning, communication, motor
August 27, 2019 e521
 Geocadin et al
functioning, feeding, and respiratory status) and has
CLINICAL STATEMENTS
recently been validated in children with various diag-
AND GUIDELINES
noses.45–48 The Vineland Adaptive Behavior Scale score
was the primary outcome in the landmark THAPCA pe-
diatric trials (Therapeutic Hypothermia After Pediatric
Cardiac Arrest). Although this instrument is validated in
children, this parent report measure can take from 20
to 60 minutes to complete, and children with a premor-
bid baseline score <70 cannot be assessed after arrest.
Other scales have been used in children but have not
been thoroughly validated.
According to the International Classification of Func-
tioning, Disability and Health from the World Health
Organization,49 assessment of health functioning and
disability includes 3 components: impairments, func-
tional ability, and actual engagement in activity and
participation. Compared with the mRS, which clearly
assesses physical functioning ability, CPC is diffuse,
with scoring based on clusters of mental impairments,
ability to perform functions, and actual activity and
participation. Perhaps it is the lumping of multiple do-
mains within the CPC that explains the lack of agree-
ment between CPC and patient-reported quality-of-life
measures.50 In addition, the CPC has limited ability to
discriminate between mild and moderate postanoxic
brain impairments,51 which are better discriminated
with the mRS.52 Finally, the CPC has been criticized
for evaluating activities such as traveling or preparing
food that are impossible to assess when the patient is
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still in the hospital.53 A recent advisory statement from
the International Liaison Committee on Resuscitation
suggested using the mRS rather than the CPC to mea-
sure functional recovery after cardiac arrest.54 The mRS
should preferably be measured by face-to-face or tele-
phone interviews with patients and their caregivers.55
The interrater reliability of mRS is substantial,56 and it
can be further improved with the use of a structured
interview,40 a web-based tool with 9 questions,57 or an
mRS calculator.58 The PSOM, Functional Systems Score,
and KOSCHI can be quickly administered in a clinical
setting by a nonexpert or estimated through conversa-
tion with parents.
The COSCA (Core Outcome Set for Cardiac Arrest)
writing group suggested the use of the mRS version in
which category 4 (moderate severe disability) includes
inability to attend to one’s own bodily needs rather
than just inability to walk without assistance (“and/
or” instead of “and”).54 The reason is that, compared
with stroke, outcome after cardiac arrest is less influ-
enced by locomotor problems. In a patient still able to
walk, this version will be more sensitive for identifying
extensive dependency related to severe cognitive im-
pairment. The IPSS (International Pediatric Stroke Study)
and EXCOR study groups have used the PSOM in all re-
porting,59,60 but the PSOM has limitations in children <2
years of age. The KOSCHI is more sensitive to a broader
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
range of outcomes and can be used as a complemen-
tary measure to the PSOM.
Dichotomization of Neurological
Outcome Measures
In much of the literature, neurological outcome after
cardiac arrest has been dichotomized into good and
poor on the basis of a threshold. However, the specific
cutoffs used to make this distinction varied over time in
published studies. Until 2006, most neurological prog-
nostication studies defined poor outcome as a CPC
score of 4 to 5 (vegetative state or death) as opposed to
a CPC score of 1 to 3 (good neurological outcome and
moderate to severe neurological disability), whereas
subsequently most studies included severe neurological
disability (CPC score of 3) among the poor outcomes.61
In a survey published in 2015 on prognostication prac-
tices in Europe,62 poor neurological outcome was de-
fined as a CPC score of 3 to 5 by 39% of respondents
and a CPC score of 4 to 5 by 58% of respondents,
whereas the remaining 3% used a different definition.
The International Liaison Committee on Resuscitation
2015 update of the Utstein Resuscitation Registry tem-
plates for OHCA defined good neurological outcome
as a CPC score of 1 to 2 or an mRS score of 0 to 3.63
The PCPC has frequently been dichotomized into 1 to 3
and 4 to 6, or favorable outcome is instead defined as
change in PCPC score <2 because many children with
cardiac arrest have premorbid disability.63,64
Although dichotomizing neurological outcomes
simplifies both outcome reporting and statistical analy-
sis, it also results in a loss of granularity. In fact, the
prevalence of individual outcome categories or scores
remains unknown. This also prevents measuring their
evolution during follow-up, which is particularly impor-
tant because many patients continue to improve over
time, transitioning from poor to good categories, de-
pending on the time of measurement.65,66 In addition,
the heterogeneity of outcome thresholds prevents their
pooling in a meta-analysis.
Reporting the Cause of Death
In common outcome measures, death is used as a neu-
rological outcome. This corresponds to 5 for CPC, 6 for
mRS, 2 for PSOM, 6 for PCPC, and 0 for KOSCHI. How-
ever, none of these measures specify the actual cause of
death. Although most commonly the cause of death in
patients resuscitated from cardiac arrest is attributed to
brain injury, as previously noted, this results mainly from
WLST based on prediction of a poor neurological out-
come.8 WLST is a confounder in the assessment of neu-
rological outcome after cardiac arrest. To clarify the death
in relation to neurological prognostication, it is suggested
that studies need to provide the (1) mode of death, either
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 Geocadin et al
brain death or somatic death (cardiac death); (2) extent
of support at time of death, with possibilities including
full medical support or full medical support with “do not
attempt resuscitation” directives or limited/nonescalating
medical support with or without “do not attempt resus-
citation”; and (3) WLST, whether as a result of perceived
neurological futility, medical futility, or both.
Despite accounting for <10% to 15% of deaths
after cardiac arrest that occur before hospital dis-
charge,67 brain death creates opportunities for organ
donation67–69 (donors after brain death) and should be
recognized and diagnosed in a timely manner. In addi-
tion to donors after brain death, an opportunity is rep-
resented by those who die of circulatory collapse after
WLST, who can become controlled donors after cardiac
death. In a retrospective study of 530 patients who died
in a cardiac arrest center and were referred to an organ
procurement organization, 20 were donors after car-
diac death and 25 were donors after brain death.70
The second most common cause of in-hospital
death after cardiac arrest is cardiovascular instability,
especially during the first 3 days after resuscitation.71
Along with multiple organ failure, cardiovascular fail-
ure may lead to a WLST decision after cardiac arrest.7
Extracerebral organ failure represents a confounder for
neurological prognostication when its contribution as
a cause of death is not assessed separately, particularly
if a patient died of extracerebral causes after neuro-
logical recovery had occurred. This is important for both
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short- and long-term outcomes. In children, the most
common cause of death in OHCA is hypoxic/ischemic
brain injury, whereas cardiovascular failure is the most
common cause of death in IHCA.64
Measures of Health-Related Quality
of Life
The recent International Liaison Committee on Re-
suscitation advisory statement on COSCA in adults
has considered 6 outcome measures of health-related
quality of life (HRQOL) after cardiac arrest.54 These in-
clude the 36-Item Short-Form Health Survey,72 12-Item
Short-Form Health Survey,73 the 15-dimension Quality
of Life questionnaire,74 the Health Utilities Index ver-
sion 3,75 and both the original and revised versions of
the EuroQol.76 After evaluation, the COSCA group sug-
gested that ≥1 among Health Utilities Index version 3,
Short-Form 36-Item Health Survey, or revised version of
the EuroQol should be used.
The correlation between HRQOL and other neuro-
logical function measures after cardiac arrest appears
to be modest, but this has been investigated mainly
for CPC,50,77 and further studies on this topic are war-
ranted. HRQOL measures are essential to ensure that
patient-reported outcomes, in addition to physician-
reported outcomes, are included in prognostic studies.
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
HRQOL assessment in the pediatric population is
CLINICAL STATEMENTS
challenging because of the wide age range and the
AND GUIDELINES
changing developmental capabilities of the patients
as they age. Although there are significant data on
neurological outcome, there are no data on HRQOL
outcomes in survivors after cardiac arrest in the pedi-
atric population by validated instruments. The Pediat-
ric Quality of Life Inventory 4.0 Cores scales, Patient-
Reported Outcomes Measurement Information System,
generic HRQOL measures, and the Child Health Ques-
tionnaire, a generic functional status measure, have pa-
tient and proxy reporting, have a wide age range (2–26
years of age), and may be administered in a reasonable
time frame. In addition, these free and commercially
available tools have been shown to be reliable, inter-
nally and externally valid, and responsive in the United
States and many other countries after language trans-
lation.78–83 Collectively, these measures assess HRQOL
across physical, psychosocial, pain, fatigue, emotional
health, social health, and school domains.
The Pediatric Cardiac Quality of Life Inventory is a re-
liable, valid, generalizable, and disease-specific HRQOL
measure with patient and parent/guardian proxy re-
porting and a wide age range; is easily self-adminis-
tered in a reasonable time frame; and has an array of
relevant constructs to describe and measure HRQOL in
the pediatric heart disease population84–87 in the United
States and United Kingdom. From a research perspec-
tive, the Pediatric Cardiac Quality of Life Inventory will
facilitate cross-sectional and prospective studies assess-
ing HRQOL in pediatric cardiac patients who have had
cardiac arrest.
Timing of Primary and Secondary
Outcome Assessment
When is the proper time to assess the impact of the
index test on neurological outcomes in neurological
prognostication studies? The important aspect in the
timing of assessment is to ensure that the neurological
deficit has stabilized and that other injuries from as-
sociated comorbidities have not occurred, which can
bias the outcome. The 2015 Utstein update guide-
lines63 recommend reporting survival after OHCA ei-
ther at 30 days or at hospital discharge, according
to the ease of collecting this information within each
healthcare system. Survival is a key component of
neurological outcome measures after cardiac arrest,
and 30 days or hospital discharge should be adopted
as the minimal timing for measuring neurological out-
come as well.
Caution should be used during the collection of
outcomes at hospital discharge rather than at a fixed
time point; status at hospital discharge is correlated
with but not identical to 30-day outcomes. Specifical-
ly, readiness for hospital discharge in patients who are
August 27, 2019 e523
 Geocadin et al
recovering from critical illness is determined by ability
CLINICAL STATEMENTS
to walk, toilet, and attend to basic activities of daily
AND GUIDELINES
living. Because these same elements are used to mea-
sure mRS and CPC scores, measurements at hospital
discharge may bias toward an overestimation of the
proportion of patients who have mRS score of 3 or a
CPC score of 2 to 3.88 Both scores may change over
the next month as patients continue recovery or are
challenged by the home environment.65,89 Finally, it is
impossible to assess function in complex activities or
participation in social activities while patients are still
in the hospital.
In pediatric patients, ongoing brain development
clouds neurodevelopmental prognostication. At the
time of full-term birth, the brain cell density is as
high as it will ever be, with an estimated 100 billion
neurons. Interneurons and neurons in the subven-
tricular zone support cortical-thalamic and cortical-
cortical connections, but the competition for con-
nections is intense and results in selective pruning
(programmed apoptosis) of many neurons. Although
the true timing of events is not known, it is thought
that neuronal proliferation and differentiation cease
at ≈18 months postnatal age, but cellular pruning
does not stop until adolescence. Connections inter-
rupted by brain injury can be compensated for, pre-
sumably by altering pruning mechanisms. Thus, the
younger the age is at the time of cardiac arrest, the
more challenging prognostication can be. Surrogate
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markers for developmental brain plasticity are lack-
ing. In pediatrics, the primary testing tools (Bayley
Scales of Infant Development) in children <6 years of
age are poorly predictive of academic achievement
or performance.90 Thus, assessments after 6 years of
age are optimal, although they are challenging to ac-
complish under the restrictions of a 5-year National
Institutes of Health grant.
In neurological prognostication after cardiac arrest,
follow-up times >30 days are both desirable and fea-
sible. In 2 reviews conducted on a total of 87 adult
neurological prognostication studies,5,6 45 studies
(52%) assessed neurological outcome between 2 and
6 months, and 10 studies (11%) assessed up to 1 year.
There is evidence that neurological outcomes evolve
between 1 and 6 months after cardiac arrest.65,66 In an
American Heart Association consensus statement on
primary outcomes after cardiac arrest, the consensus
was to assess neurological outcomes at 3 months after
discharge.91
As far as HRQOL is concerned, the COSCA advi-
sory statement provides that assessment be done at 3
months as a minimum, plus at 6 months and 1 year if
resources allow.54 Longer periods are likely necessary for
the youngest patients. Table 1 shows proposed timings
for adult and pediatric outcome measurement in neuro-
logical prognostication studies.
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
Table 1.  Proposed Timings for Outcome Measurement in Neurological
Prognostication Studies
Neurological
Age Timing Outcome HRQOL
All ages Hospital discharge/1 mo ✓ No
3 mo ✓ ✓
6 mo ✓ ✓
1y Optional Optional
Neonate to 3 y Yearly * NA
HRQOL indicates health-related quality of life; and NA, not applicable.
*Additional neurodevelopmental assessment.
QUALITY OF EVIDENCE AND SOURCES
OF BIAS IN NEUROPROGNOSTIC
STUDIES
One of the most important biases of neurological prog-
nostication studies is the self-fulfilling prophecy. This
type of bias occurs when the treating team is aware
of the results of the test and uses them for decisions
that affect the patient’s outcome (eg, decisions on
WLST) so that the results of the index test determine
those of the reference standard. The consequence is an
overestimation of test performance, especially as far as
its specificity is concerned. Self-fulfilling prophecy is a
variety of incorporation bias, and it is very common.
In a systematic review published in 2014,29 among 73
neurological prognostication studies, only 9 (12%) re-
ported blinding of the treating team from the results
of the predictor under investigation. Ideally, to avoid
self-fulfilling prophecy bias in neurological prognostica-
tion studies, the treating team should be blinded to the
results of the test being investigated. However, this is
neither feasible for some predictors such as those based
on clinical examination nor desirable for others such as
the EEG, the results of which can reveal the presence of
potentially treatable complications (eg, seizures).
Ideally, to eliminate the risk of self-fulfilling proph-
ecy, comatose resuscitated patients should be main-
tained with full medical support until the time point of
the measured outcome as specified in the study. A spe-
cial context for conducting prognostic studies without
a self-fulfilling prophecy bias is represented by those
countries or communities in which WLST does not oc-
cur because of cultural or religious reasons.92
Even when blinding is not feasible, establishing a
strict protocol for WLST, complying with it consistently,
and carefully describing the causes of death in all pa-
tients may help control for the self-fulfilling prophecy
bias during the conduct of neurological prognostication
studies.
Another source of bias in neurological prognostica-
tion studies is sedation and medications. With the ad-
vent of TTM93–95 for comatose survivors of cardiac ar-
rest, sedatives and neuromuscular blocking drugs are
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 Geocadin et al
used extensively to improve control of patient tempera-
ture and to eliminate shivering. However, these drugs
may interfere with neurological prognostication assess-
ment, especially the clinical examination. There is evi-
dence that in patients who have received sedatives <12
hours before the neurological assessment, there is an
increased risk of FPRs for predictors based on the clini-
cal examination.96 The use of short-acting drugs in this
context is highly suggested.29,97
Indirectness and Inconsistency
Indirectness in clinical studies occurs when either the
study population or the study outcomes do not com-
pletely correspond to the population of interest. In neu-
rological prognostication, indirectness occurs with stud-
ies that include patients who are not all comatose or
patients in a coma for causes other than cardiac arrest
(eg, sepsis). An example of indirect outcomes includes
studies in which a patient recovers consciousness after
cardiac arrest and then dies of a second arrest and neu-
rological outcome is incorrectly classified as having an
mRS score of 6 or a CPC score of 5 (death). This bias
should be prospectively addressed by describing the
cause of death and recording the best neurological out-
come achieved by the patient during the study period.
Inconsistency in the literature on neurological prog-
nostication has been observed at both the predictor
level and the outcome level. Predictors based on EEG
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such as status epilepticus (SE), low voltage, or burst
suppression have been defined inconsistently in prog-
nostication studies,5,6 and adoption of a standardized
definition and terminology is desirable. In 2013, the
American Clinical Neurophysiology Society (ACNS)
published a statement on critical care EEG terminol-
ogy in which the definitions of low voltage and burst
suppression were standardized.98 A multicenter study99
showed that the interrater agreement in detecting the
EEG signs of poor neurological outcome in comatose
survivors of cardiac arrest among neurophysiologists
blinded to patient outcome was substantial (r=0.71)
for burst suppression and moderate (r=0.42) for low-
voltage EEG when the ACNS guidelines were adopted.
Unfortunately, there is currently no universal consensus
on the definition of SE on EEG.
Another potential source of inconsistency may re-
sult from interobserver variation for predictors based
on the clinical examination. In a series of 5 studies re-
porting the precision of the examination of comatose
patients in general, interobserver agreement was mod-
erate to substantial.100 None of these studies focused
on the post–cardiac arrest population specifically. The
assessment of pupillary size and reactivity to light can
be standardized with a pupillometer. Clinical studies
showed that the accuracy of quantitative pupillometry
in resuscitated comatose patients is superior to that of
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
the assessment made with a penlight.101,102 A source
CLINICAL STATEMENTS
of inconsistency at the outcome level is the use of in-
AND GUIDELINES
consistent thresholds of CPC or mRS score for defin-
ing poor neurological outcome. Reporting the number
of patients per each outcome category or score rather
than solely dichotomizing outcome into favorable and
unfavorable outcome groups will help prevent this bias
(see COSCA 2018).54
Finally, the timing of outcome reporting is another
important source of inconsistency. Consistent reporting
times for both neurological function and HRQOL mea-
sures would help reduce this bias.
Imprecision
Precision is an important component of prognostic ac-
curacy. A prediction is precise (and therefore reliable)
when the CIs around the predicted values are narrow.
The width of these CIs is inversely proportional to the
size of the sample population on which the predicted
values are calculated.
There is no consensus on what represents good pre-
cision in prognostic accuracy studies. The American
Academy of Neurology’s report “Practice Parameter:
Prediction of Outcome in Comatose Survivors After
Cardiopulmonary Resuscitation (an Evidence-Based
Review)” reported predictors of neurological outcome
with FPRs <1%.16 In the current European guidelines,
imprecision was graded as serious when the upper limit
of the 95% CIs of the estimate of the FPR was >5%
and very serious when this value was >10%.
STANDARDS FOR REPORTING IN
NEUROLOGICAL PROGNOSTICATION
STUDIES
Incomplete reporting has been identified as a major
source of avoidable waste in biomedical research.103 To
achieve a substantial quality of evidence, neurological
prognostication studies should adhere to highly sug-
gested reporting standards such as STARD or TRIPOD
(Transparent Reporting of a Multivariable Prediction
Model for Individual Prognosis or Diagnosis104), ac-
cording to the study design (univariate or multivariate
model).
Prognostic Accuracy Studies (Univariate
Model)
STARD was first published in 2003 and updated in
2015.31 STARD has been developed to contribute to
the completeness and transparency of reporting of
diagnostic accuracy studies, and it can be applied to
prognostic accuracy studies investigating the univariate
association between prognosis and a single predictor or
August 27, 2019 e525
 Geocadin et al
