Is This Patient Dead, Vegetative, or Severely

Neurologically Impaired?: Assessing Outcome for

Comatose Survivors of Cardiac Arrest
Online article and related content
current as of November 16, 2009. Christopher M. Booth; Robert H. Boone; George Tomlinson; et al.
JAMA. 2004;291(7):870-879 (doi:10.1001/jama.291.7.870)

http://jama.ama-assn.org/cgi/content/full/291/7/870

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Topic collections Neurology; Coma/ Vegetative State; Patient-Physician Relationship/ Care;

End-of-life Care/ Palliative Medicine; Prognosis/ Outcomes; The Rational Clinical
Examination
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Related Letters Usefulness of the Glasgow Coma Score in Survivors of Cardiac Arrest
Zsolt T. Stockinger. JAMA. 2004;291(19):2313.

In Reply:
Christopher M. Booth et al. JAMA. 2004;291(19):2313.

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 THE RATIONAL CLINICIAN’S CORNER
CLINICAL EXAMINATION

Is This Patient Dead, Vegetative,

or Severely Neurologically Impaired?
Assessing Outcome for Comatose Survivors of Cardiac Arrest
Christopher M. Booth, MD Context Most survivors of cardiac arrest are comatose after resuscitation, and mean-
Robert H. Boone, MD, MSc ingful neurological recovery occurs in a small proportion of cases. Treatment can be lengthy,
expensive, and often difficult for families and caregivers. Physical examination is poten-
George Tomlinson, PhD
tially useful in this clinical scenario, and the information obtained may help physicians
Allan S. Detsky, MD, PhD, FRCPC and families make accurate decisions about treatment and/or withdrawal of care.
CLINICAL SCENARIO Objective To determine the precision and accuracy of the clinical examination in pre-
Case 1 dicting poor outcome in post–cardiac arrest coma.
A 65-year-old man experienced a wit- Data Sources and Study Selection We searched MEDLINE for English-
nessed ventricular fibrillation cardiac language articles (1966-2003) using the terms coma, cardiac arrest, prognosis, physi-
arrest at home 24 hours ago. A neigh- cal examination, sensitivity and specificity, and observer variation. Other sources came
bor had performed cardiopulmonary from bibliographies of retrieved articles and physical examination textbooks. Studies
resuscitation for 5 minutes until the were included if they assessed the precision and accuracy of the clinical examination
paramedics arrived and performed suc- in prognosis of post–cardiac arrest coma in adults. Eleven studies, involving 1914 pa-
tients, met our inclusion criteria.
cessful defibrillation. His electrocar-
diogram revealed a large anterior Data Extraction Two authors independently reviewed each study to determine eli-
myocardial infarction for which he un- gibility, abstract data, and classify methodological quality using predetermined crite-
ria. Disagreement was resolved by consensus.
derwent urgent coronary angioplasty.
Although still unresponsive, he with- Data Synthesis Summary likelihood ratios (LRs) were calculated from random effects
draws from a painful stimulus and his models. Five clinical signs were found to strongly predict death or poor neurological out-
pupillary and corneal reflexes are pre- come: absent corneal reflexes at 24 hours (LR, 12.9; 95% confidence interval [CI], 2.0-68.7),
absent pupillary response at 24 hours (LR, 10.2; 95% CI, 1.8-48.6), absent withdrawal
sent. The family asks you about his response to pain at 24 hours (LR, 4.7; 95% CI, 2.2-9.8), no motor response at 24 hours
chance of meaningful recovery. (LR, 4.9; 95% CI, 1.6-13.0), and no motor response at 72 hours (LR, 9.2; 95% CI, 2.1-
49.4). The proportion of individuals’ dying or having a poor neurological outcome was
Case 2 calculated by pooling the outcome data from the 11 studies (n=1914) and used as an
A 26-year-old woman presented to the estimate of the pretest probability of poor outcome. The random effects estimate of poor
emergency department with severe outcome was 77% (95% CI, 72%-80%). The highest LR increases the pretest probabil-
pleuritic chest pain and dyspnea. While ity of 77% to a posttest probability of 97% (95% CI, 87%-100%). No clinical findings
waiting for a computed tomographic were found to have LRs that strongly predicted good neurological outcome.
scan in the radiology department, she Conclusions Simple physical examination maneuvers strongly predict death or poor
had an asystolic cardiac arrest. The re- outcome in comatose survivors of cardiac arrest. The most useful signs occur at 24
suscitation lasted 20 minutes, after hours after cardiac arrest, and earlier prognosis should not be made by clinical exami-
nation alone. These data provide prognostic information, rather than treatment rec-
which she was found to have reactive
ommendations, which must be made on an individual basis incorporating many other
pupils. Three days later the family is variables.
considering withdrawing care be- JAMA. 2004;291:870-879 www.jama.com
cause she is still comatose. On exami-
Author Affiliations are listed at the end of this article. The Rational Clinical Examination Section Editors:
Corresponding Author: Allan S. Detsky, MD, PhD, David L. Simel, MD, MHS, Durham Veterans Affairs
CME available online at FRCPC, Mount Sinai Hospital, Suite 427, 600 Univer- Medical Center and Duke University Medical Center,
www.jama.com sity Ave, Toronto, Ontario, Canada M5G 1X5 Durham, NC; Drummond Rennie, MD, Deputy Edi-
([email protected]). tor, JAMA.

