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Predictors of Neurologic Outcome in Patients Resuscitated

from Out-of-Hospital Cardiac Arrest Using Classication


and Regression Tree Analysis
Amy H. Kaji, MD, PhDa,b,c, Arslan M. Hanif, MDa, Nichole Bosson, MD, MPHa,
Daniel Ostermayer, MDa, and James T. Niemann, MDa,b,c,*
The estimated survival rate of 8% to 10% after out-of-hospital cardiac arrest (OHCA)
remains dismal. Few studies have addressed predictors of functional neurologic outcome
after successful resuscitation. The objective of the study was to identify variables associated
with favorable neurologic outcomes, dened by a Glasgow Coma Scale of 14 or 15, after
OHCA. We used a propensity analysis and classication and regression tree model of 184
OHCA patients surviving to hospital admission at a cardiac arrest receiving center in Los
Angeles County from 2008 to 2013. Forty-three patients (23%) had a favorable outcome,
median age was 65 years (interquartile range [IQR] 54 to 76), and 98 (53%) were men.
Sixty-six patients (36%) presented with a shockable rhythm. The majority were witnessed,
either by a civilian (n [ 115, 63%) or a paramedic (n [ 25, 14%). Bystander cardiopulmonary resuscitation was performed on 84 patients (46%); median dose of epinephrine was
2 mg (IQR 1 to 3). Median time to return of spontaneous circulation was 21 minutes (IQR
16 to 29); the median lactate level was 5.2 mmol/L (IQR 2.8 to 9.2). Lower epinephrine
doses (<1.5 mg) and lactate levels <5 mmol/L were predictive of a normal Glasgow Coma
Scale, with 90.7% sensitivity (95% condence interval [CI] 76.9% to 96.9%), 47.5% specicity (95% CI 39.1% to 56.1%), a positive predictive value of 34.5% (95% CI 31.6% to
46.1%), a negative predictive value of 94.4% (95% CI 85.5% to 98.2%), and an area under
the curve of 0.89. The propensity scoreeadjusted logistic regression model demonstrated
that receiving <1.5 mg of epinephrine was associated with a favorable neurologic outcome
(odds ratio 3.3, 95% CI 1.1 to 10, p [ 0.04). In conclusion, for patients surviving to hospital
admission, a good neurologic outcome was associated with having received <1.5 mg of
epinephrine and a lactate level <5 mmol/L. 2014 Elsevier Inc. All rights reserved. (Am
J Cardiol 2014;114:1024e1028)
After the introduction and eventual acceptance of mild
or therapeutic hypothermia (TH) in the early 2000s for
cerebral preservation after resuscitation, studies have
focused on the outcome of neurologic function after hospital
discharge, rather than just survival. Such studies have
largely assessed the predictive value of systemic markers of
neuronal injury or the utility of imaging methods to predict
outcome after hypothermia.1,2 TH is now commonly used in
the care of patients resuscitated from out-of-hospital ventricular brillation because of its demonstrated benet in this
patient group. An increasing number of patients resuscitated
from noneventricular brillation arrest are also receiving
this intervention because of observational studies suggesting
improved neurologic outcome.3 TH is resource intensive as

is post-rewarming care and serial or repeated neurologic


assessment and management of those patients who have
failed the intervention, that is, recurrent seizures, myoclonus, and so on. Using classication and regression trees
(CARTs), we identify potential predictors of favorable
neurologic outcome in adults resuscitated from outof-hospital cardiac arrest (OHCA) using only information
or data available within the rst hour after restoration of
spontaneous circulation (ROSC). Such predictors may
identify which patients are most likely to benet from hypothermia. We hypothesized that lower lactate levels and
epinephrine requirements are associated with better periarrest perfusion and neurologic outcome.
Methods

Department of Emergency Medicine, Harbor-University of California,


Los Angeles Medical Center, Torrance, California; bThe Los Angeles
Biomedical Research Institute, Torrance, California; and cThe David Geffen
School of Medicine at University of California, Los Angeles, Los Angeles,
California. Manuscript received March 17, 2014; revised manuscript
received and accepted June 25, 2014.
Funding sources: None.
See page 1027 for disclosure information.
*Corresponding author: Tel: (310) 222-6742; fax: (310) 212-6101.
E-mail address: jniemann@emedharbor.edu (J.T. Niemann).
0002-9149/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjcard.2014.06.031

This is an observational, retrospective, cohort study of all


consecutive adult patients (18 years) with OHCA who
presented to a single public hospital in Los Angeles County
from January 1, 2008, to June 30, 2013. The institutional
review board at the participating hospital provided ethics
approval with waiver of informed consent.
Harbor-UCLA is a 553-bed general municipal teaching
hospital located in southwestern Los Angeles County, which
has a population of 11 million residents. With a catchment
area of 27 square miles, the hospital has full capabilities for
www.ajconline.org