a combination of predictors. STARD includes a checklist
CLINICAL STATEMENTS
of 30 items and a prototypical flow diagram for report-
AND GUIDELINES
ing study results. Some of the most relevant items in
the STARD checklist are rarely reported in neurological
prognostication studies. These include sample size cal-
culation, description of all outcome categories, cross-
tabulation of the index test (contingency table), and
study registration in clinical trial registries. STARD has
been used for reporting diagnostic accuracy in several
radiology105 and ophthalmology106 studies in pediatric
patients but has not been applied to cardiac arrest or
coma outcomes.
Studies Based on a Multivariate Model
Although modeling studies are not yet prominent in
neurological prognostication, an important develop-
ment in the standardized reporting of modeling re-
search in prognosis comes from the EQUATOR Network
(Enhancing the Quality and Transparency of Health Re-
search).104 In its TRIPOD consensus statement, specific
checklists have been developed for the derivation, vali-
dation, or combined evaluation of these clinical models
that have been endorsed and republished in 11 other
journals. This same group also developed the explicit
and transparent reporting standards for systematic re-
views and randomized controlled trials—PRISMA (Pre-
ferred Reporting Items for Systematic Reviews and Me-
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ta-Analyses) and CONSORT (Consolidated Standards of
Reporting Trials), respectively—and have now created a
step-by-step guide for reporting this kind of research.
IMPROVING STUDY OUTCOMES IN
THE FUTURE
As resuscitation science continues to evolve, the out-
come measurements to assess neurological recovery
must also advance. Development of standardized neu-
rological outcomes validated in cardiac arrest survivors
has lagged behind the discovery of multimodality pre-
dictive tools and hampers the ability to correlate new
physiological measurements of brain injury after cardiac
arrest with outcomes. Patient-centric outcomes are in-
creasingly important to cardiac arrest survivors. Func-
tional, cognitive, and psychological outcomes are most
relevant to patients and their families, yet there are no
validated outcomes in these areas.
In 2011, a diverse working group of experts con-
vened to create a consensus statement on the primary
outcomes for resuscitation science studies on behalf of
the American Heart Association Emergency Cardiovas-
cular Care Committee and the Council on Cardiopul-
monary, Critical Care, Perioperative and Resuscitation.91
The consensus statement focused on 3 areas related
to overall outcomes after arrest: timing, selection of
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
parameters to assess, and cost. To highlight the con-
troversial nature of outcome selection, no consensus
outcome could satisfy this working group of interna-
tional and diverse experts in the field. Using various hy-
pothetical scenarios, the group had different outcomes
to fit study design, timing, and cost. Specific to neuro-
logical outcomes, they found assessments to be highly
variable and to fluctuate over time. Global outcomes in-
corporating CPC and mRS scores were most commonly
used in adult studies and were suggested as reasonable
neurological outcome measures, with measurement at
90 days after arrest providing a better assessment of
ultimate neurological recovery for neurological prog-
nostication studies. Pediatric assessments have included
the PCPC, Vineland Adaptive Behavior Scale II, PSOM,
Functional Systems Score, and KOSCHI.
Other aspects of neurological outcome are less stud-
ied but significantly affect quality of life in survivors.
As described earlier, the COSCA writing group has en-
dorsed the use of patient-reported quality-of-life mea-
sures.54 Neurocognitive testing is underused in current
outcomes assessment. Studies have identified deficits
in memory, attention, and executive function as most
common after cardiac arrest. Cognitive impairment can
occur in up to 50% of survivors and is most often mild
to moderate in severity. Standard neuropsychological
testing is the gold standard but is limited by in-person
testing by trained personnel. Highly suggested timing
for testing is at ≥90 days. Comprehensive testing bat-
teries both increase the sensitivity of study outcome
measurement and maximize assessment decisions on
a standardized basis but are associated with higher
costs.107–109 The Pediatric Quality of Life Inventory Sur-
vey and Pediatric Cardiac Quality of Life Inventory have
been used extensively to assess long-term outcomes in
pediatric patients.84,110 Engelmann and Jordan111 pro-
vide a review of pediatric outcome measures.
In addition to cognitive recovery, psychological out-
comes are meaningful to families and patients. High
rates of psychological distress ranging from 14% to 61%
have been reported. Similarly, validated anxiety and de-
pression ratings can also be incorporated into outcome
assessments in postarrest survivors, particularly in studies
measuring delayed outcomes. These cognitive and psy-
chological outcomes greatly affect the ability of survivors
to participate in and reintegrate into society.112–114
To address this need for improving neurological
prognostication outcomes for future resuscitation
studies, we can start by determining specific second-
ary outcome measures, with highly suggested timing
for repeated measures. Ideally, these outcomes could
be correlated with a measurable physiological param-
eter associated with the known pathophysiology of
brain injury after arrest and with future measures to
advance our understanding of global hypoxic/ischemic
brain injury. Learning from other neurological diseases
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 Geocadin et al
that have embraced the use of common data elements
and standardized outcome testing such as stroke and
traumatic brain injury (National Institute of Neurologi-
cal Disorders and Stroke Common Data Elements),115
we can use similar validated tools to address the gaps
in our current studies, specifically in cognitive and psy-
chological outcome domains. For example, the National
Institutes of Health Toolbox116 currently requires all Na-
tional Institutes of Health–funded trials to incorporate
standard measurements of global outcome (mRS) with
quality-of-life scales (Quality of Life in Neurological Dis-
orders) and patient-reported outcomes.82,117
In addition, supplementary highly suggested scales
for cognition range from screening tools (Montreal
Cognitive Assessment) to comprehensive tests and can
be selected according on the goals of the study.118,119
The resources could provide specific data quality and
validation of these outcomes tests that would begin to
address the goal of improving our current outcomes
and the quality of future studies.
TIMING OF NEUROLOGICAL
PROGNOSTICATION
Ideally, neurological prognostication studies must al-
low for the natural recovery of comatose cardiac arrest
survivors until the best neurological status is attained
or death occurs. Inevitably, the longer the time is that
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is allowed for neurological recovery after cardiac arrest
resuscitation, the higher the risk is of providing futile in-
terventions to patients with minimal or no chance for a
neurologically meaningful survival. On the other hand,
premature WLST decisions may introduce “censoring”
and prevent researchers from evaluating the perfor-
mance of prognostic tests or the effectiveness of treat-
ments in clinical trials aimed to improve the outcome of
comatose survivors of cardiac arrest.
Neurological prognostication of the post–cardiac
arrest patient is a dynamic task, one that requires fre-
quent evaluation and reevaluation to gauge recovery.
Although uncertainty may decline over time, establish-
ing neurological testing algorithms and novel neuro-
logical prognostic measurements that can be accurate
throughout a patient’s recovery is necessary. To ade-
quately evaluate the accuracy of such testing, we must
address the question of timing of neurological prognos-
tication in study subjects. This can be divided primarily
into 2 categories: in the context of the study design,
determining the timing when completion of the index
test can adequately predict neurological prognosis; and
in the context of patient care, determining when clini-
cians should act on estimates of neurological prognosis
for study subjects to ensure that adequate time is given
for awakening and recovery before decisions are made
to limit care or to undertake WLST.
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
Timing of the Index Test
CLINICAL STATEMENTS
The first consideration pertains directly to when the in-
AND GUIDELINES
dex test is best deployed to determine prognosis. The
timing of when the index test is undertaken has to be
clinically relevant to the degree of injury and the mech-
anism that the index test is attempting to measure. For
example, if a new biomarker that is mechanistically re-
lated to recovery of cognitive function is elaborated 3
hours after ROSC, the study needs to capture the evo-
lution of this marker during the recovery, and it should
be measured against the function it was intended to
capture (eg, cognitive function) at the time when the
function has adequately recovered or manifested. Con-
founding variables that may affect the performance of
the index test or when the index test can be evaluated
must be accounted for in the study design (ie, drug me-
tabolism, temperature, circulatory shock).
Length of Clinical Observation
After the index test has been undertaken, how long
should the study subjects be observed before the pro-
vider establishes futility or discusses discontinuation of
life-sustaining efforts? When is the appropriate time to
consider WLST on the basis of the neurological prognos-
tication? Some of the current practice recommendations
include delaying neurological prognostication at least 72
hours after ROSC as the minimum time that providers
must wait before they can explore neurological recov-
ery via multimodal testing, and longer if the patient had
been treated with TTM.19 Multimodal algorithms, similar
to the algorithm applied in the TTM trial93 or the algo-
rithm proposed by the European Resuscitation Council
and European Society of Intensive Care Medicine,29 in-
corporate a stepwise approach to establishing an accu-
rate neurological prognosis at an appropriate time during
the span of postarrest care. However, secondary analysis
of the ROC PRIMED study (Resuscitation Outcomes Con-
sortium Prehospital Resuscitation Using an Impedance
Valve and Early Versus Delayed) has shown that despite
these recommendations, ≈30% of patients who died in
the hospital after cardiac arrest in the enrollment period
(2007–2009) had early (<72 hours after ROSC) WLST.8
Brain death caused by cerebral edema from global
hypoperfusion occurs early, often within 96 hours after
ROSC.67,68 Approximately 80% of patients destined for
a good neurological outcome will recover conscious-
ness within 3.5 days after ROSC,97 making neuroprog-
nostic studies unnecessary if decisions were delayed
at least for 72 hours. Uncertainty will persist for the
remaining patients who are comatose after this 72-
hour mark.120,121 The subsequent phase of awakening
is slow, with the majority of patients recovering be-
tween 3.5 and 7 days after ROSC; however, delayed
awakening does occur >7 days after ROSC,3,9 with pre-
August 27, 2019 e527
 Geocadin et al
vious ­literature citing the incidence of late awakeners
CLINICAL STATEMENTS
as 11% to 32% of cohorts who receive TTM.3,9,122 It is
AND GUIDELINES
unclear how much of the observed delayed awakening
can be attributed to the natural speed of recovery of
the brain from hypoxic/ischemic brain injury or to addi-
tional physiological factors, most notably residual seda-
tion.97,120,123 What is certain is that before any form of
neurological prognostication, it is critical to ensure that
the effects of confounding factors are eliminated, es-
pecially in the case of drug metabolism. In the pediatric
population, the THAPCA trial found that cause of arrest
(cardiac versus respiratory), initial cardiac rhythm, dura-
tion of chest compressions, total doses of epinephrine
administered, and arrest on a weekday versus weekend
were all associated with a higher risk for death. Time to
awakening was not considered in this trial.124
The 2011 consensus statement on outcome measures
for resuscitation research mentioned above provided
a timeline for neurological recovery that included the
postresuscitation phase (<72 hours after ROSC), the early
hospitalization phase (72 hours–7 days after ROSC), the
late hospitalization phase (>7 days after ROSC), and finally
the discharge phase.91 Clearly, patients in the postresusci-
tation phase and even the early hospitalization phase are
very susceptible to perturbations in their hemodynamics
and drug metabolism, as well as the persisting effects on
their physiology of the cause of arrest that may be con-
founders of neurological prognostication. That statement
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also specifies that the late hospitalization phase is when
the neurological injury has become more established.
Delayed reperfusion injury can be observed anywhere
between 4 hours and 7 days after ROSC, further support-
ing the suggestion that neurological injury is established
after 7 days.17 This period of observation was also applied
in the TTM trial.93 It provided that patients did not have
formal neurological prognostication until 108 hours after
ROSC, suggesting that patients require longer timelines
to establish neurological prognosis.
Estimation of prognosis may have a high uncertainty
for many days or weeks in comatose patients. To rule
out a delayed neurological recovery and to ensure maxi-
mal prognostic accuracy, studies assessing predictors of
neurological outcome after cardiac arrest should extend
the observation period to 7 days after either the end of
TTM or the suspension of sedation (whichever occurs
later). Furthermore, research studies on the accuracy of
a prognostic test may be biased if observation is trun-
cated <72 hours afterward.
PREARREST VARIABLES: PATIENT
CHARACTERISTICS AND CLINICAL
FACTORS
Numerous studies have been undertaken by using pa-
tient characteristics and clinical factors before cardiac
e528 August 27, 2019
Neurological Prognostication in Comatose Cardiac Arrest Survivors
arrest to establish neurological prognostication. Al-
though these studies offer a great deal of insight into
the severity of the injury and its impact on survival, its
reliability in neurological prognostication is limited.16–18
Some of these parameters such as age, comorbidities,
and lifestyle may affect the study design, test execu-
tion, and interpretation of results of the neurological
prognostication. Some of these parameters have also
been associated with “do not attempt resuscitation”
directives, which will affect the intensity of care, sur-
vival, and outcome.
INTRA-ARREST FACTORS AND
NEUROLOGICAL PROGNOSTICATION
Many cardiac arrest studies have been classified by the
place of arrest and the type of initial cardiac rhythm at
time of resuscitation. This classification has been useful
in stratifying the level of overall injury for intervention
trials, but its precise impact on neurological prognosti-
cation still needs to be clarified.16,17
Although intra-arrest factors such as duration of car-
diac arrest and presentation rhythm are associated with
overall survival, their significance in neurological prog-
nostication remains uncertain at this time. Some factors
that limit the use of these parameters include variability
in the determination of the duration of arrest time and
duration of CPR, objective measures of quality of CPR,
and patient characteristics during arrest. More studies
are needed to define the precise impact of these pa-
rameters on brain injury and quality of life in survivors.
The American Academy of Neurology practice pa-
rameter concluded that cardiac arrest time, duration of
CPR, cause of cardiac arrest (cardiac versus noncardiac),
and type of cardiac arrhythmia are related to poor out-
come, but none of these variables can accurately pre-
dict neurological outcomes.16 Similar statements were
made by the 2008 International Liaison Committee on
Resuscitation consensus statement “Post–Cardiac Ar-
rest Syndrome: Epidemiology, Pathophysiology, Treat-
ment, and Prognostication”17 and by the “2010 Ameri-
can Heart Association Guidelines for Cardiopulmonary
Resuscitation and Emergency Cardiovascular Care.”18
POSTARREST EVALUATION:
NEUROLOGICAL ASSESSMENT IN
COMATOSE SURVIVORS
Defining the extent of the neurological injury is crucial
in establishing neurological prognostication. The 2006
American Academy of Neurology practice guideline,
the 2008 International Liaison Committee on Resus-
citation consensus statement on post–cardiac arrest
syndrome,17 and the 2010 AHA guidelines for CPR
and emergency cardiovascular care18 recommend that
Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702
 Geocadin et al
postarrest neurological assessment is the most reliable
basis for neurological prognostication.16
We provide some key insights into the neurological
assessment as it applies to neurological prognostica-
tion. These patients have significant critical care co-
morbidities that pose significant challenges not only in
clinical assessment but also in the interpretation of the
test results. The assessment of neurological prognosis in
the comatose post–cardiac arrest patient requires strict
attention to detail for all testing performed, including
the bedside clinical examination, neurophysiological
testing, neuroimaging, and chemical biomarker testing.
Significant errors can occur with inaccurate testing.
Preferably, testing should be performed by experienced
and well-trained examiners, and the role and qualifica-
tion of examiners need to be described in the study.
Interpretation of results also requires adequate train-
ing and experience. Specifications for testing, including
laboratory testing, should be to the highest standards.
In this section, we also suggest ways to report the
findings that will help minimize bias. In addition, the
physiological state (ie, blood pressure, temperature, ox-
ygenation), active medications (ie, vasopressors, sedat-
ing and paralytic medications), and possible metabolic
confounders (ie, creatinine, sodium, acidosis, uremia) at
the time of testing should be reported concomitantly,
along with the date and time of testing in relation to
ROSC.
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Bedside Neurological Examination
Clinical signs that can be collected during a bedside
neurological examination are crucial in determining
neurological prognosis. The clinical condition (eg, he-
modynamics, sedation, temperature, metabolic param-
eters) of the patient must be meticulously noted at the
time of the examination.
Assessment of Consciousness
Consciousness is composed of wakefulness and aware-
ness. The ability to establish wakefulness in the unre-
sponsive patient after cardiac arrest is of central im-
portance because patients who awaken earlier after
ROSC typically have better outcomes. However, there
are many reports of patients with later awakening (>3
days and some >2 weeks after ROSC) who achieve
good outcomes. Cortical responses are evidenced by
responses that require integration or processing of sen-
sory information. For example, ability to localize painful
stimuli, movements that cross the midline, tracking of
motion with the eyes, or orientation to voice are simple
signs. Ability to respond appropriately to commands
and ability to communicate are signs of awakening.
The motor response to noxious stimulation is a sign that
has traditionally been valued in prognostication, with
extensor posture or no response to painful stimulus
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
correlating with poor outcome. However, this response
CLINICAL STATEMENTS
has been drawn into question more recently, given its
AND GUIDELINES
relatively high FPR.125 Its role may be more as a screen-
ing tool than for definitive prognostication.29 Establish-
ing consciousness reflects integrity of the pathways
involved in the ascending arousal system, including
projections from the rostral portion of the brainstem
(pons, midbrain) through the bilateral thalami to the
cerebral cortices. The thalamocortical connections are
the most susceptible to injury after cardiac arrest, so al-
though brainstem reflexes may be intact, some patients
achieve at most only an unresponsive wakefulness state
or minimally conscious state because of injury to the
thalami, the cortex diffusely, or the white matter path-
ways between the two. In infants and toddlers (0–4
years of age), the conscious state can be compromised
by medications and illness and is an unreliable exami-
nation finding. Defining the spectrum of wakefulness
from coma to awake in this age group is not useful.
Reporting level of consciousness can be subject to
significant bias. One of the ways to minimize this is
to use the Glasgow Coma Scale subscores as a way
to dichotomize the presence or absence of conscious-
ness. The key component of coma is the ability to be
aroused and to provide a purposeful response to ex-
ternal stimuli. A total Glasgow Coma Scale score <9
is traditionally used as the cutoff for coma; however,
this total score may reflect manifestations that do not
indicate consciousness and may be a source of bias.
A better determinant of the patient’s ability to follow
commands is the Glasgow Coma Scale motor subscore
of 6, which indicates the patient’s ability to follow com-
mands. As the patients emerge from coma, other scales
may be used to quantify their cognitive abilities during
the acute period. Some examples include the Folstein
Mini-Mental State Examination and the Montreal Cog-
nitive Assessment test. Although these tests provide
some objective assessment of the level of conscious-
ness and cognitive function in the acute period, their
precise impact on cardiac arrest survivors has not been
well validated.
Brainstem Reflexes
Determination of the presence or absence of sponta-
neous breathing (medulla), cough reflex (Cn IX, Cn X
[medulla]), gag reflex (Cn IX, X [medulla]), pupillary re-
sponse to light (Cn II, III [midbrain]), corneal reflex (Cn