870 JAMA, February 18, 2004—Vol 291, No. 7 (Reprinted) ©2004 American Medical Association. All rights reserved.

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 ASSESSING OUTCOME FOR COMATOSE SURVIVORS OF CARDIAC ARREST

nation, her pupils are now unreactive lation can only be determined when the
Table 1. Glasgow Coma Scale*
and she has no motor response or brain- true outcome of each patient is known,
Best Motor Response
stem reflexes. The nurse reports that the rather than at the time of presenta-
Obeying commands 6
patient had myoclonus 12 hours ago. tion. Recent interest has developed in Localizing to pain 5
the potential role of neurophysiologic Withdrawing to pain 4
Abnormal flexion (decorticate) 3
Why Is the Clinical testing.6-8 A recent systematic review Extensor response (decerebrate) 2
Examination Important? found somatosensory-evoked poten- None 1
With the development of closed-chest tials very useful in predicting “waken- Best Verbal Response†
cardiac massage in 1960 and the cre- ing” of comatose patients.7 Other re- Oriented 5
ation of intensive care units shortly search suggests that elevated serum Confused conversation 4
Inappropriate words 3
thereafter, it became possible to sur- levels of neuron-specific enolase may Incomprehensible sounds 2
vive cardiac arrest. Half a century later, predict poor outcome in comatose sur- None 1
cardiovascular disease is the leading vivors of cardiac arrest.8 Although these Eye Opening
cause of death in North America and Eu- results are promising, it will take some Spontaneous 4
rope—accounting for approximately half time before the precise operating char- To speech 3
To pain 2
of all deaths in the United States. At least acteristics of these tests are fully un- None 1
225 000 people die annually in the derstood and before the technology is *The score for the scale is summed across the 3 com-
ponents and ranges from 3 to 15. A lower score indi-
United States from cardiovascular dis- widely available in clinical practice. cates more severe neurological deficits. Original Glasgow
ease before they reach a hospital. Twice The physical examination has the po- Coma Scale in Teasdale and Jennett11
†Intubated patients cannot be given a score for the ver-
as many will have cardiac arrest and at- tential to be extremely useful in this bal component, so their total scores accordingly range
from 2 to 10.
tempted resuscitation during hospital- common clinical scenario because of its
ization. Survival rates for prehospital car- universal availability and ease of per-
diac arrest range from 2% to 33%, and formance. From a compassionate stand-
reported inpatient survival rates range point, the clinical evaluation yields the How to Examine a
between 0% and 29%.1,2 Most survi- first information that is relayed to fam- Comatose Patient
vors of cardiac arrest (⬇80%) are co- ily members desperate for informa- Glasgow Coma Scale. Prior to 1974, the
matose after resuscitation. After trauma tion. Thus, it is crucial for physicians clinical assessment of coma relied on
and drug overdose, cardiac arrest is now to understand the precision and accu- qualitative, descriptive terminology, and
the third most common cause of coma.3,4 racy of the clinical examination in de- the presence or absence of brainstem re-
With increasing public education in ba- termining prognosis in hypoxic- flexes. Plum and Posner10 described the
sic life support and with the use of au- ischemic coma. widely used definition of coma as “a state
tomated defibrillators in public places, of unarouseable unresponsiveness.” In
such as in airports and shopping malls, Pathophysiology 1974, Teasdale and Jennett11 published
post–cardiac arrest coma has become a Unlike traumatic or focal ischemic the first description of the Glasgow Coma
common and important clinical syn- causes of coma, cardiac arrest pre- Scale (GCS, TABLE 1), which has since
drome. sents a global ischemic insult to the been used worldwide as a means of clas-
With the increased success of resus- brain. The extent of cerebral damage is sifying coma. Although originally de-
citation from cardiac arrest comes a mul- largely influenced by the duration of in- scribed for traumatic coma, it is equally
titude of medical, ethical, and eco- terrupted cerebral blood flow. Accord- applicable to the assessment of nontrau-
nomic questions. Once spontaneous ingly, minimizing both the arrest (no- matic coma. This ordinal scale is calcu-
circulation has been restored, recovery flow) time and cardiopulmonary lated from the sum of 3 components: mo-
is far from certain. Possible outcomes resuscitation (low-flow) time are criti- tor response, verbal response, and eye
range from complete neurological re- cal. With the return of spontaneous cir- opening. In assessing the motor re-
covery to death to the persistent vegeta- culation comes a transient period of ce- sponse, it is important to apply central
tive state. In admitted patients who sur- rebral hyperemia, which is followed by pain because spinal reflexes may occur
vive the initial cardiac arrest, rates of vasospasm and protracted global and with peripheral stimulation and do not
meaningful neurological recovery range multifocal hypoperfusion. Cerebral oxy- represent a true motor response. A pain-
from 10% to 30%.5 This uncertainty fur- gen stores and consciousness are lost ful stimulus may be applied to the su-
thers the emotional distress of a griev- within 20 seconds of the onset of car- praorbital region (deep pinching of the
ing and anxious family. Accordingly, it diac arrest while glucose and adeno- skin) or the sternum (firm twisting pres-
is important for families and physi- sine triphosphate stores are lost by 5 sure applied with the examiner’s knuck-
cians to have an understanding of a pa- minutes. A cascade of complex chemi- les). The minimum GCS score is 3 and
tient’s chance of meaningful recovery. cal derangements ensue, which leads to maximum is 15.
Unfortunately the result of the gold neuronal death and culminates in the Physical Examination Maneuvers. In
standard test for prognosis in this popu- post–cardiac arrest coma.9 addition to the GCS, various brain-
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, February 18, 2004—Vol 291, No. 7 871