Coronary Artery Disease/Neurologic Outcome After Cardiac Arrest

percutaneous coronary intervention and the implementation


of hypothermia after cardiac arrest. In Los Angeles County,
emergency medical services are provided by way of a
2-tiered response activated by a central dispatch 911
network with >3,500 licensed paramedics, certied in
advanced cardiac life support. Paramedics are authorized to
initiate protocols adhering to advanced cardiac life support
guidelines, with online medical control.
Three abstractors (AMH, DO, and JTN), who were
blinded to the hypothesis of the study, were trained to review and cull data from paramedic run sheets, nursing
charts, and physician medical records. Cardiac arrest subjects were included only if they survived to hospital
admission, as dened by ROSC that is achieved either in the
eld or in the emergency department (ED) and sustained
such that they are assigned a hospital bed. Exclusion criteria
included age <18 years, patients with traumatic arrest, and
those with an arrest related to a denite respiratory cause, a
drug overdose, strangulation, electrocution, or drowning.
The abstractors used a standardized abstraction form to record data, which included age, gender, rst documented
rhythm on paramedic arrival, witnessed or nonwitnessed
arrest, presence or absence of bystander cardiopulmonary
resuscitation (CPR), administration of epinephrine by
emergency medical service personnel, where ROSC was
achieved (eld vs in the ED), lactate level within 60 minutes
of ED arrival, and the Glasgow Coma Score (GCS) on
hospital discharge. A priori precise operational denitions
for the variables were outlined. The primary end point was
survival to hospital discharge with favorable neurologic
outcome, dened as a GCS of 14 or 15. The data sheets
were randomly checked by the senior abstractor, and disagreements were discussed until consensus was achieved.
The data were entered into a Microsoft Excel (Seattle,
Washington) spreadsheet, using DBMS/Copy, version 8
(DataFlux Corporation, Cary, North Carolina) to convert the
le into an SAS v.9.3 (Cary, North Carolina) database.
Descriptive statistics and univariate comparisons were done
to evaluate baseline known factors for survival to hospital
discharge after resuscitation from cardiac arrest: gender,
age, rhythm on paramedic arrival, witnessed or nonwitnessed arrest, and presence or absence of bystander CPR.
We assessed the association of time to ROSC, epinephrine
dose, and lactate level with neurologic outcomes, with a
type I error threshold of p <0.05. Odds ratios (ORs) with
respective 95% condence intervals (CIs) were calculated.
In general, continuous numerical variables are summarized
using medians and interquartile ranges and were compared
using the Wilcoxon rank sum test. Proportions were
compared using Fishers exact test or ORs with 95% CIs, as
appropriate, and no adjustment was made for multiple
comparisons. The Salford systems (http://www.salfordsystems.comSalford Predictive Mining Suite, 2011) were
used for the CART recursive partitioning analysis to identify
predictors and cut points for continuous variables for a
favorable neurologic outcome. CART has multiple potential
advantages over multivariate logistic regression. The classication tree is cross-validated 10 times using a bootstrapping technique in which the tree is developed using
90% of the patients and then tested using patients not
included in the development of the tree. The following

1025

Table 1
Characteristics of the study population (n 184)
Characteristics
Age (years)
Men
Women
Ventricular brillation or ventricular
tachycardia
Pulseless electrical activity
Asystole
Citizen witnessed
Paramedic witnessed
Unwitnessed
Bystander cardio-pulmonary resuscitation
Field return of spontaneous circulation
Emergency department return of
spontaneous circulation
Time to resuscitation (minutes)
Lactate (mmol/L)
Survival to hospital discharge
Survival with GCS of 14 or 15

Median 65, IQR 54e76


98 (54%)
86 (47%)
66 (36%)
66
52
116
25
43
59
145
39

(36%)
(28%)
(63%)
(14%)
(24%)
(32%)
(79%)
(21%)

Median 21, IQR 16e29


Median 5, IQR 2.8e9.2
75 (41%)
43 (23%)