V, VII [pons]), and oculocephalic/oculovestibular reflexes
(Cn VIII, III, IV, VI [midbrain, pons]) can reveal the in-
tegrity of most of the Cns and brainstem. Heart rate
variability (Cn X, medulla) is also evidence of brainstem
integrity.126 The brainstem is the least susceptible to in-
jury from anoxia. Thus, many patients, even those with
poor outcomes, may have fully or partially intact brain-
stem function; however, when dysfunction is present, it
likely reflects more severe brain injury. Ischemic damage
August 27, 2019 e529
 Geocadin et al
typically occurs more in the rostral portion of the brain-
CLINICAL STATEMENTS
stem, with a caudal progression either directly from an-
AND GUIDELINES
oxic injury or from central herniation with severe global
injury. From a prognostication standpoint, pupillary and
corneal reflexes have traditionally and consistently been
most valuable,16,19,29,125 and attention to technique in
testing is paramount.
It is quite likely that the examination technique has
affected the validity of reported findings in many neu-
rological prognostication studies; most do not routinely
describe techniques used, and the impact of this could
be profound (eg, predicting poor prognosis with absent
pupillary or corneal reflexes when the testing was inad-
equate/confounded).127 The advent of pupillometry has
added to the validity of pupillary testing.128,129 At the
very least, it can alert the clinician to a possibly reactive
pupillary reflex that could merit further observation.
However, it may also provide insight into recovery; a
present pupillary reflex can be quantified and followed
up serially.
The absence of pupillary responses 24 hours after
arrest (after hypothermia) in children was helpful in pre-
dicting poor short-term outcomes.130 In a report from
the Children’s Hospital of Philadelphia, absent pupil-
lary responses 24 hours after arrest (after hypothermia)
were helpful in predicting poor short-term outcomes.130
Although automated measures of corneal responses
are not currently available, testing of this reflex is also
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likely faulty and inaccurate. A maximal stimulus at the
proper location on the cornea is mandatory for declar-
ing the reflex present or absent. If other Cns are tested,
similar meticulousness with testing is encouraged to
best elicit the reflex.
In the absence of objective measurement in other Cn
reflexes, it is suggested to report Cn responses as either
present or absent. A significant bias is introduced when
Cn responses are assessed as partial, and the prognostic
significance of partial response at this time is unclear.
Seizures
Seizures occur in some patients after cardiac arrest and
can range from obvious tonic-clonic seizures to sub-
tle twitching of eyelids or extremities. Nonconvulsive
seizures and SE also exist on this spectrum and may
present with no motor component, thereby requiring
neurophysiological monitoring for detection. Seizures
may be harder to detect during TTM, particularly when
paralytics are used. Seizures or other forms of electric
dysfunction are likely reflective of cortical rather than
subcortical injury but do not necessarily portend a poor
outcome because even patients with electrographic SE
have achieved good outcomes. Seizures may be related
to a worse prognosis131 but also may respond readily to
treatment with antiseizure medications, thereby allow-
ing recovery to a good neurological state.132 Clinicians
e530 August 27, 2019
Neurological Prognostication in Comatose Cardiac Arrest Survivors
are urged to use the formal definitions from the ACNS
for myoclonic SE, seizure, and SE.133
Reporting seizures as part of a neurological prognos-
tication study requires the use of EEG. EEG-confirmed
seizures can be reported on the basis of both ACNS defi-
nitions and the response to interventions. Within the cate-
gory of SE are conditions that may signify worse prognosis;
these include intractable or refractory SE and superrefrac-
tory SE. Refractory SE is defined as recurrent seizure activ-
ity despite 2 appropriately selected and dosed antiseizure
drugs, including a benzodiazepine. Superrefractory SE is
SE that continues or recurs ≥24 hours after the initiation
of treatment with anesthetic antiseizure drugs.134
In newborns and infants, seizures are likely to be elec-
trographic only, so EEG monitoring is necessary for detec-
tion.135,136 Worse EEG background at 24 hours after ROSC
was also associated with worse short-term outcomes and
death, with the odds ratio of death being 3.63 (95%
CI, 2.18–6.00; P<0.001) and the odds of unfavorable
neurological outcome being 4.38 (95% CI, 2.51–7.17;
P=0.001).137 Late treatment of refractory convulsive SE
with first benzodiazepine was associated with a higher
frequency of death and longer convulsion.138
Myoclonus
Brief episodes of nonrhythmic jerks that are not a clonic
seizure occur in a large proportion of patients after car-
diac arrest. Myoclonic jerks may involve just the eyes
or face but can also extend to the torso and extremi-
ties. Myoclonic jerks that occur continuously and are
sustained for >30 minutes are referred to as status
myoclonus. Older literature refers to this syndrome as
myoclonic SE, but this term is confusing to nonneurolo-
gists because these jerks do not necessarily have an
electrographic correlate. Distinguishing at the bedside
between myoclonic jerking and seizures can be quite
challenging, and EEG is required to accurately detect
and therefore treat seizures appropriately. The origins
of myoclonus after cardiac arrest are unclear; cortical,
subcortical, and even spinal sources have been postu-
lated. The presence of persistent generalized myoclo-
nus involving the face, extremities, and trunk has tra-
ditionally portended a poor prognosis,139,140 but more
recently, many reports have surfaced of patients with
these findings who achieved good outcomes.125,141–146
Reporting myoclonus as part of the neurological
prognostication study must include the objective crite-
ria of myoclonus type, duration, and response to treat-
ment. EEG results must be provided, and consultation
with a neurologist is suggested.
Ancillary Testing
Ancillary testing augments the clinical examination but
does not replace its importance (except in situations in
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 Geocadin et al
which patients cannot be examined in detail because
of the inability to eliminate the effect of sedatives or
paralytics). Ancillary testing takes the forms of neuro-
physiology (EEG and SSEP), biochemical markers, and
neuroimaging.
Electroencephalography
EEG is the recording of cortical electric activity; the rou-
tine use of depth electrodes to record from deeper in
the brain is in its infancy for this disease state, and thus
conventional EEG reflects only cortical surface activity.
EEG may be recorded once (a 20- to 30-minute record-
ing is typical) or continuously over time. EEG can be per-
formed in the intensive care unit. The number of elec-
trodes placed on the scalp varies, with larger numbers
providing greater anatomic information and improved
ability to discriminate signal from artifact. EEG signals
can be interpreted by neurophysiologists according to
a standard nomenclature (ACNS).133 In addition, auto-
mated software can calculate a number of quantitative
descriptors of EEG patterns based on amplitude, power,
frequency, spectral analysis, or other parameters.
Reporting of EEG results in neurological prognostica-
tion studies must be consistent with the standard nomen-
clature (ACNS)133 and interpreted by a certified electro-
encephalographer. EEG reactivity is defined as changes
in the signal in response to stimuli, but standardization
of reactivity testing is currently lacking in studies.147,148
To date, lack of reactivity has correlated with poor out-
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come.149–151 Reports may include electrographic pat-
terns that may correlate with poor outcome and include
malignant features152,153 such as burst-suppression pat-
tern,154,155 low voltage,156–158 SE,159–163 stimulus-induced
rhythmic, periodic or ictal discharges,164 and identical
bursts.165 If quantitative EEG is used, the presence and
duration of quantified parameters should be reported.
Evoked Potentials
Evoked potentials (EPs) are electric signals recorded in
different parts of the nervous system in response to a
stimulus applied in some part of the body.166 Multiple
stimuli are applied over time, and the recordings are
signal averaged to eliminate noise and artifact. EPs can
be performed in the intensive care unit. The types of
EP used in neurological prognostication are SSEPs and
brainstem auditory EPs. From a physiological stand-
point, EPs reflect the integrity of the neural pathways
from a peripheral point to a cortical location and thus
demonstrate peripheral nerve function, white matter
tract integrity, and cortical function.
Somatosensory EPs
SSEPs include tests with an electric stimulus to a sen-
sory nerve, typically the median nerve, to elicit an
electric response that propagates to the contralateral
somatosensory cortex. Detection of the signal in the
arm, brachial plexus, and cervical region confirms ad-
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
equate ­technique and transmission. Absence of cortical
CLINICAL STATEMENTS
responses suggests loss of integrity of thalamocortical
AND GUIDELINES
projections (the N20 potentials) and has correlated with
poor outcome.167–173 Long-latency EPs, or the N70 po-
tentials, measure the cortico-cortical pathways; they are
more technically challenging and not commonly used in
neurological prognostication after cardiac arrest.173,174
Brainstem Auditory Evoked Responses
Brainstem auditory evoked responses test the integrity
of the sensorineural auditory pathways to the auditory
cortex. Their use in assessing patients with cardiac ar-
rest has been limited to date, but they may be a future
method for providing complementary information.175,176
Reporting of EPs in neurological prognostication
studies must include the presence or absence of the
response tested. The extent of the delay in EPs or re-
duction in amplitude or asymmetry of results may be
helpful in characterizing the injury.
Biochemical Markers
Several chemicals are released from damaged cells in
the nervous system. Increased levels of these chemicals
in blood or CSF may provide evidence of injury. Mea-
surement of CSF biomarkers requires a lumbar punc-
ture, whereas serological tests may use routine blood
sampling. Many studies have examined neuron-specific
enolase (NSE), which is derived from neurons,177–180 and
S-100 protein,181–185 which is derived from glia. Fewer
studies are available for other neuron-derived proteins
(creatine kinase-BB)186 or glia-derived proteins (myelin
basic protein187 and glial fibrillary acidic protein188). All
chemical biomarkers lack specificity for individual brain
regions and rather are reflective of the degree of global
injury, regardless of the cell of origin. Serum biomark-
ers commonly face the challenge of contamination; for
example, NSE is also found in red blood cells and plate-
lets, and post–cardiac arrest patients commonly have
hemolysis, which raises the NSE levels without neces-
sarily reflecting brain injury. Although harder to obtain,
CSF samples have the advantage that the biomarker
need not be transported across the blood-brain barrier
for detection, thus greatly reducing the contamination
issue. Factors that affect the results of tests such as he-
molysis with NSE need to be reported in studies.
Reporting of blood and CSF biomarkers must include
clear definitions of normal ranges by age (if applicable).
Serial testing that reflects progressive injury (ie, worsen-
ing over time) is highly suggested rather than relying on
any individual value.
Neuroimaging
Imaging of the brain includes computed tomogra-
phy, magnetic resonance imaging, positron emission
August 27, 2019 e531
 Geocadin et al
t­ omography, and single-photon emission computed to-
CLINICAL STATEMENTS
mography. Computed tomography is often performed
AND GUIDELINES
early in the admission to rule out a cerebral cause of the
arrest (eg, intracerebral hemorrhage) but is typically not
helpful for prognostication until several days after ar-
rest, given the typical delay in the imaging appearance
of hypoxic/ischemic changes early after arrest.189–194 Al-
though magnetic resonance imaging, particularly with
diffusion-weighted imaging, is much more sensitive for
detecting acute ischemia, it also can be normal in the
first 1 to 2 days after arrest; thus, it is best performed
3 to 5 days after arrest.195–197 Neuroimaging can give
information about structural damage in specific brain
regions, as well as the integrity of white matter path-
ways and quantitative information about the degree
of imaging. However, it is not yet validated for use in
neurological prognostication in major guidelines.195
The timing of changes on magnetic resonance imag-
ing reflects the pattern of sequential injury seen on a
structural basis. In the first 24 to 48 hours after arrest,
diffusion-weighted changes (reflecting acute ischemia)
are most pronounced in the basal ganglia and cerebel-
lum (Purkinje cells), reflecting their high metabolic rate
and sensitivity to early injury. On days 3 to 5 after ar-
rest, the cerebral cortex is more involved, particularly
the parietal and occipital cortices. At 10 to 14 days after
arrest, the white matter may reflect diffusion-weighted
changes, whereas the previous changes seen become
more prominent on fluid-attenuated inversion recov-
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ery sequences, reflecting more permanent injury.196–198
Resting-state magnetic resonance imaging is a promis-
ing technique in neurological prognostication after ar-
rest. Positron emission tomography and single-photon
emission computed tomography may be helpful for as-
sessing patients in chronic states but are not typically
useful or feasible in the acute setting.
In a pediatric cohort (median age, 2.3 years), early
computed tomography with loss of gray-white matter
differentiation, basilar cistern effacement, and sulcal ef-
facement was highly predictive of death, and loss of gray-
white matter differentiation and basilar cistern efface-
ment were predictive of poor neurological outcome.199
Reporting of neuroimaging in neurological prognos-
tication studies may be provided as an objective quan-
tification of the volume of injury, as a qualitative as-
sessment based on the site of injury in relation to the
functional outcome and prognosis, or as a combination
of quantitative and qualitative assessment of injury. For
qualitative reporting, it is essential that specific neu-
roanatomic areas and laterality of the abnormality are
reported. For functional testing of specific areas of the
brain, it may be reported either quantitatively or quali-
tatively. It is also suggested that neuroimaging studies
be undertaken multiple times during the patient’s ad-
mission to capture and quantify the evolution of the
brain injury.
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
POSTARREST VARIABLES AND
NEUROLOGICAL ASSESSMENT
Medications and Therapies
Neurological prognostication studies should account
for the alteration in effects of pharmacological agents
used in resuscitation and periresuscitation manage-
ment. The effects in the expected pharmacokinetics
and pharmacodynamics of drugs caused by decreased
temperature and multiorgan failure on expected time
to awakening or neural prognostication are not well
characterized.200 During rewarming, the kinetic and
dynamic parameters of drugs will also shift. Drug re-
ceptors can become more sensitive to drug effect, and
the volume of distribution can decrease, resulting in
toxic concentrations and decreased efficacy, depend-
ing on the tissue versus plasma concentrations of the
drug.201 Several groups have attempted to identify
patterns of time to awakening on the basis of various
pharmacological treatments. The studies are difficult
to compare because awakening is defined differently,
depending on the study.9
Systemic Organ Failure
Neurological prognostication studies should define
how the parameter they are studying is affected by the
degree and extent of organ failure in study subjects.
Up to 96% of patients resuscitated after cardiac ar-
rest demonstrate some degree of organ dysfunction,
with two-thirds having at least 2 extracerebral organs
involved.202 Nonsurvivors have a greater incidence of
renal, respiratory, and cardiovascular failure on admis-
sion than survivors. Similar patterns are seen in pa-
tients with unfavorable versus favorable neurological
outcomes.203
Extracorporeal Membrane Oxygenation
Extracorporeal membrane oxygenation is being used
with increasing frequency for patients with refractory
cardiac arrest and those who achieve ROSC and have
ongoing hemodynamic instability. Some studies have
shown that when used early by an experienced team,
extracorporeal membrane oxygenation can improve
survival and neurological outcome in a subpopulation
of patients with cardiac arrest who would otherwise
uniformly die.204–206 Extracorporeal membrane oxygen-
ation programs have defined patient selection criteria
to optimize the benefits of this intentionally lifesaving
therapy. Limited studies show that downtime, age, and
presenting rhythm affect outcomes in patients under-
going extracorporeal membrane oxygenation resuscita-
tion, but data on early prognosticators of neurological
outcome are lacking.
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 Geocadin et al
Table 2.  Key Points and Suggestions in Neurological Prognostication Studies
State of neurological prognostication studies
Neurological basis of prognostication
Design of neurological prognostication studies
Timing of primary and secondary outcome assessment
Quality of evidence and source of bias
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Improving study outcomes in the future
Timing of neurological prognostication
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Neurological Prognostication in Comatose Cardiac Arrest Survivors
CLINICAL STATEMENTS
Overall, the quality of studies is low, and the confidence in prognostication is also low.
AND GUIDELINES
It is desirable that the development of index tests be based on neurological functions that are directly
related to the functional outcome and contribute to the quality of life of cardiac arrest survivors.
Measures of accuracy and precision
 The contingency table (true positive, false positive, true negative, and false negative) should be
reported, along with summary measures (sensitivity, specificity, and predictive values).
 For continuous variables, summary measures based on dichotomization (sensitivity, specificity,
predictive values, and ROC curve) and a dot plot showing the distribution of test values per each
outcome category should be provided.
 In accordance with STARD accuracy studies, both the intended sample size of the prognostic
accuracy study and the method used for its calculation should be reported.
Measures of functional outcome and cause of death
  The mRS should preferably be used to measure functional outcome after cardiac arrest in adults.
 The causes of death (mRS score 6, CPC score 5, or KOSCHI score 0) should be reported, specifically
as cardiovascular or neurological as the determining factor.
  Reporting measures of organ failure such as SOFA can be useful.
  Time of DNAR orders in relation to ROSC should be reported.
 In patients who die before hospital discharge, the rates of death resulting from WLST vs brain
death should be reported separately.
A combined assessment of both neurological outcome and HRQOL should be made at 3 and 6 mo at
a minimum, plus at 1 y if resources permit.
Proposed timings are provided in Table 1.
Reducing risk of bias
  Studies should clearly report WLST criteria and the rates of WLST with reasons.
 Investigators should report the protocol for sedation and ensure that sedatives and neuromuscular
blocking drugs are suspended long enough to avoid interference with clinical assessment.
 Research in communities where indefinite supportive care is provided because of cultural, ethical,
or religious reasons should be encouraged.
Standards for reporting neurological prognostication studies
 In prognostic accuracy studies, STARD and TRIPOD are suggested, according with the adopted
predictive model (univariate or multivariable, respectively).
In studies reporting a dichotomized neurological outcome, the number of patients in each
neurological outcome category should be reported.
When neurological outcome is dichotomized, it is suggested that good outcome is defined as an mRS
score 0–3, CPC score 1–2, KOSCHI score 4–5, and PCPC score 1–3 vs change <2 or no change in
neurological status.
For functional outcomes, studies should describe which domain of classification of functioning (ie,
impairment, activity, participation) is measured and the psychometric properties (concordance with
other measures, interrater and test-retest reliability).
The time point and method used to assess the outcome should be described (ie, via face to face,
telephone, case note review).
Secondary outcomes should include, as a minimum, HRQOL and screening measures of cognitive (eg,
MoCA, CAMCI) and psychological (eg, HADS) outcomes at a minimum of 90 d after arrest.
The timing for assessing index tests should be based on the time course of the underlying
neuropathological process they are presumed to reflect.
If the patient satisfies death by neurological criteria, cessation of interventions that sustain systemic
functions can be undertaken at that time.
To ensure maximal prognostic accuracy, studies assessing index tests should extend from the
observation period to 7 d after either the end of rewarming after TTM or the suspension of sedation
(whichever occurs later). Ideally, patients should be allowed to recover toward the predefined period
for assessment time as identified in the study.
Prognostication testing for clinical use should be done by an independent assessor (ie, a healthcare
provider who is not directly involved in the neurological prognostication study).
Using the index text under investigation as the prognosticator for clinical use in study patient is
discouraged.
(Continued )
August 27, 2019 e533
 Geocadin et al Neurological Prognostication in Comatose Cardiac Arrest Survivors