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ASSESSING OUTCOME FOR COMATOSE SURVIVORS OF CARDIAC ARREST

lated sudden muscular contractions and

Box. Glasgow-Pittsburgh Cerebral Performance Categories* may be either focal or generalized con-
1. Good Cerebral Performance
tractions of axial and limb muscula-
ture. In patients with seizures, the
Conscious: Alert, able to work and lead a normal life. May have minor psycho-
logical or neurological deficits (mild dysphasia, nonincapacitating hemiparesis, or physical examination should be re-
minor cranial nerve abnormalities). peated after the postictal period.
Finally, mechanically ventilated pa-
2. Moderate Cerebral Disability
tients are frequently sedated and/or para-
Conscious. Sufficient cerebral function for part-time work in sheltered environ- lyzed. Accordingly, when performing a
ment or independent activities of daily life (dressing, traveling by public trans-
detailed neurological examination it is
portation, and preparing food). May have hemiplegia, seizures, ataxia, dsysar-
thria, dysphasia, or permanent memory or mental changes. crucial that these medications be at least
temporarily discontinued.
3. Severe Cerebral Disability
Conscious. Dependent on others for daily support because of impaired brain func- Outcomes of Interest
tion (in an institution or at home with exceptional family effort). At least limited The neurological outcome of coma-
cognition. Includes a wide range of cerebral abnormalities from ambulatory with
tose patients is most often described us-
severe memory disturbance or dementia precluding independent existence to para-
lytic and able to communicate only with eyes, as in the locked-in syndrome. ing the Cerebral Performance Catego-
ries (CPC) 1 to 5 as shown in the BOX.13
4. Coma, Vegetative State
Not conscious. Unaware of surroundings, no cognition. No verbal or psychologi- METHODS
cal interactions with environment. Search Strategy
5. Death and Quality Review
Certified brain dead or dead by traditional criteria. We conducted a computerized biblio-
*Adapted with permission from Cummings et al.13 graphic search of MEDLINE and
EMBASE for the years 1966 to 2003
to determine the precision and accu-
racy of components of the clinical ex-
stem reflexes are used in the physical brain and vestibular reflexes, the eyes amination in prognosis of hypoxic-
examination of comatose patients.10,12 will move in a direction opposite to that ischemic coma. Search terms included
The pupillary reflex involves cranial in which the head is moved. If this re- coma, cardiac arrest, prognosis, physi-
nerves II and III. Shining a penlight into flex is lost, the globes will remain fixed cal examination, sensitivity and specific-
one eye and then the other tests the pa- within the head and the eyes will con- ity, and observer variation. The search
tient’s pupillary light response; the ex- tinue to stare in whatever direction the was conducted using a previously pub-
aminer observes the direct and consen- head is pointed. This reflex should not lished search strategy for The Rational
sual response (constriction of the be tested in cases of suspected cervical Clinical Examination series. 14 We
opposite eye). The corneal reflex in- trauma. Cold water caloric testing (ocu- checked the reference lists of all re-
volves cranial nerves V and VII. Touch- lovestibular reflex) also tests the ves- view articles and primary studies for ad-
ing the cornea with a piece of cotton tibular and oculomotor systems. To ditional articles that were not identi-
or tissue should cause both eyes to perform the test, first examine the tym- fied on the computerized search.
blink. The gag and cough reflexes test panic membrane to ensure there is Standard physical examination text-
cranial nerves IX and X. To elicit a gag, no perforation or impacted cerumen. books and personal communications
apply a tongue depressor to the poste- With the head 30° higher than the with the authors of primary studies pro-
rior pharynx. The soft palate should rise horizontal, irrigate up to 120 mL of ice vided additional citations. Finally, we
symmetrically. In patients who are in- cold water into the auditory canal. In manually reviewed published ab-
tubated, assess the cough (or carinal) the unconscious patient with intact stracts from the annual scientific meet-
reflex by applying deep suction through brainstem function, there will be slow ings of the American Neurological As-
the endotracheal tube to the carina. The tonic deviation of eyes towards the ir- sociation, the American Academy of
suction will produce a gasp followed by rigated ear. Neurology, the Society of Critical Care
several rapid coughs. It is also important to note the pres- Medicine, and the European Society for
Vestibular signs are also commonly ence of seizures or myoclonus when ex- Intensive Care Medicine for the years
examined in the comatose patient. The amining the comatose patient, for some 1997-2003.
oculocephalic (or “Doll’s eye”) reflex clinicians believe they may be useful in One of the authors (C.M.B.) ini-
involves observing the patient’s eyes prognosis of comatose survivors of car- tially screened the titles and abstracts
during passive rotation of the skull. In diac arrest. Seizures may be general- of the search results and classified them
a comatose patient with intact mid- ized or focal. Myoclonus refers to iso- as primary studies, review articles, or
872 JAMA, February 18, 2004—Vol 291, No. 7 (Reprinted) ©2004 American Medical Association. All rights reserved.

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 ASSESSING OUTCOME FOR COMATOSE SURVIVORS OF CARDIAC ARREST

not relevant. Because we were inter- outcome data in this fashion and be- cal variables at various times after car-
ested in both the precision and accu- cause we could not combine studies that diac arrest. Likelihood ratios were mod-
racy of the clinical examination in post– had differing definitions of good vs poor eled using a method described by Warn
cardiac arrest coma, we included outcomes. Furthermore, we thought it et al22 for relative risks, also using the
primary studies of each type. Because was reasonable to assume that most cli- prior distributions used therein. Post-
a preliminary review of the literature re- nicians, patients, and families would not test probabilities were computed from
vealed very few precision studies, the consider severe neurological disability the estimated pretest probability and
inclusion criteria for this type of study (defined as CPC 3) a desirable out- LRs.23 All analyses were done using the
were broadened. Precision studies were come. WinBUGS software package.24
included if they assessed the interob- The methodological quality of each
server agreement in the neurological ex- primary study was assessed in dupli- Likelihood Ratios
amination of comatose adult patients. cate using modified criteria previ- Likelihood ratios are a method of con-
We included both traumatic and non- ously developed for the Rational Clini- verting pretest information (ie, prob-
traumatic forms of coma. cal Examination series.21 Because this ability, or more precisely, odds) into
Primary studies of accuracy were in- study was assessing prognosis and not posttest information.25 The pretest in-
dependently reviewed by 2 of us diagnosis, investigators were consid- formation is the probability of a poor
(C.M.B. and R.H.B.) and included if ered blinded if the study was prospec- outcome among all comatose survivors
they assessed the accuracy of the clini- tive and clinical variables were as- of cardiac arrest. The results of the clini-
cal examination in prognosis of hy- sessed before patient outcome was cal examination, reflected in the LRs for
poxic-ischemic coma in patients older known. Level 1 studies were prospec- the findings, are combined with the pre-
than 10 years. Other criteria for study tive studies with 100 or more consecu- test information to estimate the post-
selection were the presentation of out- tive unselected patients. Level 2 stud- test probability of a poor outcome. For
come data for individual clinical vari- ies were similar but involved fewer than clinicians, the easiest way to interpret
ables measured at discrete time inter- 100 patients. Level 3 studies were ret- LRs is to keep in mind that when an ab-
vals. Selected studies also presented rospective chart reviews, and level 4 normal clinical finding is present in a co-
neurological outcome data as defined studies included selected (ie, noncon- matose survivor (eg, absent pupillary
by the Cerebral Performance Catego- secutive) patients. response), the likelihood of a poor out-
ries (CPCs) or in such a manner that come increases and the LR will be greater
an equivalent CPC score could be de- Statistical Methods than 1. Similarly, if the finding does not
termined (Box). Studies were ex- Two authors (C.M.B. and R.H.B.) in- indicate a poor prognosis (eg, present
cluded if they involved patients with dependently extracted data for analy- pupillary response), an LR of less than
coma from other medical conditions or sis; we resolved disagreement by con- 1 will occur.
trauma. sensus. When data were missing or
Based on our findings in a prelimi- unclear, we contacted the primary in- RESULTS
nary literature search, we realized there vestigators requesting further informa- Search Results and Quality
were 2 types of accuracy studies in the tion. Published raw data were used to of the Evidence
literature. The majority of studies di- calculate positive and negative likeli- Our search yielded 5 studies of preci-
chotomized patient outcome as good or hood ratios (LRs) for specific clinical sion that met our inclusion criteria
poor. Unfortunately there is not a uni- variables. To create 2 ⫻ 2 evidence (TABLE 2).26-30 Two other studies of pre-
form definition of what constitutes a tables we dichotomized CPC 1 and 2 cision were excluded because neither
good vs a poor outcome. Most studies as good outcome and CPC 3 through 5 rates of agreement (␬) nor raw data
combined outcome data for severe neu- as poor outcome. Sensitivity was de- were presented.31,32 Fourteen accu-
rological disability, vegetative state, and fined as the proportion of patients with racy articles describing 11 different
death (ie, CPC 3-5) as a poor outcome and a poor neurological outcome who had studies met our inclusion criteria
normal or moderate disability (ie, CPC a particular physical finding; specific- (TABLE 3).33-46 We had 100% agree-
1-2) as a good outcome. However, there ity was the proportion of patients who ment on the inclusion of studies for the
were 6 studies that included severe neu- had a good neurological outcome who systematic review. Reasons for exclud-
rological disability (ie, CPC 3) as a good did not have the particular finding. ing relevant studies included studies
outcome; 4 of which included fewer than Where 3 or more studies examined that did not present neurological out-
65 patients.15-20 We included only stud- the same clinical variable at the same comes as CPC 1 and 2 as good and CPC
ies from which combined outcome data time after cardiac arrest, we calculated 3 to 5 as poor outcomes,15-20 studies in
for severe neurological disability, veg- summary LRs and 95% confidence in- which patients were not comatose,47-52
etative state, and death (ie, CPC 3-5) tervals (CIs) using Bayesian random- studies that included only patients in
could be extracted. We did this be- effects meta-analyses. We also present persistent vegetative state,53,54 studies
cause most primary studies presented the strongest LRs for individual clini- that included other forms of medical
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, February 18, 2004—Vol 291, No. 7 873

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ASSESSING OUTCOME FOR COMATOSE SURVIVORS OF CARDIAC ARREST

coma,55,56 and studies that presented the We reached 100% agreement on the 2 as level 4. The studies and method-
same data set.3,57 One study was a sys- methodological quality scores. Of the ological quality scores are summa-
tematic review of clinical and neuro- 11 accuracy studies, 5 were classified rized in Table 3.
physiological variables.6 as level 1, 3 as level 2, 1 as level 3, and
Precision of the Clinical
Table 2. Interobserver Agreement of Clinical Examination for Coma Examination of Coma
No. of Observer’s Level Variable Agreement, Five studies have reported the preci-
Source Observers of Experience Assessed ␬ Statistic sion of the examination of comatose pa-
Braakman et al,26 1977 12 Neurosurgeons and GCS motor 0.72 tients (Table 2). Heterogeneity in study
residents
20 Neurosurgical nurses GCS motor 0.75
methodology, patient population, and
Teasdale et al,27 1978 7 Neurosurgeons GCS eye DR = 14.3%
variables assessed, precluded a quan-
GCS verbal DR = 5.4% titative synthesis of results; thus, these
GCS motor DR = 10.9% studies were reviewed qualitatively. As
Pupil response DR = 4.3% presented in Table 2, interobserver
van den Berge et al,28 6 Neurosurgeons Oculocephalic 0.49 agreement was moderate to substan-
1979 response tial in each of the studies. Three stud-
Spontaneous eye 0.46 ies found no difference in interob-
movement
server agreement between experienced
Pupil response 0.65
nurses, residents, and physicians.26-28
Minderhoud et al,29 1982 4 Physicians GCS eye 0.62
One study did find precision to be di-
GCS verbal 0.59
minished in groups of less experi-
GCS motor 0.68
enced examiners.30 No study exam-
Pupil response 0.79
ined only patients with nontraumatic
Oculocephalic 0.74
response causes of coma. In summary, there was
Born et al,30 1987 6 Neurosurgeons GCS motor 0.65 reasonable consistency among stud-
Brainstem score 0.69 ies, and the precision of the clinical ex-
Pupil response 0.70 amination of coma (including compo-
6 Other physicians GCS motor 0.36 nents of the GCS and brainstem
Brainstem reflexes 0.42 reflexes) has been found to be moder-
Abbreviations: DR, reported disagreement rate; GCS, Glasgow Coma Scale. ate to substantial.