Table 2. Continued
CLINICAL STATEMENTS

Prearrest variables and neurological prognostication For prearrest variables, neurological prognostication studies need to carefully consider the
AND GUIDELINES

Intra-arrest factors and neurological prognostication
Postarrest evaluation and neurological prognostication
Special consideration: patients and families
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interference of age and other patient characteristics in neurological prognostication, intensity of care,
and DNAR decisions.
Studies need to account for prearrest lifestyle and comorbidities for their possible effects on
neurological and systemic injury and impact on neurological prognostication.
The intra-arrest factors may help provide information about the extent of systemic injury, but they are
not reliable surrogates of neurological injury.
The intra-arrest factors should be included in neurological prognostication studies because they
provide a clearer definition of the patients and their clinical circumstances.
Future research needs to look into the refinement of prognostication across the spectrum of location
and intra-arrest factors.
Postarrest neurological assessment in comatose survivors is the basis for neurological prognostication.
Testing should consider the age of the patient and appropriateness of the test.
The index test should be undertaken in a blinded fashion whenever possible.
Testing should be specific to brain injury with minimal contamination from other injured organ
systems or medications used in the post–cardiac arrest patient.
The physiological variables (ie, temperature, hemodynamics) that are active during prognostic testing
should be carefully recorded.
Medications administered during prognostic testing that can interfere with neurological assessment
should be reported.
Studies should account for organ failure and how it may affect prognostic testing.
How the developing interventions (ie, ECMO) will affect neurological prognostication should be
considered.
How the test being studied complements or improves on existing technologies should be considered.
Families should be prepared for a WLST discussion with openness in relation to the current state of
neurological prognostication studies and the spectrum outcome of comatose survivors of cardiac
arrest.
Necessary support should be provided for families and surrogates during study.

As appropriate, informed consent must be obtained from a legally authorized representative.

CAMCI indicates Computer Assessment of Memory and Cognitive Impairment; CPC, Cerebral Performance Categories; DNAR, do not attempt resuscitation;
ECMO, extracorporeal membrane oxygenation; HADS, Hospital Anxiety and Depression Scale; HRQOL, health-related quality of life; KOSCHI, King’s Outcome
Scale for Childhood Head Injury; MoCA, Montreal Cognitive Assessment; mRS, modified Rankin Scale; PCPC, Pediatric Cerebral Performance Category; ROC,
receiver-operating characteristics; ROSC, return of spontaneous circulation; SOFA, Sequential Organ Failure Assessment; STARD, Standards for Reporting of
Diagnostic Accuracy Studies; TRIPOD, Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis; TTM, targeted temperature
management; and WLST, withdrawal of life-sustaining treatment.

unit, the literature in relation to the process of WLST

SPECIAL CONSIDERATION: PATIENTS
AND FAMILIES
Because suggestions were made related to the design of
neurological prognostication studies, we also add that
to undertake a clinical trial, the applicability of informed
consent from a legally authorized representative must
be included. As applicable to the study and community
setting, investigators may also opt for “Guidance for
Institutional Review Boards, Clinical Investigators, and
Sponsors: Exception From Informed Consent Require-
ment for Emergency Research.”207
Family members or surrogates are called on to help
make decisions about the care of the comatose survi-
vor after cardiac arrest, which may include the deci-
sion related to WLST. Often, the family is unprepared
for this role and relies on healthcare professionals to
clearly communicate and provide guidance in decision-
making. Although there is growing literature on family-
centered care and decision-making in the intensive care
and families in intensive care units is still very limited.208
In preparing families for the discussion of WLST, it is
important that clear conceptualization of the relation-
ship between the medically focused WLST and patient/
family–centered end-of-life care is undertaken.209
Families need to be prepared for WLST, with the key
issue that quality of neurological prognostication stud-
ies currently is low, which may result in unreliable pre-
diction of outcome. Furthermore, the spectrum of pos-
sible clinical outcomes in relation to recent advances in
postarrest care, with the need for a longer observation
period and proportion of late awakeners, also needs to
be addressed. To support the family during this period,
some recommendations include family support coor-
dinators, structured communication programs, sug-
gested communication interventions, open or flexible
visiting hours, a comfortable physical environment for
the family, information leaflets, and family participation
in daily rounds.210 In addition, Kon et al211 recommend

e534 August 27, 2019 Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702

 Geocadin et al Neurological Prognostication in Comatose Cardiac Arrest Survivors

that shared decision-making start at the time of hospi- ARTICLE INFORMATION

CLINICAL STATEMENTS
talization and include setting clear goals, using the best The American Heart Association makes every effort to avoid any actual or po-

evidence, and basing decisions on the preferences of
the patient, family, or surrogate.
CONCLUSIONS
Although efforts to improve cardiac arrest resuscitation
and post–cardiac arrest care have increased significantly
over recent years, the mortality of cardiac arrest survi-
vors has not been reduced substantially. We are real-
izing that a major cause of death in cardiac arrest sur-
vivors is related to WLST, which is heavily dependent
on neurological prognostication. With the low quality
of existing neurological prognostication studies, errors
are more likely. This is an area of opportunity for posi-
tive change. Suggestions (Table 2) are made at multiple
levels of study design, execution, and interpretation of
tests. The writing group hopes that these instructions
will improve the quality of neurological prognostication
studies, which will, in turn, improve the quality of care
provided and affect clinical outcomes and the conduct
of clinical investigations in this area.
AND GUIDELINES
tential conflicts of interest that may arise as a result of an outside relationship or
a personal, professional, or business interest of a member of the writing panel.
Specifically, all members of the writing group are required to complete and
submit a Disclosure Questionnaire showing all such relationships that might be
perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science
Advisory and Coordinating Committee on April 1, 2019, and the American Heart
Association Executive Committee on June 4, 2019. A copy of the document is
available at https://professional.heart.org/statements by using either “Search
for Guidelines & Statements” or the “Browse by Topic” area. To purchase ad-
ditional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.
The American Heart Association requests that this document be cited as fol-
lows: Geocadin RG, Callaway CW, Fink EL, Golan E, Greer DM, Ko NU, Lang E, Li-
cht DJ, Marino BS, McNair ND, Peberdy MA, Perman SM, Sims DB, Soar J, Sandro-
ni C; on behalf of the American Heart Association Emergency Cardiovascular Care
Committee. Standards for studies of neurological prognostication in comatose
survivors of cardiac arrest: a scientific statement from the American Heart Associa-
tion. Circulation. 2019;140:e517–e542. doi: 10.1161/CIR.0000000000000702.
The expert peer review of AHA-commissioned documents (eg, scientific
statements, clinical practice guidelines, systematic reviews) is conducted by the
AHA Office of Science Operations. For more on AHA statements and guidelines
development, visit https://professional.heart.org/statements. Select the “Guide-
lines & Statements” drop-down menu, then click “Publication Development.”
Permissions: Multiple copies, modification, alteration, enhancement, and/
or distribution of this document are not permitted without the express permis-
sion of the American Heart Association. Instructions for obtaining permission
are located at https://www.heart.org/permissions. A link to the “Copyright Per-
missions Request Form” appears in the second paragraph (https://www.heart.
org/en/about-us/statements-and-policies/copyright-request-form).

Disclosures
Writing Group Disclosures

Other Speakers’ Consultant/

Downloaded from http://ahajournals.org by on May 10, 2021

Writing Group Research Bureau/ Expert Ownership Advisory

Member Employment Research Grant Support Honoraria Witness Interest Board Other
Romergryko G. Johns Hopkins University School NIH (research grant None None Medicolegal None None None
Geocadin of Medicine funding provided consulting*
to his institution)†;
NIH (DSMB for SIREN
research)*
Claudio Università Cattolica del Sacro None None None None None None None
Sandroni Cuore (Italy)
Clifton W. University of Pittsburgh NIH (grants to study None None None None None None
Callaway emergency care)†
Ericka L. Fink Children’s Hospital of Pittsburgh NIH† None None None None None None
of UPMC
Eyal Golan Mackenzie Health (Canada) None None None None None None None
David M. Greer Bedford VA Medical Center, NIH (cardiac arrest None None None None None None
Boston University School of research R01)*
Medicine, School of Public
Health
Nerissa U. Ko University of California at San None None None None None None None
Francisco
Eddy Lang University of Calgary (Canada) None None None None None None None
Daniel J. Licht Children’s Hospital of None None None None None None None
Philadelphia
Bradley S. Ann and Robert H. Lurie None None None Legal firms* None None None
Marino Children’s Hospital of Chicago
Norma D. Retired None None None None None None None
McNair

(Continued )

Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702 August 27, 2019 e535

 Geocadin et al Neurological Prognostication in Comatose Cardiac Arrest Survivors

Writing Group Disclosures Continued

CLINICAL STATEMENTS

Other Speakers’ Consultant/

AND GUIDELINES

Writing Group Research Bureau/ Expert Ownership Advisory

Member Employment Research Grant Support Honoraria Witness Interest Board Other
Mary Ann Virginia Commonwealth None None None None None None None
Peberdy University
Sarah M. University of Colorado School of NIH/NHLBI (research None None None None None None
Perman Medicine funding)†
Daniel B. Sims Albert Einstein College of None None None None None None None
Medicine
Jasmeet Soar Southmead Hospital North None None None None None None None
Bristol, NHS Trust Bristol (United
Kingdom)

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on
the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if
(a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the
voting stock or share of the entity or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than
“significant” under the preceding definition.
*Modest.
†Significant.

Reviewer Disclosures

Other Speakers’ Consultant/

Research Bureau/ Expert Ownership Advisory
Reviewer Employment Research Grant Support Honoraria Witness Interest Board Other
Robert A. Berg Children’s Hospital of NICHD (NICHD R21 grant to evaluate None None None None None None
Philadelphia pulmonary vasodilator therapy for
hemodynamic-directed CPR)†; NICHD
Collaborative Pediatric Critical Care
Network (CHOP site PI, analyzing data
on appropriate BP targets during CPR)†;
NHLBI (co-investigator on grant to study
Downloaded from http://ahajournals.org by on May 10, 2021

the effects of debriefing on outcomes

from pediatric IHCA; my comments on
references problems and inaccurate
pediatric IHCA incidence information
are unrelated to my grant topics)*
Michael Washington University None None None None None None None
Diringer School of Medicine
Stephan A. Henry Ford Health None None None None None None None
Meyer System
Jerry P. Nolan University of Bristol, None None None None None None None
Royal United Hospital
(United Kingdom)

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure
Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more
during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns
$10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*Modest.
†Significant.