Table 3. Studies of the Accuracy of the Clinical Examination in Prognosis of Hypoxic-Ischemic Coma*
Neurological
Outcomes§
Level of Site of Mean No. of Outcome
Source Evidence Study Population Arrest Age, y† Patients Good Poor Assessment
Berek et al,33 1997 2 Post–cardiac arrest coma PH 68 42 13 29 At discharge
Chen et al,34 1996 4 Patients in hypoxic-ischemic coma PH or IH 58 34 7 27 3 mo㛳
at 24 h
Earnest et al,35 1979 1 Post–cardiac arrest coma PH 62 100 30 70 At discharge
Edgren et al,36 1987 4 Post–cardiac arrest coma PH or IH 71 32 11 21 6 mo㛳
Edgren et al,37 1994‡ 1 Post–cardiac arrest coma PH or IH 58 262 89 173 12 mo㛳
Krumholz et al,38 1988 1 Patients in post–cardiac arrest coma PH or IH 67 114 21 93 At discharge
at 24 h
Levy et al,39 1985 1 Hypoxic-ischemic coma PH or IH 61 210 26 184 12 mo㛳
Madl et al,40 2000 1 Patients in post–cardiac arrest coma PH or IH 57 209 49 160 6 mo㛳
at 24 h
Madl et al,41 1993 2 Post–cardiac arrest coma PH or IH 58 66 17 49 At discharge㛳
Sasser,42 1999‡ 1 Patients in post–cardiac arrest coma PH or IH 63 937 230 707 6 mo㛳
at 12 h
Snyder et al,43-45 1980/1981 2 Post–cardiac arrest coma PH 64 63 25 38 6 mo㛳
Widjiks et al,46 1994 3 Post–cardiac arrest coma PH 63 107 15 92 6 mo
Abbreviations: IH, in-hospital cardiac arrest; PH, prehospital cardiac arrest.
*The 14 sources represent 11 studies
†When the mean age was not provided, the median age of the study population is listed.
‡This article includes patients from the first Brain Resuscitation Clinical Trial (BRCT), also included in Sasser’s dissertation, which involves all 3 BRCTs.
§Good neurological outcome refers to cerebral performance categories (CPCs) 1 and 2. Poor outcome includes CPCs 3 through 5. See the Box for a definition of CPCs.
㛳Outcome refers to best ever CPC in specified time period.

874 JAMA, February 18, 2004—Vol 291, No. 7 (Reprinted) ©2004 American Medical Association. All rights reserved.

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 ASSESSING OUTCOME FOR COMATOSE SURVIVORS OF CARDIAC ARREST

Accuracy of the Clinical of cardiac arrest were assessed for the 2915 patients were randomly as-
Examination of Coma use of a barbiturate (thiopental). In signed to receive standard- or high-
Fourteen articles involving 11 differ- BRCT II59 (1984-1989), 516 comatose dose epinephrine during cardiac ar-
ent studies of the accuracy of the clini- patients were randomly assigned to re- rest. All 3 of the BRCT studies reported
cal examination were included (Table ceive placebo or a calcium channel negative results; there was no differ-
3). These studies provided a sample size blocker (lidoflazine) following car- ence found in survival or neurological
of 1914 comatose survivors of cardiac diac arrest. In BRCT III42 (1989-1992), outcome among treatment groups. Two
arrest. The proportion of individuals dy-
ing or having a poor neurological out- Table 4. Useful Clinical Findings in the Prognosis of Post–Cardiac Arrest Coma Organized by
come was calculated by pooling the out- Time After Onset of Coma (Not Pooled)*
come data from the 11 studies and was LR of Poor Neurological Outcome
used as an estimate of the pretest prob- (95% Confidence Interval)
ability of poor outcome (Table 3). The Clinical Finding Study Positive Negative
random effects estimate of poor out- At Time of Coma Onset
come was 77% (95% CI, 72%-80%). Absent pupillary reflex Earnest et al35 7.2 (1.9-28.0) 0.5 (0.4-0.6)
This value represents an estimate of the Absent motor response Levy et al39 3.5 (1.4-8.6) 0.6 (0.4-0.7)
pretest probability of death or a poor Absent corneal reflex Levy et al39 3.2 (1.1-9.5) 0.7 (0.6-0.8)
outcome for the entire population of co- Absent oculocephalic reflex Earnest et al35 2.5 (1.3-4.8) 0.4 (0.3-0.6)
matose survivors of cardiac arrest, and Absent spontaneous eye movement Levy et al39 2.2 (1.3-4.0) 0.4 (0.3-0.6)
it is combined with the LRs for vari- ICS ⬍4 Berek et al33 2.2 (1.1-4.5) 0.2 (0.1-0.6)
ous clinical findings to revise the esti- GCS ⬍5 Madl et al40 1.4 (1.1-1.6) 0.3 (0.2-0.5)
mated probability of a poor clinical Absent verbal effort Levy et al39 1.2 (0.9-1.6) 0.1 (0.0-0.7)
outcome. At 12 Hours
Absent cough reflex Sasser42 13.4 (4.4-40.3) 0.3 (0.2-0.4)
Motor Response and Absent corneal reflex Sasser42 9.1 (3.9-21.1) 0.3 (0.2-0.4)
Brainstem Reflexes Absent gag reflex Sasser42 8.7 (4.0-18.9) 0.4 (0.4-0.5)
Six studies examined the association be- Absent pupillary reflex Sasser42 4.0 (2.5-6.6) 0.5 (0.5-0.6)
tween motor and brainstem function GCS ⬍5 Sasser42 3.5 (2.4-5.2) 0.4 (0.3-0.4)
and the recovery of comatose survi- Absent motor response Sasser42 3.2 (2.2-4.6) 0.4 (0.3-0.5)
vors of cardiac arrest. Data for specific Absent withdrawal to pain Sasser42 2.4 (1.9-3.1) 0.2 (0.1-0.2)
clinical findings were pooled if they Absent verbal effort Sasser42 1.6 (1.4-1.9) 0.1 (0.0-0.1)
were assessed in at least 3 studies. At 24 Hours
TABLE 4 shows potentially useful clini- Absent cough reflex Sasser42 84.6 (5.3-1342.0) 0.4 (0.3-0.5)
cal findings from individual studies. Absent gag reflex Sasser,42 24.9 (6.3-98.3) 0.5 (0.4-0.5)
Summary measures for pooled vari- GCS ⬍5 Sasser42 8.8 (5.1-15.1) 0.4 (0.3-0.4)
ables are shown in TABLE 5. Absent eye opening to pain Sasser42 5.9 (3.9-9.0) 0.3 (0.3-0.4)
In 1987, Edgren et al36 reported mo- Absent spontaneous eye movement Levy et al39 3.5 (1.4-8.8) 0.5 (0.4-0.7)
tor and brainstem function in 32 co- Absent eye opening to pain Levy et al39 3.0 (1.5-6.2) 0.4 (0.3-0.5)
matose patients at 24 and 48 hours af- Absent oculocephalic reflex Sasser42 2.9 (1.8-4.6) 0.5 (0.5-0.6)
ter cardiac arrest. It is important to note Absent spontaneous eye movement Sasser42 2.7 (2.1-3.4) 0.3 (0.2-0.3)
that patients were weaned from inten- Absent verbal effort Sasser42 2.4 (2.0-2.9) 0.1 (0.0-0.1)
sive care at 72 hours if they did not re- At 48 Hours
spond to pain and had no evidence of GCS ⬍6 Madl et al41 2.8 (1.3-5.9) 0.3 (0.1-0.5)
brainstem reflexes. Chen and col- GCS ⬍10 Madl et al41 1.3 (1.0-1.7) 0.0 (0.0-0.7)
leagues34 examined similar clinical vari- At 72 Hours
ables in a study of 34 comatose pa- Absent withdrawal to pain Levy et al39 36.5 (2.3-569.9) 0.3 (0.2-0.4)
tients. As in Edgren’s study patients Absent spontaneous eye movement Levy et al39 11.5 (1.7-79.0) 0.6 (0.5-0.7)
with absent brainstem reflexes at 24 Absent verbal effort Levy et al39 7.4 (2.0-28.0) 0.3 (0.2-0.5)
hours were excluded from this study. Absent eye opening to pain Levy et al39 6.9 (1.8-27.0) 0.5 (0.4-0.6)
The Brain Resuscitation Clinical At 7 Days
Trials (BRCTs) were a series of 3 large Absent withdrawal to pain Levy et al39 29.7 (1.9-466.0) 0.4 (0.3-0.6)
prospective, randomized, multicenter Absent verbal effort Levy et al39 14.1 (2.0-97.7) 0.4 (0.2-0.6)
studies of pharmacologic interven- Abbreviations: GCS, Glasgow Coma Scale; ICS, Innsbruck Coma Scale33; LR, likelihood ratio.
tions in cardiac arrest. In BRCT I58 *Clinical findings that have a positive LR greater than 2 and lower confidence interval boundary greater than 1 are
presented with the corresponding negative LR.
(1979-1984), 262 comatose survivors
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ASSESSING OUTCOME FOR COMATOSE SURVIVORS OF CARDIAC ARREST