2. Dragancea I, Rundgren M, Englund E, Friberg H, Cronberg T. The influ-

REFERENCES
1. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW,
Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, Delling FN,
Djousse L, Elkind MSV, Ferguson JF, Fornage M, Jordan LC, Khan SS,
Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH,
Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE,
Mussolino ME, O’Flaherty M, Pandey A, Perak AM, Rosamond WD,
Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Spartano NL,
Stokes A, Tirschwell DL, Tsao CW, Turakhia MP, VanWagner LB, Wilkins JT,
Wong SS, Virani SS; on behalf of the American Heart Association Council
on Epidemiology and Prevention Statistics Committee and Stroke Statistics
Subcommittee. Heart disease and stroke statistics—2019 update: a report
from the American Heart Association. Circulation. 2019;139:e56–e528.
doi: 10.1161/CIR.0000000000000659.
ence of induced hypothermia and delayed prognostication on the mode
of death after cardiac arrest. Resuscitation. 2013;84:337–342. doi:
10.1016/j.resuscitation.2012.09.015
3. Mulder M, Gibbs HG, Smith SW, Dhaliwal R, Scott NL, Sprenkle MD,
Geocadin RG. Awakening and withdrawal of life-sustaining treatment in
cardiac arrest survivors treated with therapeutic hypothermia. Crit Care
Med. 2014;42:2493–2499. doi: 10.1097/CCM.0000000000000540
4. Golan E, Barrett K, Alali AS, Duggal A, Jichici D, Pinto R, Morrison L,
Scales DC. Predicting neurologic outcome after targeted temperature
management for cardiac arrest: systematic review and meta-analysis. Crit
Care Med. 2014;42:1919–1930. doi: 10.1097/CCM.0000000000000335
5. Sandroni C, Cavallaro F, Callaway CW, Sanna T, D’Arrigo S, Kuiper M,
Biancone M, Della Marca G, Nolan JP. Predictors of poor neurological
outcome in adult comatose survivors of cardiac arrest: a systematic review