articles described the association be- tion. In 1994, Edgren et al37 reported I who had survived to 72 hours. In an
tween clinical neurological signs and the neurological examination and out- analysis of all 3 BRCT studies, Sasser42
outcome in the BRCT study popula- comes of the 109 individuals in BRCT assessed the prognostic utility of mo-
tor response and brainstem reflexes at
Table 5. Pooled Clinical Signs in the Prognosis of Post–Cardiac Arrest Coma 12 and 24 hours after cardiac arrest. As
LR of Poor Neurological Outcome (95% in all studies of cardiac arrest, there was
Confidence Interval) a high degree of early mortality. Ac-
Source Positive Negative cordingly, only 1450 patients of the
At Time of Coma Onset* original 3693 studied in all 3 BRCTs
Absent Withdrawal to Pain survived to 12 hours. Of this group, 506
Summary LR 1.7 (0.7-4.2) 0.4 (0.1-1.1) patients were sedated or anesthetized
Earnest et al35 3.7 (1.6-8.2) 0.4 (0.3-0.6) at the time of neurological examina-
Levy et al39 1.4 (1.0-1.9) 0.4 (0.2-0.7) tion and therefore were not included in
Snyder et al43 1.4 (0.9-2.1) 0.5 (0.2-1.2) Sasser’s review. Of the remaining 944
At 24 Hours patients, outcome data was available for
Absent Withdrawal to Pain 937. This is the largest population of
Summary LR 4.7 (2.2-9.8) 0.2 (0.1-0.6) comatose survivors of cardiac arrest re-
Edgren et al36 3.9 (1.1-14) 0.4 (0.2-0.8)
ported to date.
Levy et al39 6.8 (2.3-19.8) 0.2 (0.2-0.3)
Summary measures for clinical vari-
Sasser42 5.1 (3.6-7.3) 0.2 (0.1-0.2)
ables that were assessed in at least 3
Snyder et al43 6.5 (1.0-42.0) 0.3 (0.1-0.7)
studies are presented in Table 5. Five
Absent Pupil Response
Summary LR 10.2 (1.8-48.6) 0.8 (0.4-1.4) pooled variables were found to have a
Chen et al34 0.9 (0.0-19.1) 1.0 (0.8-1.2) 95% CI lying entirely above 1. The clini-
Edgren et al36 5.6 (0.3-95.0) 0.8 (0.6-1.1) cal signs at 24 hours with the highest
Levy et al39 10.7 (0.7-170.0) 0.8 (0.7-0.9) LRs were absent corneal reflexes (LR,
Sasser42 39.2 (5.6-276.6) 0.6 (0.6-0.7) 12.9; 95% CI, 2.0-68.7), absent pupil-
Absent Motor Response lary reflexes (LR, 10.2; 95% CI,
Summary LR 4.9 (1.6-13.0) 0.6 (0.3-1.3) 1.8-48.6), absent motor response (LR,
Chen et al34 3.7 (0.2-59.1) 0.8 (0.6-1.1) 4.9; 95% CI, 1.6-13.0), and absent with-
Levy et al39 5.5 (1.4-21.0) 0.6 (0.5-0.8) drawal to pain (LR, 4.7; 95% CI,
Sasser42 7.6 (4.6-12.6) 0.4 (0.3-0.4) 2.2-9.8). At 72 hours after cardiac ar-
Snyder et al43 3.5 (0.5-24.3) 0.7 (0.5-1.1) rest, absent motor response was found
Absent Corneal Reflex to accurately predict death or poor neu-
Summary LR 12.9 (2.0-68.7) 0.6 (0.2-1.9)
Edgren et al36 1.8 (0.2-15.4) 0.9 (0.7-1.2)
rological outcome (LR, 9.2; 95% CI,
Levy et al39 14.8 (0.9-233.0) 0.7 (0.7-0.8)
2.1-49.4). No clinical findings were
Sasser42 90.9 (5.7-1442.9) 0.4 (0.4-0.5)
found to accurately predict good neu-
rological outcome (ie, no useful nega-
At 72 Hours
tive LRs).
Absent Pupil Response
Summary LR 3.4 (0.5-23.6) 0.9 (0.4-2.1)
Chen et al34 0.9 (0.0-19.1) 1.0 (0.8-1.2)
Coma Scales
Edgren et al37 5.3 (0.3-84.0) 0.8 (0.7-1.0) Four studies assessed composite coma
Levy et al39 5.8 (0.4-94.0) 0.9 (0.8-1.0) scores as prognostic indicators in post–
Absent Motor Response cardiac arrest coma. Madl and col-
Summary LR 9.2 (2.1-49.4) 0.7 (0.3-1.3) leagues41 reported 2 studies that as-
Chen et al34 2.0 (0.1-34.8) 0.9 (0.7-1.2) sessed the role of the GCS in predicting
Edgren et al37 12.6 (0.8-193.0) 0.6 (0.5-0.7) neurological recovery. In 1993 this
Levy et al39 16.5 (1.1-261.0) 0.7 (0.6-0.8) group reported on a series of 66 coma-
Snyder et al43 3.0 (0.2-38.8) 0.6 (0.3-1.1) tose patients who survived cardiac ar-
Seizure or Myoclonus† rest.41 The GCS at 48 hours was com-
Summary LR 1.4 (0.5-3.9) 0.8 (0.3-2.1)
Krumholz et al38 1.7 (0.8-3.4) 0.7 (0.5-1.0)
pared with survival and functional
Levy et al39 1.1 (0.5-2.3) 1.0 (0.8-1.2)
recovery. A second study of 209 pa-
Snyder et al44 1.7 (0.7-4.2) 0.8 (0.6-1.1)
tients measured GCS on admission to
Abbreviation: LR, likelihood ratio. the intensive care unit following car-
*Times reflect number of hours since cardiac arrest. diac arrest.40 In the BRCT reports, GCS
†These figures refer to the presence of seizures or myoclonus at any time after cardiac arrest.
scores at 12, 24, and 72 hours were
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 ASSESSING OUTCOME FOR COMATOSE SURVIVORS OF CARDIAC ARREST