e536 August 27, 2019 Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702

 Geocadin et al
and meta-analysis, part 1: patients not treated with therapeutic hypothermia.
Resuscitation. 2013;84:1310–1323. doi: 10.1016/j.resuscitation.2013.05.013
6. Sandroni C, Cavallaro F, Callaway CW, D’Arrigo S, Sanna T, Kuiper MA,
Biancone M, Della Marca G, Farcomeni A, Nolan JP. Predictors of poor
neurological outcome in adult comatose survivors of cardiac arrest:
a systematic review and meta-analysis, part 2: patients treated with
therapeutic hypothermia. Resuscitation. 2013;84:1324–1338. doi:
10.1016/j.resuscitation.2013.06.020
7. Dragancea I, Wise MP, Al-Subaie N, Cranshaw J, Friberg H, Glover G,
Pellis T, Rylance R, Walden A, Nielsen N, Cronberg T; TTM Trial In-
vestigators. Protocol-driven neurological prognostication and with-
drawal of life-sustaining therapy after cardiac arrest and targeted
temperature management. Resuscitation. 2017;117:50–57. doi:
10.1016/j.resuscitation.2017.05.014
8. Elmer J, Torres C, Aufderheide TP, Austin MA, Callaway CW, Golan E,
Herren H, Jasti J, Kudenchuk PJ, Scales DC, Stub D, Richardson DK, Zive DM;
Resuscitation Outcomes Consortium. Association of early withdrawal
of life-sustaining therapy for perceived neurological prognosis with
mortality after cardiac arrest. Resuscitation. 2016;102:127–135. doi:
10.1016/j.resuscitation.2016.01.016
9. Grossestreuer AV, Abella BS, Leary M, Perman SM, Fuchs BD, Kolansky DM,
Beylin ME, Gaieski DF. Time to awakening and neurologic outcome in
therapeutic hypothermia-treated cardiac arrest patients. Resuscitation.
2013;84:1741–1746. doi: 10.1016/j.resuscitation.2013.07.009
10. Zanyk-McLean K, Sawyer KN, Paternoster R, Shievitz R, Devlin W, Swor R.
Time to awakening is often delayed in patients who receive targeted
temperature management after cardiac arrest. Ther Hypothermia Temp
Manag. 2017;7:95–100. doi: 10.1089/ther.2016.0030
11. Grossestreuer AV, Gaieski DF, Abella BS, Wiebe DJ, Moskowitz A, Ikeda DJ,
Haukoos JS, Perman SM. Factors associated with post-arrest withdraw-
al of life-sustaining therapy. Resuscitation. 2017;110:114–119. doi:
10.1016/j.resuscitation.2016.10.021
12. Wintermann GB, Weidner K, Strauß B, Rosendahl J, Petrowski K. Pre-
dictors of posttraumatic stress and quality of life in family members of
chronically critically ill patients after intensive care. Ann Intensive Care.
2016;6:69. doi: 10.1186/s13613-016-0174-0
13. Kentish-Barnes N, Seegers V, Legriel S, Cariou A, Jaber S, Lefrant JY,
Floccard B, Renault A, Vinatier I, Mathonnet A, Reuter D, Guisset O,
Downloaded from http://ahajournals.org by on May 10, 2021
Cracco C, Seguin A, Durand-Gasselin J, Eon B, Thirion M, Rigaud JP,
Philippon-Jouve B, Argaud L, Chouquer R, Adda M, Papazian L, Dedrie C,
Georges H, Lebas E, Rolin N, Bollaert PE, Lecuyer L, Viquesnel G, Léone M,
Chalumeau-Lemoine L, Cohen-Solal Z, Garrouste-Orgeas M, Tamion F,
Falissard B, Chevret S, Azoulay E. CAESAR: a new tool to assess relatives’ ex-
perience of dying and death in the ICU. Intensive Care Med. 2016;42:995–
1002. doi: 10.1007/s00134-016-4260-4
14. Gries CJ, Engelberg RA, Kross EK, Zatzick D, Nielsen EL, Downey L,
Curtis JR. Predictors of symptoms of posttraumatic stress and depression
in family members after patient death in the ICU. Chest. 2010;137:280–
287. doi: 10.1378/chest.09-1291
15. Tasker RC, Menon DK. Critical care and the brain. JAMA. 2016;315:749–
750. doi: 10.1001/jama.2016.0701
16. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S; Quality Standards
Subcommittee of the American Academy of Neurology. Practice param-
eter: prediction of outcome in comatose survivors after cardiopulmonary
resuscitation (an evidence-based review): report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology.
2006;67:203–210. doi: 10.1212/01.wnl.0000227183.21314.cd
17. Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Böttiger BW, Callaway C,
Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT Jr,
Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP,
Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Vanden Hoek T.
Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment,
and prognostication: a consensus statement from the International Liai-
son Committee on Resuscitation (American Heart Association, Australian
and New Zealand Council on Resuscitation, European Resuscitation Coun-
cil, Heart and Stroke Foundation of Canada, InterAmerican Heart Foun-
dation, Resuscitation Council of Asia, and the Resuscitation Council of
Southern Africa); the American Heart Association Emergency Cardiovas-
cular Care Committee; the Council on Cardiovascular Surgery and Anes-
thesia; the Council on Cardiopulmonary, Perioperative, and Critical Care;
the Council on Clinical Cardiology; and the Stroke Council. Circulation.
2008;118:2452–2483. doi: 10.1161/CIRCULATIONAHA.108.190652
18. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL,
Donnino M, Gabrielli A, Silvers SM, Zaritsky AL, Merchant R,
Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702
Neurological Prognostication in Comatose Cardiac Arrest Survivors
Vanden Hoek TL, Kronick SL. Part 9: post–cardiac arrest care: 2010 Ameri-
CLINICAL STATEMENTS
can Heart Association guidelines for cardiopulmonary resuscitation and
AND GUIDELINES
emergency cardiovascular care. Circulation. 2010;122(suppl 3):S768–
S786. doi: 10.1161/CIRCULATIONAHA.110.971002
19. Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E,
Kern KB, Leary M, Meurer WJ, Peberdy MA, Thompson TM,
Zimmerman JL. Part 8: post–cardiac arrest care: 2015 American Heart As-
sociation guidelines update for cardiopulmonary resuscitation and emer-
gency cardiovascular care. Circulation. 2015;132(suppl 2):S465–S482.
doi: 10.1161/cir.0000000000000262
20. Harukuni I, Bhardwaj A. Mechanisms of brain injury after global cerebral
ischemia. Neurol Clin. 2006;24:1–21. doi: 10.1016/j.ncl.2005.10.004
21. Greer DM. Mechanisms of injury in hypoxic-ischemic encephalopa-
thy: implications to therapy. Semin Neurol. 2006;26:373–379. doi:
10.1055/s-2006-948317
22. Hoesch RE, Koenig MA, Geocadin RG. Coma after global ischemic
brain injury: pathophysiology and emerging therapies. Crit Care Clin.
2008;24:25–44, vii. doi: 10.1016/j.ccc.2007.11.003
23. Plum F, Posner JB. The Diagnosis of Stupor and Coma. 3rd ed. Philadel-
phia, PA: FA Davis Co; 1980.
24. Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, Kelly JP,
Rosenberg JH, Whyte J, Zafonte RD, Zasler ND. The minimally conscious
state: definition and diagnostic criteria. Neurology. 2002;58:349–353.
doi: 10.1212/wnl.58.3.349
25. Fink EL, Panigrahy A, Clark RS, Fitz CR, Landsittel D, Kochanek PM,
Zuccoli G. Regional brain injury on conventional and diffusion weighted
MRI is associated with outcome after pediatric cardiac arrest. Neurocrit
Care. 2013;19:31–40. doi: 10.1007/s12028-012-9706-0
26. Oualha M, Gatterre P, Boddaert N, Dupic L, De Saint Blanquat L, Hubert P,
Lesage F, Desguerre I. Early diffusion-weighted magnetic resonance imag-
ing in children after cardiac arrest may provide valuable prognostic in-
formation on clinical outcome. Intensive Care Med. 2013;39:1306–1312.
doi: 10.1007/s00134-013-2930-z
27. Guldenmund P, Soddu A, Baquero K, Vanhaudenhuyse A, Bruno MA,
Gosseries O, Laureys S, Gómez F. Structural brain injury in patients with
disorders of consciousness: a voxel-based morphometry study. Brain Inj.
2016;30:343–352. doi: 10.3109/02699052.2015.1118765
28. Judaš M, Sedmak G, Kostović I. The significance of the subplate for evolu-
tion and developmental plasticity of the human brain. Front Hum Neuro-
sci. 2013;7:423. doi: 10.3389/fnhum.2013.00423
29. Sandroni C, Cariou A, Cavallaro F, Cronberg T, Friberg H, Hoedemaekers C,
Horn J, Nolan JP, Rossetti AO, Soar J. Prognostication in comatose survi-
vors of cardiac arrest: an advisory statement from the European Resuscita-
tion Council and the European Society of Intensive Care Medicine. Resus-
citation. 2014;85:1779–1789. doi: 10.1016/j.resuscitation.2014.08.011
30. Dragancea I, Horn J, Kuiper M, Friberg H, Ullén S, Wetterslev J, Cranshaw J,
Hassager C, Nielsen N, Cronberg T; TTM Trial Investigators. Neurological
prognostication after cardiac arrest and targeted temperature management
33°C versus 36°C: results from a randomised controlled clinical trial. Re-
suscitation. 2015;93:164–170. doi: 10.1016/j.resuscitation.2015.04.013
31. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L,
Lijmer JG, Moher D, Rennie D, de Vet HC, Kressel HY, Rifai N, Golub RM,
Altman DG, Hooft L, Korevaar DA, Cohen JF; STARD Group. STARD 2015:
an updated list of essential items for reporting diagnostic accuracy stud-
ies. BMJ. 2015;351:h5527. doi: 10.1136/bmj.h5527
32. Buderer NM. Statistical methodology, I: incorporating the prevalence of
disease into the sample size calculation for sensitivity and specificity. Acad
Emerg Med. 1996;3:895–900.
33. Bachmann LM, Puhan MA, ter Riet G, Bossuyt PM. Sample sizes of studies
on diagnostic accuracy: literature survey. BMJ. 2006;332:1127–1129. doi:
10.1136/bmj.38793.637789.2F
34. Ebell MH, Jang W, Shen Y, Geocadin RG; Get With the Guidelines–Resus-
citation Investigators. Development and validation of the Good Outcome
Following Attempted Resuscitation (GO-FAR) score to predict neurologically
intact survival after in-hospital cardiopulmonary resuscitation. JAMA Intern
Med. 2013;173:1872–1878. doi: 10.1001/jamainternmed.2013.10037
35. Hsieh FY, Bloch DA, Larsen MD. A simple method of sample size calcula-
tion for linear and logistic regression. Stat Med. 1998;17:1623–1634.
36. Youn CS, Callaway CW, Rittenberger JC; Post Cardiac Arrest Service. Com-
bination of initial neurologic examination, quantitative brain imaging and
electroencephalography to predict outcome after cardiac arrest. Resusci-
tation. 2017;110:120–125. doi: 10.1016/j.resuscitation.2016.10.024
37. Rankin J. Cerebral vascular accidents in patients over the age of 60, II: prog-
nosis. Scott Med J. 1957;2:200–215. doi: 10.1177/003693305700200504
August 27, 2019 e537
 Geocadin et al
38. Brain Resuscitation Clinical Trial I Study Group. A randomized clinical study
CLINICAL STATEMENTS
of cardiopulmonary-cerebral resuscitation: design, methods, and patient
AND GUIDELINES
characteristics. Am J Emerg Med. 1986;4:72–86.
39. Balouris SA, Raina KD, Rittenberger JC, Callaway CW, Rogers JC,
Holm MB. Development and validation of the Cerebral Performance
Categories-Extended (CPC-E). Resuscitation. 2015;94:98–105. doi:
10.1016/j.resuscitation.2015.05.013
40. Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the Glasgow
Outcome Scale and the extended Glasgow Outcome Scale: guidelines for
their use. J Neurotrauma. 1998;15:573–585. doi: 10.1089/neu.1998.15.573
41. Fiser DH, Long N, Roberson PK, Hefley G, Zolten K, Brodie-Fowler M.
Relationship of Pediatric Overall Performance Category and Pediatric Ce-
rebral Performance Category scores at pediatric intensive care unit dis-
charge with outcome measures collected at hospital discharge and 1- and
6-month follow-up assessments. Crit Care Med. 2000;28:2616–2620.
42. Fiser DH. Assessing the outcome of pediatric intensive care. J Pediatr.
1992;121:68–74.
43. Calvert S, Miller HE, Curran A, Hameed B, McCarter R, Edwards RJ,
Hunt L, Sharples PM. The King’s Outcome Scale for Childhood Head
Injury and injury severity and outcome measures in children with trau-
matic brain injury. Dev Med Child Neurol. 2008;50:426–431. doi:
10.1111/j.1469-8749.2008.02061.x
44. Fiume A, Deveber G, Jang SH, Fuller C, Viner S, Friefeld S. Development
and validation of the Pediatric Stroke Quality of Life Measure. Dev Med
Child Neurol. 2018;60:587–595. doi: 10.1111/dmcn.13684
45. Pollack MM, Holubkov R, Glass P, Dean JM, Meert KL, Zimmerman J,
Anand KJ, Carcillo J, Newth CJ, Harrison R, Willson DF, Nicholson C; Eu-
nice Kennedy Shriver National Institute of Child Health and Human Devel-
opment Collaborative Pediatric Critical Care Research Network. Functional
Status Scale: new pediatric outcome measure. Pediatrics. 2009;124:e18–
e28. doi: 10.1542/peds.2008-1987
46. Pollack MM, Holubkov R, Funai T, Clark A, Moler F, Shanley T, Meert K,
Newth CJ, Carcillo J, Berger JT, Doctor A, Berg RA, Dalton H, Wessel DL,
Harrison RE, Dean JM, Jenkins TL. Relationship between the Functional
Status Scale and the Pediatric Overall Performance Category and Pediat-
ric Cerebral Performance Category scales. JAMA Pediatr. 2014;168:671–
676. doi: 10.1001/jamapediatrics.2013.5316
47. Pollack MM, Holubkov R, Funai T, Clark A, Berger JT, Meert K, Newth CJ,
Downloaded from http://ahajournals.org by on May 10, 2021
Shanley T, Moler F, Carcillo J, Berg RA, Dalton H, Wessel DL, Harrison RE,
Doctor A, Dean JM, Jenkins TL; Eunice Kennedy Shriver National Institute
of Child Health and Human Development Collaborative Pediatric Critical
Care Research Network. Pediatric intensive care outcomes: development
of new morbidities during pediatric critical care. Pediatr Crit Care Med.
2014;15:821–827. doi: 10.1097/PCC.0000000000000250
48. Pinto NP, Rhinesmith EW, Kim TY, Ladner PH, Pollack MM. Long-
term function after pediatric critical illness: results from the Survivor
Outcomes Study. Pediatr Crit Care Med. 2017;18:e122–e130. doi:
10.1097/PCC.0000000000001070
49. World Health Organization. International Classification of Functioning,
Disability and Health. 2001. http://www.who.int/classifications/icf/en/.
Accessed May 3, 2018.
50. Stiell IG, Nesbitt LP, Nichol G, Maloney J, Dreyer J, Beaudoin T,
Blackburn J, Wells GA; OPALS Study Group. Comparison of the Ce-
rebral Performance Category score and the Health Utilities Index for
survivors of cardiac arrest. Ann Emerg Med. 2009;53:241–248. doi:
10.1016/j.annemergmed.2008.03.018
51. Raina KD, Callaway C, Rittenberger JC, Holm MB. Neurological and func-
tional status following cardiac arrest: method and tool utility. Resuscita-
tion. 2008;79:249–256. doi: 10.1016/j.resuscitation.2008.06.005
52. Banks JL, Marotta CA. Outcomes validity and reliability of the modi-
fied Rankin Scale: implications for stroke clinical trials: a literature re-
view and synthesis. Stroke. 2007;38:1091–1096. doi: 10.1161/01.STR.
0000258355.23810.c6
53. Rittenberger JC, Raina K, Holm MB, Kim YJ, Callaway CW. Association
between Cerebral Performance Category, modified Rankin Scale, and
discharge disposition after cardiac arrest. Resuscitation. 2011;82:1036–
1040. doi: 10.1016/j.resuscitation.2011.03.034
54. Haywood K, Whitehead L, Nadkarni VM, Achana F, Beesems S, Böttiger BW,
Brooks A, Castrén M, Ong ME, Hazinski MF, Koster RW, Lilja G, Long J,
Monsieurs KG, Morley PT, Morrison L, Nichol G, Oriolo V, Saposnik G,
Smyth M, Spearpoint K, Williams B, Perkins GD; COSCA Collaborators.
COSCA (Core Outcome Set for Cardiac Arrest) in adults: an advisory state-
ment from the International Liaison Committee on Resuscitation. Circula-
tion. 2018;137:e783–e801. doi: 10.1161/CIR.0000000000000562
e538 August 27, 2019
Neurological Prognostication in Comatose Cardiac Arrest Survivors
55. Harrison JK, McArthur KS, Quinn TJ. Assessment scales in stroke: clinimet-
ric and clinical considerations. Clin Interv Aging. 2013;8:201–211. doi:
10.2147/CIA.S32405
56. Quinn TJ, Dawson J, Walters MR, Lees KR. Reliability of the modi-
fied Rankin Scale. Stroke. 2007;38:e144; author reply e145. doi:
10.1161/STROKEAHA.107.490110
57. mRS-9Q: the modified Rankin Scale calculator. http://www.modifiedrankin.
com. Accessed May 7, 2018.
58. Patel N, Rao VA, Heilman-Espinoza ER, Lai R, Quesada RA, Flint AC. Simple
and reliable determination of the modified Rankin Scale score in neurosur-
gical and neurological patients: the mRS-9Q. Neurosurgery. 2012;71:971–
975. doi: 10.1227/NEU.0b013e31826a8a56
59. Kitchen L, Westmacott R, Friefeld S, MacGregor D, Curtis R, Allen A, Yau I,
Askalan R, Moharir M, Domi T, deVeber G. The Pediatric Stroke Outcome
Measure: a validation and reliability study. Stroke. 2012;43:1602–1608.
doi: 10.1161/STROKEAHA.111.639583
60. Fraser CD Jr, Jaquiss RD, Rosenthal DN, Humpl T, Canter CE, Blackstone EH,
Naftel DC, Ichord RN, Bomgaars L, Tweddell JS, Massicotte MP,
Turrentine MW, Cohen GA, Devaney EJ, Pearce FB, Carberry KE, Kroslowitz R,
Almond CS; Berlin Heart Study Investigators. Prospective trial of a pe-
diatric ventricular assist device. N Engl J Med. 2012;367:532–541. doi:
10.1056/NEJMoa1014164
61. Sandroni C, Nolan JP. Neuroprognostication after cardiac arrest in Eu-
rope: new timings and standards. Resuscitation. 2015;90:A4–A5. doi:
10.1016/j.resuscitation.2015.02.020
62. Friberg H, Cronberg T, Dünser MW, Duranteau J, Horn J, Oddo M. Survey on
current practices for neurological prognostication after cardiac arrest. Re-
suscitation. 2015;90:158–162. doi: 10.1016/j.resuscitation.2015.01.018
63. Perkins GD, Jacobs IG, Nadkarni VM, Berg RA, Bhanji F, Biarent D,
Bossaert LL, Brett SJ, Chamberlain D, de Caen AR, Deakin CD, Finn JC,
Gräsner JT, Hazinski MF, Iwami T, Koster RW, Lim SH, Huei-Ming Ma M,
McNally BF, Morley PT, Morrison LJ, Monsieurs KG, Montgomery W, Nichol G,
Okada K, Eng Hock Ong M, Travers AH, Nolan JP; Utstein Collaborators.
Cardiac arrest and cardiopulmonary resuscitation outcome reports: up-
date of the Utstein Resuscitation Registry Templates for Out-of-Hospital
Cardiac Arrest: a statement for healthcare professionals from a task force
of the International Liaison Committee on Resuscitation (American Heart
Association, European Resuscitation Council, Australian and New Zea-
land Council on Resuscitation, Heart and Stroke Foundation of Canada,
InterAmerican Heart Foundation, Resuscitation Council of Southern Af-
rica, Resuscitation Council of Asia); and the American Heart Association
Emergency Cardiovascular Care Committee and the Council on Car-
diopulmonary, Critical Care, Perioperative and Resuscitation [published
correction appears in Circulation. 2015;132:e168–e169]. Circulation.
2015;132:1286–1300. doi: 10.1161/CIR.0000000000000144
64. Moler FW, Meert K, Donaldson AE, Nadkarni V, Brilli RJ, Dalton HJ,
Clark RS, Shaffner DH, Schleien CL, Statler K, Tieves KS, Hackbarth R,
Pretzlaff R, van der Jagt EW, Levy F, Hernan L, Silverstein FS, Dean JM;
Pediatric Emergency Care Applied Research Network. In-hospital versus
out-of-hospital pediatric cardiac arrest: a multicenter cohort study. Crit
Care Med. 2009;37:2259–2267. doi: 10.1097/CCM.0b013e3181a00a6a
65. Tong JT, Eyngorn I, Mlynash M, Albers GW, Hirsch KG. Functional neuro-
logic outcomes change over the first 6 months after cardiac arrest. Crit Care
Med. 2016;44:e1202–e1207. doi: 10.1097/CCM.0000000000001963
66. Arrich J, Zeiner A, Sterz F, Janata A, Uray T, Richling N, Behringer W, Herkner H.
Factors associated with a change in functional outcome between one
month and six months after cardiac arrest: a retrospective cohort study. Re-
suscitation. 2009;80:876–880. doi: 10.1016/j.resuscitation.2009.04.045
67. Sandroni C, D’Arrigo S, Callaway CW, Cariou A, Dragancea I, Taccone FS,
Antonelli M. The rate of brain death and organ donation in patients resus-
citated from cardiac arrest: a systematic review and meta-analysis. Inten-
sive Care Med. 2016;42:1661–1671. doi: 10.1007/s00134-016-4549-3
68. Adrie C, Haouache H, Saleh M, Memain N, Laurent I, Thuong M, Darques L,
Guerrini P, Monchi M. An underrecognized source of organ donors: pa-
tients with brain death after successfully resuscitated cardiac arrest. Inten-
sive Care Med. 2008;34:132–137. doi: 10.1007/s00134-007-0885-7
69. Sandroni C, Adrie C, Cavallaro F, Marano C, Monchi M, Sanna T,