compared with neurological recov- rological outcome. In discussing this signs accurately predict the patient’s
ery.37,42 In 1997, Berek et al33 exam- with the family, it is important to ex- outcome. Finally, no clinical findings
ined the utility of Innsbruck Coma Scale plain that although there are no signs were found to have LRs that strongly
in 42 comatose patients who survived suggestive of poor outcome, the physi- predicted good neurological outcome.
prehospital arrest.33 The Innsbruck cal examination is much less useful in The results of our meta-analysis
Coma Scale (ICS) includes an assess- predicting good outcome. Conse- should be interpreted in the context of
ment of the GCS components in addi- quently, his probability of poor neuro- study limitations. To calculate LRs from
tion to various brainstem reflexes. A logical outcome remains unchanged (ie, 2⫻2 tables, there must be a delinea-
score from 0 to 23 is assigned. A lower 77%). tion between what constitues a good vs
score indicates more severe neurologi- In the second case, the young woman a poor neurological outcome. We chose
cal deficits. has no brainstem reflexes or response to define poor outcome as death, veg-
Although the composite coma scores to painful stimuli at 3 days. Unfortu- etative state, or severe neurological im-
did predict poor neurological out- nately these findings all suggest an ex- pairment (precluding independent
come, they were not as predictive as the tremely poor chance of meaningful neu- living). We made this decision be-
individual motor and brainstem reflex rological recovery. The most powerful cause that is where most primary stud-
components. This is demonstrated in of these indicators elevates her post- ies dichotomize outcome. Further-
Table 4. test probability of poor neurological more, we believe most patients, families,
outcome to 97%. Although the exist- and physicians would not consider se-
Seizures ing literature does not examine the vere neurological impairment to be a
Four studies have examined whether combined effects of different physical desirable outcome. However, in apply-
seizures in the postarrest period accu- examination predictors, because she has ing the results of this study to indi-
rately predict outcome. In 1988 Krum- multiple poor prognostic findings her vidual patients, physicians must real-
holz et al38 described 114 comatose sur- prognosis may be even worse. You note ize that some families and patients may
vivors of cardiac arrest. Nearly half of that the observation of reactive pupils have different perceptions of what con-
the patients (44%) had some seizure ac- immediately following cardiac arrest situtes an acceptable neurological out-
tivity. In Snyder’s study44 of 63 pa- and the presence of myoclonus are not come. It was not the purpose of this
tients, 19 (30%) of 63 had seizures or useful in determining her neurologi- study to provide an ethical framework
myoclonus. In 1994 Widjiks and col- cal prognosis. for treatment decisions in the manage-
leagues46 described the prevalence of ment of comatose survivors of cardiac
myoclonus status in a group of 107 pa- THE BOTTOM LINE arrest; rather, we attempted to summa-
tients. Forty (37%) of the 107 patients In this systematic review we found that rize the exisiting literature to provide
had myoclonus status within 24 hours. the precision of the neurological ex- guidance to clinicians and families
In Levy’s study39 of 210 patients, 53 amination in comatose patients is mod- about prognostic probabilities.
(25%) had seizure or myoclonic activ- erate to substantial. Based on our re- Any study of prognosis in the criti-
ity. Most clinicians infer that seizures sults, we suggest that in patients who cally ill is potentially influenced by the
portend a poor prognosis in comatose lack pupillary and corneal reflexes at tendency for poor prognoses to be self-
survivors of cardiac arrest. However, 24 hours and have no motor response fulfilling. It is difficult to determine if
none of the individual studies or the at 72 hours, the chance of meaningful poor neurological outcomes are caused
summary measures established that neurological recovery is extremely by decisions to withdraw or withhold
seizures accurately predict outcome small. This meta-analysis includes al- therapy based on a perceived poor neu-
(Table 5). most 2000 patients and is the largest rological prognosis. This has the po-
such review to date. In addition to pro- tential to artificially elevate positive LRs.
SCENARIO RESOLUTION viding other information, it corrobo- Although there is no empirical evi-
In both cases an estimate of the pre- rates the findings of the oft-quoted Levy dence that this occurred in our study
test probability (derived from our over- study39 in which none of the 210 pa- population, this clinical reality does re-
all study population) of poor neuro- tients who had any of these 3 clinical main a limitation of the existing litera-
logical outcome is 77%. (It is important findings ever regained an indepen- ture.
to recognize that this figure will vary dent lifestyle. It would be potentially useful to as-
based on comorbid disease, duration of In our study population the ran- sess whether combinations of neuro-
cardiopulmonary resuscitation, and dom effects estimate of poor outcome logical findings could improve the ac-
other clinical variables.) The 65-year- was 77% (95% CI, 72%-80%). The curacy of prognosis in comatose
old man who withdraws to pain and has highest LR increases the pretest prob- survivors of cardiac arrest. Unfortu-
intact brainstem reflexes 24 hours af- ability of 77% to a posttest probability nately we were unable to perform this
ter cardiac arrest has none of the clini- of 97% (95% CI, 87%-100%). Imme- analysis because the available litera-
cal findings associated with poor neu- diately after cardiac arrest, no clinical ture does not provide this data. In 3
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ASSESSING OUTCOME FOR COMATOSE SURVIVORS OF CARDIAC ARREST

studies, combinations of findings were Analysis and interpretation of data: Booth, Boone, 17. Longstreth WT Jr, Diehr P, Inui TS. Prediction of
Tomlinson, Detsky. awakening after out-of-hospital cardiac arrest. N Engl
assessed. In the analysis of 262 pa- Drafting of the manuscript: Booth, Tomlinson, Detsky. J Med. 1983;308:1378-1382.
tients by Edgren et al,37 no combina- Critical revision of the manuscript for important in- 18. Mullie A, Verstringe P, Buylaert W, et al, for the
tellectual content: Booth, Boone, Tomlinson, Detsky. Cerebral Resuscitation Study Group of the Belgian So-
tion of findings was found to be more Statistical expertise: Booth, Tomlinson, Detsky. ciety for Intensive Care. Predictive value of Glasgow
predictive than the individual vari- Obtained funding: Detsky coma score for awakening after out-of-hospital car-
ables. Sasser,42 who performed a very Administrative, technical, or material support: Booth, diac arrest. Lancet. 1988;1:137-140.
Boone, Detsky. 19. Pifferi S, Codazzi D, Savioli M, Langer M. Early
detailed analysis of combined neuro- Supervision: Detsky. prediction of neurologic prognosis after post-anoxic
logical findings and demographic, co- Funding/Support: This project was partially funded coma. Intensive Care Med. 1998;24:535-536.
through the financial support of Griffen Rotman. 20. Sacco RL, VanGool R, Mohr JP, Hauser WA. Non-
morbidity, and cardiopulmonary re- Acknowledgment: We thank David Simel, MD, for traumatic coma: Glasgow Coma Score and coma eti-
suscitation variables, did not find any his valuable guidance during the course of this study. ology as predictors of 2-week outcome. Arch Neu-
We also thank Tom Stewart, MD, Marika Hohol, MD, rol. 1990;47:1181-1184.
additional predictive value of the algo- Karen Welty-Wolfe, MD, James Tulsky, MD, and How- 21. Holleman DR, Simel DL. Does the clinical exami-
rithm (sensitivity 59%, specificity 93%). ell Sasser, PhD, for their expert advice and comments nation predict airflow limitation? JAMA. 1995;273:
on this article.
Only Levy et al39 found practical and 313-319.
22. Warn DE, Thompson SG, Spiegelhalter DJ.
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