Antonelli M. Are patients brain-dead after successful resuscitation from
cardiac arrest suitable as organ donors? A systematic review. Resuscita-
tion. 2010;81:1609–1614. doi: 10.1016/j.resuscitation.2010.08.037
70. Reynolds JC, Rittenberger JC, Callaway CW: and the Post Cardiac Ar-
rest Service. Patterns of organ donation among resuscitated patients at
a regional cardiac arrest center. Resuscitation. 2014;85:248–252. doi:
10.1016/j.resuscitation.2013.11.001
Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702
 Geocadin et al
71. Lemiale V, Dumas F, Mongardon N, Giovanetti O, Charpentier J,
Chiche JD, Carli P, Mira JP, Nolan J, Cariou A. Intensive care unit mor-
tality after cardiac arrest: the relative contribution of shock and brain
injury in a large cohort. Intensive Care Med. 2013;39:1972–1980. doi:
10.1007/s00134-013-3043-4
72. Ware JE Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Sur-
vey (SF-36), I: conceptual framework and item selection. Med Care.
1992;30:473–483.
73. Jenkinson C, Stewart-Brown S, Petersen S, Paice C. Assessment of the
SF-36 version 2 in the United Kingdom. J Epidemiol Community Health.
1999;53:46–50. doi: 10.1136/jech.53.1.46
74. Sintonen H. The 15D instrument of health-related quality of life: proper-
ties and applications. Ann Med. 2001;33:328–336.
75. Feeny D, Furlong W, Torrance GW, Goldsmith CH, Zhu Z, DePauw S,
Denton M, Boyle M. Multiattribute and single-attribute utility func-
tions for the Health Utilities Index Mark 3 System. Med Care. 2002;40:
113–128.
76. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D,
Bonsel G, Badia X. Development and preliminary testing of the new five-
level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727–1736.
doi: 10.1007/s11136-011-9903-x
77. Hsu JW, Madsen CD, Callaham ML. Quality-of-life and formal function-
al testing of survivors of out-of-hospital cardiac arrest correlates poorly
with traditional neurologic outcome scales. Ann Emerg Med. 1996;28:
597–605.
78. Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pe-
diatric Quality of Life Inventory version 4.0 generic core scales in healthy
and patient populations. Med Care. 2001;39:800–812.
79. Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL 4.0 as a pediatric
population health measure: feasibility, reliability, and validity. Ambul Pedi-
atr. 2003;3:329–341.
80. Landgraf JM, Abezt L, Ware JE. The CHQ User’s Manual. Boston, MA:
Health Institute, New England Medical Center; 1996.
81. DeWalt DA, Gross HE, Gipson DS, Selewski DT, DeWitt EM, Dampier CD,
Hinds PS, Huang IC, Thissen D, Varni JW. PROMIS(®) pediatric self-report
scales distinguish subgroups of children within and across six common
pediatric chronic health conditions. Qual Life Res. 2015;24:2195–2208.
doi: 10.1007/s11136-015-0953-3
Downloaded from http://ahajournals.org by on May 10, 2021
82. Cella D, Yount S, Rothrock N, Gershon R, Cook K, Reeve B, Ader D,
Fries JF, Bruce B, Rose M; PROMIS Cooperative Group. The Patient-
Reported Outcomes Measurement Information System (PROMIS): progress
of an NIH Roadmap Cooperative Group during its first two years. Med
Care. 2007;45(suppl 1):S3–S11. doi: 10.1097/01.mlr.0000258615.
42478.55
83. Irwin DE, Stucky BD, Thissen D, Dewitt EM, Lai JS, Yeatts K,
Varni JW, DeWalt DA. Sampling plan and patient characteristics of the
PROMIS pediatrics large-scale survey. Qual Life Res. 2010;19:585–594.
doi: 10.1007/s11136-010-9618-4
84. Marino BS, Shera D, Wernovsky G, Tomlinson RS, Aguirre A, Gallagher M,
Lee A, Cho CJ, Stern W, Davis L, Tong E, Teitel D, Mussatto K, Ghanayem N,
Gleason M, Gaynor JW, Wray J, Helfaer MA, Shea JA. The development of
the Pediatric Cardiac Quality of Life Inventory: a quality of life measure for
children and adolescents with heart disease. Qual Life Res. 2008;17:613–
626. doi: 10.1007/s11136-008-9323-8
85. Marino BS, Tomlinson RS, Wernovsky G, Drotar D, Newburger JW,
Mahony L, Mussatto K, Tong E, Cohen M, Andersen C, Shera D, Khoury PR,
Wray J, Gaynor JW, Helfaer MA, Kazak AE, Shea JA; Pediatric Cardiac
Quality of Life Inventory Testing Study Consortium. Validation of the Pedi-
atric Cardiac Quality of Life Inventory. Pediatrics. 2010;126:498–508. doi:
10.1542/peds.2009-2973
86. Marino BS, Drotar D, Cassedy A, Davis R, Tomlinson RS, Mellion K,
Mussatto K, Mahony L, Newburger JW, Tong E, Cohen MI, Helfaer MA,
Kazak AE, Wray J, Wernovsky G, Shea JA, Ittenbach R. External validity of
the Pediatric Cardiac Quality of Life Inventory. Qual Life Res. 2011;20:205–
214. doi: 10.1007/s11136-010-9731-4
87. Wray J, Franklin R, Brown K, Cassedy A, Marino BS. Testing the Pediatric
Cardiac Quality of Life Inventory in the United kingdom. Acta Paediatr.
2013;102:e68–e73. doi: 10.1111/apa.12074
88. Nichol G, Guffey D, Stiell IG, Leroux B, Cheskes S, Idris A, Kudenchuk PJ,
Macphee RS, Wittwer L, Rittenberger JC, Rea TD, Sheehan K, Rac VE,
Raina K, Gorman K, Aufderheide T; Resuscitation Outcomes Consor-
tium Investigators. Post-discharge outcomes after resuscitation from
out-of-hospital cardiac arrest: a ROC PRIMED substudy. Resuscitation.
2015;93:74–81. doi: 10.1016/j.resuscitation.2015.05.011
Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702
Neurological Prognostication in Comatose Cardiac Arrest Survivors
89. Raina KD, Rittenberger JC, Holm MB, Callaway CW. Functional outcomes:
CLINICAL STATEMENTS
one year after a cardiac arrest. Biomed Res Int. 2015;2015:283608. doi:
AND GUIDELINES
10.1155/2015/283608
90. Bellinger DC. Lead. Pediatrics. 2004;113(suppl):1016–1022.
91. Becker LB, Aufderheide TP, Geocadin RG, Callaway CW, Lazar RM,
Donnino MW, Nadkarni VM, Abella BS, Adrie C, Berg RA, Merchant RM,
O’Connor RE, Meltzer DO, Holm MB, Longstreth WT, Halperin HR; on be-
half of the American Heart Association Emergency Cardiovascular Care
Committee; Council on Cardiopulmonary, Critical Care, Perioperative
and Resuscitation. Primary outcomes for resuscitation science studies: a
consensus statement from the American Heart Association. Circulation.
2011;124:2158–2177. doi: 10.1161/CIR.0b013e3182340239
92. Scarpino M, Lanzo G, Lolli F, Carrai R, Moretti M, Spalletti M,
Cozzolino M, Peris A, Amantini A, Grippo A. Neurophysiological and
neuroradiological multimodal approach for early poor outcome pre-
diction after cardiac arrest. Resuscitation. 2018;129:114–120. doi:
10.1016/j.resuscitation.2018.04.016
93. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J,
Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M,
Wise MP, Åneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I,
Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Køber L, Langørgen J,
Lilja G, Møller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P,
Friberg H; TTM Trial Investigators. Targeted temperature management at
33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369:2197–
2206. doi: 10.1056/NEJMoa1310519
94. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypo-
thermia to improve the neurologic outcome after cardiac arrest. N Engl J
Med. 2002;346:549–556.
95. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G,
Smith K. Treatment of comatose survivors of out-of-hospital cardiac ar-
rest with induced hypothermia. N Engl J Med. 2002;346:557–563. doi:
10.1056/NEJMoa003289
96. Samaniego EA, Mlynash M, Caulfield AF, Eyngorn I, Wijman CA.
Sedation confounds outcome prediction in cardiac arrest survivors
treated with hypothermia. Neurocrit Care. 2011;15:113–119. doi:
10.1007/s12028-010-9412-8
97. Paul M, Bougouin W, Dumas F, Geri G, Champigneulle B, Guillemet L,
Ben Hadj Salem O, Legriel S, Chiche JD, Charpentier J, Mira JP, Sandroni C,
Cariou A. Comparison of two sedation regimens during targeted tem-
perature management after cardiac arrest. Resuscitation. 2018;128:204–
210. doi: 10.1016/j.resuscitation.2018.03.025
98. Hirsch LJ, Laroche SM, Gaspard N, Gerard E, Svoronos A, Herman ST,
Mani R, Arif H, Jette N, Minazad Y, Kerrigan JF, Vespa P, Hantus S, Claassen J,
Young GB, So E, Kaplan PW, Nuwer MR, Fountain NB, Drislane FW. Amer-
ican Clinical Neurophysiology Society’s standardized critical care EEG
terminology: 2012 version. J Clin Neurophysiol. 2013;30:1–27. doi:
10.1097/WNP.0b013e3182784729
99. Westhall E, Rosén I, Rossetti AO, van Rootselaar AF, Wesenberg Kjaer T,
Friberg H, Horn J, Nielsen N, Ullén S, Cronberg T. Interrater variability of
EEG interpretation in comatose cardiac arrest patients. Clin Neurophysiol.
2015;126:2397–2404. doi: 10.1016/j.clinph.2015.03.017
100. Booth CM, Boone RH, Tomlinson G, Detsky AS. Is this patient dead,
vegetative, or severely neurologically impaired? Assessing outcome for
comatose survivors of cardiac arrest. JAMA. 2004;291:870–879. doi:
10.1001/jama.291.7.870
101. Suys T, Bouzat P, Marques-Vidal P, Sala N, Payen JF, Rossetti AO,
Oddo M. Automated quantitative pupillometry for the prognostication
of coma after cardiac arrest. Neurocrit Care. 2014;21:300–308. doi:
10.1007/s12028-014-9981-z
102. Couret D, Boumaza D, Grisotto C, Triglia T, Pellegrini L, Ocquidant P,
Bruder NJ, Velly LJ. Reliability of standard pupillometry practice in neurocrit-
ical care: an observational, double-blinded study. Crit Care. 2016;20:99.
doi: 10.1186/s13054-016-1239-z
103. Glasziou P, Altman DG, Bossuyt P, Boutron I, Clarke M, Julious S,
Michie S, Moher D, Wager E. Reducing waste from incomplete or un-
usable reports of biomedical research. Lancet. 2014;383:267–276. doi:
10.1016/S0140-6736(13)62228-X
104. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent Reporting
of a multivariable prediction model for Individual Prognosis Or Diagno-
sis (TRIPOD): the TRIPOD Statement. Br J Surg. 2015;102:148–158. doi:
10.1002/bjs.9736
105. Offiah AC, Burke D. The diagnostic accuracy of cross-sectional imaging
for detecting acute scaphoid fractures in children: a systematic review. Br
J Radiol. 2018;91:20170883. doi: 10.1259/bjr.20170883
August 27, 2019 e539
 Geocadin et al
106. Virgili G, Michelessi M, Miele A, Oddone F, Crescioli G, Fameli V, Lucenteforte E.
CLINICAL STATEMENTS
STARD 2015 was reproducible in a large set of studies on glaucoma. PLoS
AND GUIDELINES
One. 2017;12:e0186209. doi: 10.1371/journal.pone.0186209
107. Koller AC, Rittenberger JC, Repine MJ, Morgan PW, Kristan J,
Callaway CW; Post-Cardiac Arrest Service. Comparison of three cogni-
tive exams in cardiac arrest survivors. Resuscitation. 2017;116:98–104.
doi: 10.1016/j.resuscitation.2017.04.011
108. Moulaert VR, Verbunt JA, van Heugten CM, Wade DT. Cognitive impair-
ments in survivors of out-of-hospital cardiac arrest: a systematic review. Re-
suscitation. 2009;80:297–305. doi: 10.1016/j.resuscitation.2008.10.034
109. Moulaert VR, Verbunt JA, van Heugten CM, Bakx WG, Gorgels AP,
Bekkers SC, de Krom MC, Wade DT. Activity and Life After Survival of a
Cardiac Arrest (ALASCA) and the effectiveness of an early intervention
service: design of a randomised controlled trial. BMC Cardiovasc Disord.
2007;7:26. doi: 10.1186/1471-2261-7-26
110. Elias MD, Achuff BJ, Ittenbach RF, Ravishankar C, Spray TL, Fuller S,
Montenegro LM, Gaynor JW, O’Connor MJ. Long-term outcomes of
pediatric cardiac patients supported by extracorporeal membrane
oxygenation. Pediatr Crit Care Med. 2017;18:787–794. doi:
10.1097/PCC.0000000000001227
111. Engelmann KA, Jordan LC. Outcome measures used in pediatric
stroke studies: a systematic review. Arch Neurol. 2012;69:23–27. doi:
10.1001/archneurol.2011.1015
112. Wilder Schaaf KP, Artman LK, Peberdy MA, Walker WC, Ornato JP,
Gossip MR, Kreutzer JS; Virginia Commonwealth University ARCTIC In-
vestigators. Anxiety, depression, and PTSD following cardiac arrest: a sys-
tematic review of the literature. Resuscitation. 2013;84:873–877. doi:
10.1016/j.resuscitation.2012.11.021
113. Clements PT, Stenerson HJ. Surviving sudden loss: when life,
death, and technology collide. J Vasc Nurs. 2004;22:134–137. doi:
10.1016/j.jvn.2004.08.002
114. Wachelder EM, Moulaert VR, van Heugten C, Verbunt JA, Bekkers SC,
Wade DT. Life after survival: long-term daily functioning and quality of
life after an out-of-hospital cardiac arrest. Resuscitation. 2009;80:517–
522. doi: 10.1016/j.resuscitation.2009.01.020
115. National Institute of Neurological Disorders and Stroke. NINDS common
data elements. https://www.commondataelements.ninds.nih.gov. Ac-
cessed May 8, 2018.
Downloaded from http://ahajournals.org by on May 10, 2021
116. Northwestern University. HealthMeasures. http://www.healthmeasures.
net. Accessed May 8, 2018.
117. Gershon RC, Lai JS, Bode R, Choi S, Moy C, Bleck T, Miller D, Peterman A,
Cella D. Neuro-QOL: quality of life item banks for adults with neuro-
logical disorders: item development and calibrations based upon clinical
and general population testing. Qual Life Res. 2012;21:475–486. doi:
10.1007/s11136-011-9958-8
118. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V,
Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment,
MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr
Soc. 2005;53:695–699. doi: 10.1111/j.1532-5415.2005.53221.x
119. Saxton J, Morrow L, Eschman A, Archer G, Luther J, Zuccolotto A. Computer
assessment of mild cognitive impairment. Postgrad Med. 2009;121:177–
185. doi: 10.3810/pgm.2009.03.1990
120. Paul M, Bougouin W, Geri G, Dumas F, Champigneulle B, Legriel S,
Charpentier J, Mira JP, Sandroni C, Cariou A. Delayed awakening after
cardiac arrest: prevalence and risk factors in the Parisian registry. Inten-
sive Care Med. 2016;42:1128–1136. doi: 10.1007/s00134-016-4349-9
121. Kim F, Nichol G, Maynard C, Hallstrom A, Kudenchuk PJ, Rea T,
Copass MK, Carlbom D, Deem S, Longstreth WT Jr, Olsufka M, Cobb LA.
Effect of prehospital induction of mild hypothermia on survival and neu-
rological status among adults with cardiac arrest: a randomized clinical
trial. JAMA. 2014;311:45–52. doi: 10.1001/jama.2013.282173
122. Gold B, Puertas L, Davis SP, Metzger A, Yannopoulos D, Oakes DA, Lick CJ,
Gillquist DL, Holm SY, Olsen JD, Jain S, Lurie KG. Awakening after cardiac ar-
rest and post resuscitation hypothermia: are we pulling the plug too early?
Resuscitation. 2014;85:211–214. doi: 10.1016/j.resuscitation.2013.10.030
123. Polderman KH. Mechanisms of action, physiological effects, and compli-
cations of hypothermia. Crit Care Med. 2009;37(suppl):S186–S202. doi:
10.1097/CCM.0b013e3181aa5241
124. Meert KL, Donaldson A, Nadkarni V, Tieves KS, Schleien CL, Brilli RJ,
Clark RS, Shaffner DH, Levy F, Statler K, Dalton HJ, van der Jagt EW,
Hackbarth R, Pretzlaff R, Hernan L, Dean JM, Moler FW; Pediatric Emer-
gency Care Applied Research Network. Multicenter cohort study of
in-hospital pediatric cardiac arrest. Pediatr Crit Care Med. 2009;10:544–
553. doi: 10.1097/PCC.0b013e3181a7045c
e540 August 27, 2019
Neurological Prognostication in Comatose Cardiac Arrest Survivors
125. Greer DM, Yang J, Scripko PD, Sims JR, Cash S, Wu O, Hafler JP,
Schoenfeld DA, Furie KL. Clinical examination for prognostication in co-
matose cardiac arrest patients. Resuscitation. 2013;84:1546–1551. doi:
10.1016/j.resuscitation.2013.07.028
126. Thomsen JH, Hassager C, Bro-Jeppesen J, Søholm H, Nielsen N,
Wanscher M, Køber L, Pehrson S, Kjaergaard J. Sinus bradycardia during
hypothermia in comatose survivors of out-of-hospital cardiac arrest: a
new early marker of favorable outcome? Resuscitation. 2015;89:36–42.
doi: 10.1016/j.resuscitation.2014.12.031
127. Olson DM, Stutzman S, Saju C, Wilson M, Zhao W, Aiyagari V. Interrater
reliability of pupillary assessments. Neurocrit Care. 2016;24:251–257.
doi: 10.1007/s12028-015-0182-1
128. Solari D, Rossetti AO, Carteron L, Miroz JP, Novy J, Eckert P, Oddo M.
Early prediction of coma recovery after cardiac arrest with blinded pupil-
lometry. Ann Neurol. 2017;81:804–810. doi: 10.1002/ana.24943
129. Oddo M, Sandroni C, Citerio G, Miroz JP, Horn J, Rundgren M,
Cariou A, Payen JF, Storm C, Stammet P, Taccone FS. Quantitative ver-
sus standard pupillary light reflex for early prognostication in coma-
tose cardiac arrest patients: an international prospective multicenter
double-blinded study. Intensive Care Med. 2018;44:2102–2111. doi:
10.1007/s00134-018-5448-6
130. Abend NS, Topjian AA, Kessler SK, Gutierrez-Colina AM, Berg RA,
Nadkarni V, Dlugos DJ, Clancy RR, Ichord RN. Outcome prediction by
motor and pupillary responses in children treated with therapeutic hypo-
thermia after cardiac arrest. Pediatr Crit Care Med. 2012;13:32–38. doi:
10.1097/PCC.0b013e3182196a7b
131. Lybeck A, Friberg H, Aneman A, Hassager C, Horn J, Kjærgaard J,
Kuiper M, Nielsen N, Ullén S, Wise MP, Westhall E, Cronberg T; TTM-Trial
Investigators. Prognostic significance of clinical seizures after cardiac ar-
rest and target temperature management. Resuscitation. 2017;114:146–
151. doi: 10.1016/j.resuscitation.2017.01.017
132. Reynolds AS, Claassen J. Treatment of seizures and postanoxic status epi-
lepticus. Semin Neurol. 2017;37:33–39. doi: 10.1055/s-0036-1593862
133. Tsuchida TN, Wusthoff CJ, Shellhaas RA, Abend NS, Hahn CD, Sullivan JE,
Nguyen S, Weinstein S, Scher MS, Riviello JJ, Clancy RR; American Clinical
Neurophysiology Society Critical Care Monitoring Committee. American
Clinical Neurophysiology Society standardized EEG terminology and cat-
egorization for the description of continuous EEG monitoring in neo-
nates: report of the American Clinical Neurophysiology Society Critical
Care Monitoring Committee. J Clin Neurophysiol. 2013;30:161–173.
doi: 10.1097/WNP.0b013e3182872b24
134. Hocker S, Tatum WO, LaRoche S, Freeman WD. Refractory and super-
refractory status epilepticus–an update. Curr Neurol Neurosci Rep.
2014;14:452. doi: 10.1007/s11910-014-0452-x
135. Naim MY, Gaynor JW, Chen J, Nicolson SC, Fuller S, Spray TL, Dlugos DJ,
Clancy RR, Costa LV, Licht DJ, Xiao R, Meldrum H, Abend NS. Subclinical
seizures identified by postoperative electroencephalographic monitoring
are common after neonatal cardiac surgery. J Thorac Cardiovasc Surg.
2015;150:169–78; discussion 178. doi: 10.1016/j.jtcvs.2015.03.045
136. Lin JJ, Banwell BL, Berg RA, Dlugos DJ, Ichord RN, Kilbaugh TJ, Kirsch RE,
Kirschen MP, Licht DJ, Massey SL, Naim MY, Rintoul NE, Topjian AA,
Abend NS. Electrographic seizures in children and neonates undergo-
ing extracorporeal membrane oxygenation. Pediatr Crit Care Med.
2017;18:249–257. doi: 10.1097/PCC.0000000000001067
137. Topjian AA, Sánchez SM, Shults J, Berg RA, Dlugos DJ, Abend NS.
Early electroencephalographic background features predict outcomes
in children resuscitated from cardiac arrest. Pediatr Crit Care Med.
2016;17:547–557. doi: 10.1097/PCC.0000000000000740
138. Gaínza-Lein M, Sánchez Fernández I, Jackson M, Abend NS,
Arya R, Brenton JN, Carpenter JL, Chapman KE, Gaillard WD, Glauser TA,
Goldstein JL, Goodkin HP, Kapur K, Mikati MA, Peariso K, Tasker RC,
Tchapyjnikov D, Topjian AA, Wainwright MS, Wilfong A, Williams K,
Loddenkemper T; Pediatric Status Epilepticus Research Group. Associa-
tion of time to treatment with short-term outcomes for pediatric patients
with refractory convulsive status epilepticus. JAMA Neurol. 2018;75:410–
418. doi: 10.1001/jamaneurol.2017.4382
139. Krumholz A, Stern BJ, Weiss HD. Outcome from coma after cardiopul-
monary resuscitation: relation to seizures and myoclonus. Neurology.
1988;38:401–405. doi: 10.1212/wnl.38.3.401
140. Wijdicks EF, Young GB. Myoclonus status in comatose patients after car-
diac arrest. Lancet. 1994;343:1642–1643.
141. Arnoldus EP, Lammers GJ. Postanoxic coma: good recovery despite
myoclonus status. Ann Neurol. 1995;38:697–698. doi: 10.1002/ana.
410380427
Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702
 Geocadin et al
142. Bouwes A, van Poppelen D, Koelman JH, Kuiper MA, Zandstra DF,
Weinstein HC, Tromp SC, Zandbergen EG, Tijssen MA, Horn J. Acute
posthypoxic myoclonus after cardiopulmonary resuscitation. BMC Neu-
rol. 2012;12:63. doi: 10.1186/1471-2377-12-63
143. Elmer J, Rittenberger JC, Faro J, Molyneaux BJ, Popescu A, Callaway CW,
Baldwin M; Pittsburgh Post-Cardiac Arrest Service. Clinically distinct elec-
troencephalographic phenotypes of early myoclonus after cardiac arrest.
Ann Neurol. 2016;80:175–184. doi: 10.1002/ana.24697
144. Sandroni C, Nolan JP. Neurologically favorable outcome is still possible
despite myoclonus in comatose survivors of cardiac arrest. Crit Care Med.
2015;43:e396–e397. doi: 10.1097/CCM.0000000000001070
145. Seder DB, Sunde K, Rubertsson S, Mooney M, Stammet P,
Riker RR, Kern KB, Unger B, Cronberg T, Dziodzio J, Nielsen N. Neu-
rologic outcomes and postresuscitation care of patients with myoc-
lonus following cardiac arrest. Crit Care Med. 2015;43:965–972. doi:
10.1097/ccm.0000000000000880
146. Greer DM. Unexpected good recovery in a comatose post-cardiac arrest
patient with poor prognostic features. Resuscitation. 2013;84:e81–e82.
doi: 10.1016/j.resuscitation.2013.02.011
147. Hermans MC, Westover MB, van Putten MJAM, Hirsch LJ, Gaspard N.
Quantification of EEG reactivity in comatose patients. Clin Neurophysiol.
2016;127:571–580. doi: 10.1016/j.clinph.2015.06.024
148. Noirhomme Q, Lehembre R, Lugo Zdel R, Lesenfants D, Luxen A,
Laureys S, Oddo M, Rossetti AO. Automated analysis of background
EEG and reactivity during therapeutic hypothermia in comatose pa-
tients after cardiac arrest. Clin EEG Neurosci. 2014;45:6–13. doi:
10.1177/1550059413509616
149. Rossetti AO, Urbano LA, Delodder F, Kaplan PW, Oddo M. Prognostic
value of continuous EEG monitoring during therapeutic hypothermia af-
ter cardiac arrest. Crit Care. 2010;14:R173. doi: 10.1186/cc9276
150. Rossetti AO, Tovar Quiroga DF, Juan E, Novy J, White RD, Ben-Hamouda N,
Britton JW, Oddo M, Rabinstein AA. Electroencephalography predicts
poor and good outcomes after cardiac arrest: a two-center study. Crit
Care Med. 2017;45:e674–e682. doi: 10.1097/ccm.0000000000002337
151. Tsetsou S, Novy J, Oddo M, Rossetti AO. EEG reactivity to pain in co-
matose patients: importance of the stimulus type. Resuscitation.
2015;97:34–37. doi: 10.1016/j.resuscitation.2015.09.380
152. Amorim E, Rittenberger JC, Baldwin ME, Callaway CW, Popescu A;
Downloaded from http://ahajournals.org by on May 10, 2021
Post Cardiac Arrest Service. Malignant EEG patterns in cardiac ar-
rest patients treated with targeted temperature management who
survive to hospital discharge. Resuscitation. 2015;90:127–132. doi:
10.1016/j.resuscitation.2015.03.005
153. Mettenburg JM, Agarwal V, Baldwin M, Rittenberger JC. Discordant
observation of brain injury by MRI and malignant electroencephalog-
raphy patterns in comatose survivors of cardiac arrest following thera-
peutic hypothermia. AJNR Am J Neuroradiol. 2016;37:1787–1793. doi:
10.3174/ajnr.A4839
154. Thömke F, Brand A, Weilemann SL. The temporal dynamics of postanoxic
burst-suppression EEG. J Clin Neurophysiol. 2002;19:24–31.
155. Andresen JM, Girard TD, Pandharipande PP, Davidson MA, Ely EW,
Watson PL. Burst suppression on processed electroencephalography as a
predictor of postcoma delirium in mechanically ventilated ICU patients. Crit
Care Med. 2014;42:2244–2251. doi: 10.1097/CCM.0000000000000522
156. Cloostermans MC, van Meulen FB, Eertman CJ, Hom HW, van Putten MJ.
Continuous electroencephalography monitoring for early prediction
of neurological outcome in postanoxic patients after cardiac arrest: a
prospective cohort study. Crit Care Med. 2012;40:2867–2875. doi:
10.1097/CCM.0b013e31825b94f0
157. Hofmeijer J, Beernink TM, Bosch FH, Beishuizen A, Tjepkema-
Cloostermans MC, van Putten MJ. Early EEG contributes to multimodal
outcome prediction of postanoxic coma. Neurology. 2015;85:137–143.
doi: 10.1212/WNL.0000000000001742
158. Sivaraju A, Gilmore EJ, Wira CR, Stevens A, Rampal N, Moeller JJ, Greer DM,
Hirsch LJ, Gaspard N. Prognostication of post-cardiac arrest coma: early
clinical and electroencephalographic predictors of outcome. Intensive
Care Med. 2015;41:1264–1272. doi: 10.1007/s00134-015-3834-x
159. Dragancea I, Backman S, Westhall E, Rundgren M, Friberg H, Cronberg T.
Outcome following postanoxic status epilepticus in patients with tar-
geted temperature management after cardiac arrest. Epilepsy Behav.
2015;49:173–177. doi: 10.1016/j.yebeh.2015.04.043
160. Geocadin RG, Ritzl EK. Seizures and status epilepticus in post cardiac ar-
rest syndrome: therapeutic opportunities to improve outcome or basis to
withhold life sustaining therapies? Resuscitation. 2012;83:791–792. doi:
10.1016/j.resuscitation.2012.04.003
Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702
Neurological Prognostication in Comatose Cardiac Arrest Survivors
161. Kaplan PW, Morales Y. Re: Status epilepticus: an independent outcome pre-
CLINICAL STATEMENTS
dictor after cerebral anoxia. Neurology. 2008;70:1295; author reply 1295–
AND GUIDELINES
1295; author reply 1296. doi: 10.1212/01.wnl.0000312074.77793.a4
162. Mikhaeil-Demo Y, Gavvala JR, Bellinski II, Macken MP, Narechania A,
Templer JW, VanHaerents S, Schuele SU, Gerard EE. Clinical classification
of post anoxic myoclonic status. Resuscitation. 2017;119:76–80. doi:
10.1016/j.resuscitation.2017.07.035
163. Rossetti AO, Logroscino G, Liaudet L, Ruffieux C, Ribordy V, Schaller MD,
Despland PA, Oddo M. Status epilepticus: an independent outcome
predictor after cerebral anoxia. Neurology. 2007;69:255–260. doi:
10.1212/01.wnl.0000265819.36639.e0
164. Alvarez V, Oddo M, Rossetti AO. Stimulus-induced rhythmic, periodic or
ictal discharges (SIRPIDs) in comatose survivors of cardiac arrest: char-
acteristics and prognostic value. Clin Neurophysiol. 2013;124:204–208.
doi: 10.1016/j.clinph.2012.06.017
165. Hofmeijer J, Tjepkema-Cloostermans MC, van Putten MJ. Burst-sup-
pression with identical bursts: a distinct EEG pattern with poor out-
come in postanoxic coma. Clin Neurophysiol. 2014;125:947–954. doi:
10.1016/j.clinph.2013.10.017
166. American Clinical Neurophysiology Society. Guideline 9D: guidelines
on short-latency somatosensory evoked potentials. J Clin Neurophysiol.
2006;23:168–179.
167. Bassetti C, Bomio F, Mathis J, Hess CW. Early prognosis in coma after car-
diac arrest: a prospective clinical, electrophysiological, and biochemical
study of 60 patients. J Neurol Neurosurg Psychiatry. 1996;61:610–615.
doi: 10.1136/jnnp.61.6.610
168. Bouwes A, Binnekade JM, Verbaan BW, Zandbergen EG, Koelman JH,
Weinstein HC, Hijdra A, Horn J. Predictive value of neurological exami-
nation for early cortical responses to somatosensory evoked potentials
in patients with postanoxic coma. J Neurol. 2012;259:537–541. doi:
10.1007/s00415-011-6224-5
169. Bouwes A, Binnekade JM, Zandstra DF, Koelman JH, van Schaik IN,
Hijdra A, Horn J. Somatosensory evoked potentials during mild hypo-
thermia after cardiopulmonary resuscitation. Neurology. 2009;73:1457–
1461. doi: 10.1212/WNL.0b013e3181bf98f4
170. Chen R, Bolton CF, Young B. Prediction of outcome in patients with
anoxic coma: a clinical and electrophysiologic study. Crit Care Med.
1996;24:672–678.
171. Endisch C, Storm C, Ploner CJ, Leithner C. Amplitudes of SSEP and out-
come in cardiac arrest survivors: a prospective cohort study. Neurology.
2015;85:1752–1760. doi: 10.1212/WNL.0000000000002123
172. Fugate JE, Wijdicks EF, Mandrekar J, Claassen DO, Manno EM,
White RD, Bell MR, Rabinstein AA. Predictors of neurologic outcome in
hypothermia after cardiac arrest. Ann Neurol. 2010;68:907–914. doi:
10.1002/ana.22133
173. Zandbergen EG, Koelman JH, de Haan RJ, Hijdra A; PROPAC-Study
Group. SSEPs and prognosis in postanoxic coma: only short or
also long latency responses? Neurology. 2006;67:583–586. doi:
10.1212/01.wnl.0000230162.35249.7f
174. Wu D, Xiong W, Jia X, Geocadin RG, Thakor NV. Short- and long-la-
tency somatosensory neuronal responses reveal selective brain injury
and effect of hypothermia in global hypoxic ischemia. J Neurophysiol.
2012;107:1164–1171. doi: 10.1152/jn.00681.2011
175. Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brain-
stem auditory evoked potentials in cardiac arrest patients treated with
hypothermia. Crit Care Med. 2005;33:1736–1740.
176. Morlet D, Fischer C. MMN and novelty P3 in coma and other altered
states of consciousness: a review. Brain Topogr. 2014;27:467–479. doi:
10.1007/s10548-013-0335-5
177. Choi S, Park K, Ryu S, Kang T, Kim H, Cho S, Oh S. Use of S-100B, NSE,
CRP and ESR to predict neurological outcomes in patients with return of
spontaneous circulation and treated with hypothermia. Emerg Med J.
2016;33:690–695. doi: 10.1136/emermed-2015-205423
178. Ekmektzoglou KA, Xanthos T, Papadimitriou L. Biochemical markers
(NSE, S-100, IL-8) as predictors of neurological outcome in patients af-
ter cardiac arrest and return of spontaneous circulation. Resuscitation.
2007;75:219–228. doi: 10.1016/j.resuscitation.2007.03.016
179. Kim J, Choi BS, Kim K, Jung C, Lee JH, Jo YH, Rhee JE, Kim T, Kang KW.
Prognostic performance of diffusion-weighted MRI combined with NSE
in comatose cardiac arrest survivors treated with mild hypothermia. Neu-
rocrit Care. 2012;17:412–420. doi: 10.1007/s12028-012-9773-2
180. Oksanen T, Tiainen M, Skrifvars MB, Varpula T, Kuitunen A, Castrén M,
Pettilä V. Predictive power of serum NSE and OHCA score regarding
6-month neurologic outcome after out-of-hospital ventricular fibrillation
August 27, 2019 e541
 Geocadin et al
and therapeutic hypothermia. Resuscitation. 2009;80:165–170. doi:
CLINICAL STATEMENTS
10.1016/j.resuscitation.2008.08.017
AND GUIDELINES
181. Helánová K, Pařenica J, Jarkovský J, Dostálová L, Littnerová S, Klabenešová I,
Cermáková Z, Lokaj P, Kala P, Poloczek M, Toman O, Gimunová O, Maláska J,
Spinar J. S-100B protein elevation in patients with the acute coronary
syndrome after resuscitation is a predictor of adverse neurological prog-
nosis [in Czech]. Vnitr Lek. 2012;58:266–272.
182. Mörtberg E, Zetterberg H, Nordmark J, Blennow K, Rosengren L,
Rubertsson S. S-100B is superior to NSE, BDNF and GFAP in predicting
outcome of resuscitation from cardiac arrest with hypothermia treatment.
Resuscitation. 2011;82:26–31. doi: 10.1016/j.resuscitation.2010.10.011
183. Mussack T, Biberthaler P, Kanz KG, Wiedemann E, Gippner-Steppert C,
Mutschler W, Jochum M. Serum S-100B and interleukin-8 as predic-
tive markers for comparative neurologic outcome analysis of patients
after cardiac arrest and severe traumatic brain injury. Crit Care Med.
2002;30:2669–2674. doi: 10.1097/01.CCM.0000037963.51270.44
184. Shinozaki K, Oda S, Sadahiro T, Nakamura M, Abe R, Nakada TA,
Nomura F, Nakanishi K, Kitamura N, Hirasawa H. Serum S-100B is su-
perior to neuron-specific enolase as an early prognostic biomarker for
neurological outcome following cardiopulmonary resuscitation. Resusci-
tation. 2009;80:870–875. doi: 10.1016/j.resuscitation.2009.05.005
185. Topjian AA, Lin R, Morris MC, Ichord R, Drott H, Bayer CR, Helfaer MA,
Nadkarni V. Neuron-specific enolase and S-100B are associated with
neurologic outcome after pediatric cardiac arrest. Pediatr Crit Care Med.
2009;10:479–490. doi: 10.1097/PCC.0b013e318198bdb5
186. Longstreth WT Jr, Clayson KJ, Sumi SM. Cerebrospinal fluid and serum
creatine kinase BB activity after out-of-hospital cardiac arrest. Neurology.
1981;31:455–458.
187. Fink EL, Berger RP, Clark RS, Watson RS, Angus DC, Richichi R,
Panigrahy A, Callaway CW, Bell MJ, Kochanek PM. Serum biomarkers
of brain injury to classify outcome after pediatric cardiac arrest. Crit Care
Med. 2014;42:664–674. doi: 10.1097/01.ccm.0000435668.53188.80
188. Helwig K, Seeger F, Hölschermann H, Lischke V, Gerriets T, Niessner M,
Foerch C. Elevated serum glial fibrillary acidic protein (GFAP) is associated
with poor functional outcome after cardiopulmonary resuscitation. Neu-
rocrit Care. 2017;27:68–74. doi: 10.1007/s12028-016-0371-6
189. Kim SH, Choi SP, Park KN, Youn CS, Oh SH, Choi SM. Early brain
computed tomography findings are associated with outcome in pa-
Downloaded from http://ahajournals.org by on May 10, 2021
tients treated with therapeutic hypothermia after out-of-hospital
cardiac arrest. Scand J Trauma Resusc Emerg Med. 2013;21:57. doi:
10.1186/1757-7241-21-57
190. Langkjær S, Hassager C, Kjaergaard J, Salam I, Thomsen JH, Lippert FK,
Wanscher M, Køber L, Nielsen N, Søholm H. Prognostic value of reduced
discrimination and oedema on cerebral computed tomography in a daily
clinical cohort of out-of-hospital cardiac arrest patients. Resuscitation.
2015;92:141–147. doi: 10.1016/j.resuscitation.2015.03.023
191. Lee BK, Jeung KW, Lee HY, Jung YH, Lee DH. Combining brain com-
puted tomography and serum neuron specific enolase improves the
prognostic performance compared to either alone in comatose cardiac
arrest survivors treated with therapeutic hypothermia. Resuscitation.
2013;84:1387–1392. doi: 10.1016/j.resuscitation.2013.05.026
192. Wu O, Batista LM, Lima FO, Vangel MG, Furie KL, Greer DM. Predict-
ing clinical outcome in comatose cardiac arrest patients using early
noncontrast computed tomography. Stroke. 2011;42:985–992. doi:
10.1161/STROKEAHA.110.594879
193. Moseby-Knappe M, Pellis T, Dragancea I, Friberg H, Nielsen N,
Horn J, Kuiper M, Roncarati A, Siemund R, Undén J, Cronberg T; TTM-
Trial Investigators. Head computed tomography for prognostication
of poor outcome in comatose patients after cardiac arrest and tar-
geted temperature management. Resuscitation. 2017;119:89–94. doi:
10.1016/j.resuscitation.2017.06.027
194. Torbey MT, Geocadin R, Bhardwaj A. Brain Arrest Neurologi-
cal Outcome Scale (BrANOS): predicting mortality and severe dis-
ability following cardiac arrest. Resuscitation. 2004;63:55–63. doi:
10.1016/j.resuscitation.2004.03.021
195. Hahn DK, Geocadin RG, Greer DM. Quality of evidence in studies evalu-
ating neuroimaging for neurologic prognostication in adult patients
resuscitated from cardiac arrest. Resuscitation. 2014;85:165–172. doi:
10.1016/j.resuscitation.2013.10.031
196. Greer DM, Scripko PD, Wu O, Edlow BL, Bartscher J, Sims JR, Camargo EE,
Singhal AB, Furie KL. Hippocampal magnetic resonance imaging abnor-
malities in cardiac arrest are associated with poor outcome. J Stroke
Cerebrovasc Dis. 2013;22:899–905. doi: 10.1016/j.jstrokecerebrovasdis.
2012.08.006
e542 August 27, 2019
Neurological Prognostication in Comatose Cardiac Arrest Survivors
197. Greer D, Scripko P, Bartscher J, Sims J, Camargo E, Singhal A, Furie K.
Serial MRI changes in comatose cardiac arrest patients. Neurocrit Care.
2011;14:61–67. doi: 10.1007/s12028-010-9457-8
198. Mlynash M, Campbell DM, Leproust EM, Fischbein NJ, Bammer R,
Eyngorn I, Hsia AW, Moseley M, Wijman CA. Temporal and spatial profile of
brain diffusion-weighted MRI after cardiac arrest. Stroke. 2010;41:1665–
1672. doi: 10.1161/STROKEAHA.110.582452
199. Starling RM, Shekdar K, Licht D, Nadkarni VM, Berg RA, Topjian AA.
Early head CT findings are associated with outcomes after pediatric out-
of-hospital cardiac arrest. Pediatr Crit Care Med. 2015;16:542–548. doi:
10.1097/PCC.0000000000000404
200. Anderson KB, Poloyac SM, Kochanek PM, Empey PE. Effect of hypother-
mia and targeted temperature management on drug disposition and
response following cardiac arrest: a comprehensive review of preclinical
and clinical investigations. Ther Hypothermia Temp Manag. 2016;6:169–
179. doi: 10.1089/ther.2016.0003
201. van den Broek MP, Groenendaal F, Egberts AC, Rademaker CM. Effects
of hypothermia on pharmacokinetics and pharmacodynamics: a sys-
tematic review of preclinical and clinical studies. Clin Pharmacokinet.
2010;49:277–294. doi: 10.2165/11319360-000000000-00000
202. Roberts BW, Kilgannon JH, Chansky ME, Mittal N, Wooden J, Parrillo JE,
Trzeciak S. Multiple organ dysfunction after return of spontaneous cir-
culation in postcardiac arrest syndrome. Crit Care Med. 2013;41:1492–
1501. doi: 10.1097/CCM.0b013e31828a39e9
203. Nobile L, Taccone FS, Szakmany T, Sakr Y, Jakob SM, Pellis T, Antonelli M,
Leone M, Wittebole X, Pickkers P, Vincent JL; ICON Investigators. The
impact of extracerebral organ failure on outcome of patients after car-
diac arrest: an observational study from the ICON database. Crit Care.
2016;20:368. doi: 10.1186/s13054-016-1528-6
204. Sakamoto T, Morimura N, Nagao K, Asai Y, Yokota H, Nara S, Hase M,
Tahara Y, Atsumi T; SAVE-J Study Group. Extracorporeal cardiopulmonary
resuscitation versus conventional cardiopulmonary resuscitation in adults
with out-of-hospital cardiac arrest: a prospective observational study. Re-
suscitation. 2014;85:762–768. doi: 10.1016/j.resuscitation.2014.01.031
205. Lamhaut L, Hutin A, Puymirat E, Jouan J, Raphalen JH, Jouffroy R, Jaffry M,
Dagron C, An K, Dumas F, Marijon E, Bougouin W, Tourtier JP, Baud F,
Jouven X, Danchin N, Spaulding C, Carli P. A pre-hospital extracorporeal car-
dio pulmonary resuscitation (ECPR) strategy for treatment of refractory out
hospital cardiac arrest: an observational study and propensity analysis. Re-
suscitation. 2017;117:109–117. doi: 10.1016/j.resuscitation.2017.04.014
206. Lasa JJ, Rogers RS, Localio R, Shults J, Raymond T, Gaies M, Thiagarajan R,
Laussen PC, Kilbaugh T, Berg RA, Nadkarni V, Topjian A. Extracorporeal
cardiopulmonary resuscitation (E-CPR) during pediatric in-hospital car-
diopulmonary arrest is associated with improved survival to discharge: a
report from the American Heart Association’s Get With The Guidelines–
Resuscitation (GWTG-R) Registry. Circulation. 2016;133:165–176. doi:
10.1161/CIRCULATIONAHA.115.016082
207. US Department of Health and Human Services, Food and Drug Adminis-
tration, Office of Good Clinical Practice, Center for Drug Evaluation and
Research, Center for Biologics Evaluation and Research, Center for Devices
and Radiological Health. Guidance for institutional review boards, clinical
investigators, and sponsors: exception from informed consent requirements
for emergency research. March 2011. https://www.fda.gov/downloads/
regulatoryinformation/guidances/ucm249673.pdf. Accessed April 2013.
208. Davidson JE, Aslakson RA, Long AC, Puntillo KA, Kross EK, Hart J, Cox CE,
Wunsch H, Wickline MA, Nunnally ME, Netzer G, Kentish-Barnes N,
Sprung CL, Hartog CS, Coombs M, Gerritsen RT, Hopkins RO, Franck LS,
Skrobik Y, Kon AA, Scruth EA, Harvey MA, Lewis-Newby M, White DB,
Swoboda SM, Cooke CR, Levy MM, Azoulay E, Curtis JR. Guidelines for
family-centered care in the neonatal, pediatric, and adult ICU. Crit Care
Med. 2017;45:103–128. doi: 10.1097/CCM.0000000000002169
209. Coombs MA, Parker R, Ranse K, Endacott R, Bloomer MJ. An integrative
review of how families are prepared for, and supported during withdraw-
al of life-sustaining treatment in intensive care. J Adv Nurs. 2017;73:39–
55. doi: 10.1111/jan.13097
210. Kynoch K, Chang A, Coyer F, McArdle A. The effectiveness of interven-
tions to meet family needs of critically ill patients in an adult intensive
care unit: a systematic review update. JBI Database System Rev Imple-
ment Rep. 2016;14:181–234. doi: 10.11124/JBISRIR-2016–2477
211. Kon AA, Davidson JE, Morrison W, Danis M, White DB. Shared deci-
sion-making in intensive care units. executive summary of the American
College of Critical Care Medicine and American Thoracic Society pol-
icy statement. Am J Respir Crit Care Med. 2016;193:1334–1336. doi:
10.1164/rccm.201602-0269ED
Circulation. 2019;140:e517–e542. DOI: 10.1161/CIR.0000000000000702