variables were selected to develop a prediction model: age,


gender, witnessed arrest (yes or no), bystander CPR (yes or
no), arrest rhythm (shockable or not), time to ROSC,
epinephrine administration, and serum lactate level. The
sensitivity and specicity of the model with respective 95%
CIs were determined.
Because epinephrine administration was not randomly
assigned in the study population, we also assigned a propensity score, which is a conditional probability from 0 to 1,
that a subject will be treated based on an observed group of
covariates. Because patients who received epinephrine may
differ systematically from those who did not, the propensity
score was used to minimize the differences and improve the
comparability between the groups. Finally, we developed a
logistic regression model, which included the propensity
score, as well as the variables identied by CART, for
the end point of favorable neurologic outcome. Model t
was assessed with the Hosmer-Lemeshow goodness-of-t
statistic.
A target sample size of 184 subjects was determined
based on the number of factors predicting a good neurologic
outcome (for each factor predicting a GCS of 14 or 15, we
anticipated requiring at least 10 patients) and the anticipated
number of patients with the outcome (approximately 40% or
20% among those who survive to hospital admission). Thus,
4 risk factors could be assessed in a robust fashion.
Results
A total of 184 patients met our inclusion criteria. Fortythree patients (23%) had a GCS of 14 or 15 on hospital
discharge. See Table 1 for the details of our study patients.
On univariate analysis, the predictors of a favorable
neurologic status on discharge included the following
(Table 2): younger age, shockable rhythm, witnessed arrest,
having bystander CPR, achieving ROSC in the eld (vs the
ED), lower dose of epinephrine administered, a shorter time
to resuscitation, and a lower serum lactate level. The results
of the adjusted ORs for a multivariate analysis including

1026

The American Journal of Cardiology (www.ajconline.org)

Table 2
Characteristics by outcome (n 184)
Characteristic
Age (years)
Men
Shockable rhythm
Witnessed arrest
Bystander cardiopulmonary resuscitation
Field return of spontaneous circulation
Time to resuscitation (minutes)
Epinephrine administered (mg)
Lactate (mmol/L)
Survival to hospital discharge

GCS 14 or 15 (n 43)

GCS <14 (n 141)

p-Value

Median 59, IQR 49e70


25 (58%)
30 (70%)
38 (88%)
26 (61%)
42 (98%)
Median 17.5, IQR 11e20
Median 1, 0e2
Median 3.3, IQR 2.3e4.8
43 (100%)

Median 65, IQR 56e78


73 (52%)
36 (26%)
103 (73%)
59 (42%)
103 (73%)
Median 23, IQR 18e32
Median 2, IQR 2e3.3
Median 6.1, IQR 3.4e10.2
32 (23%)

0.03
0.5
<0.0001
0.04
0.03
<0.01
<0.0001
<0.0001
<0.01
<0.0001

Table 3
Adjusted odds ratios for baseline predictors of favorable neurologic
outcome
Variable
Age
Witnessed arrest
Shockable rhythm
Bystander cardiopulmonary
resuscitation
Time to return of spontaneous
circulation
Emergency department as site of
resuscitation
Lactate
Epinephrine

Odds Ratio, 95% CI, p-Value


0.98
1.1
3.7
1.6

(0.94e1.01), p 0.2
(0.3e4.1), p 0.9
(1.4e10.0), p 0.01
(0.5e4.6), p 0.4

1.0 (0.9e1.0), p 0.2


1.3 (0.1e17.3), p 0.8
0.9 (0.7e1.1), p 0.2
0.8 (0.5e1.2), p 0.3

Hosmer-Lemeshow goodness-of-t chi-square statistic 7.6, p 0.5.

signicant univariate predictors are described in Table 3.


The recursive partitioning yielded 2 notable predictor variables: epinephrine administration and serum lactate with cut
points of 1.5 mg and 5 mmol/L, respectively. Thirty of the
43 subjects with a favorable neurologic discharge received
<1.5 mg of epinephrine. Of the remaining 13 subjects with
a normal discharge GCS, 9 subjects had a serum lactate
level <5 mmol/L. The sensitivity of this 2-predictor model
was 90.7% (95% CI 76.9% to 96.9%), a specicity of 47.5%
(95% CI 39.1% to 56.1%), a positive predictive value of
34.5% (95% CI 31.6% to 46.1%), a negative predictive
value of 94.4% (95% CI 85.5% to 98.2%).
As noted in Table 4, there were differences in the cohort
that received epinephrine versus those that did not. Those
receiving epinephrine had longer times to resuscitation,
higher lactate levels, and were less likely to have the
following characteristics: male gender, shockable arrest
rhythm, bystander CPR, witnessed arrest, and survival to
discharge. A propensity scoreeadjusted model (for
receiving epinephrine), which included lactate level and
epinephrine administration, demonstrated that receiving
<1.5 mg of epinephrine was associated with a favorable
neurologic outcome (OR 3.3, 95% CI 1.1 to 10, p 0.04).
Discussion
Postresuscitation care is an important link in the chain of
survival, but the intensive monitoring required for providing

such care is costly and resource intensive. Our study demonstrates that receiving as little as1.5 mg of epinephrine
during resuscitation efforts and an admission lactate level
>5 mmol/L, which is about twice the upper limit of normal
in our institutions laboratory, are associated with poor
neurologic outcome at hospital discharge. Such data are
likely to be available within an hour of admission to the ED.
Early identication of predictors of neurologic outcome is
important to help identify which patients should be
considered for aggressive postresuscitation care. Dened
and generally accepted predictors of outcome after resuscitation from OHCA have focused on survival to hospital
discharge, whereas few studies have addressed postresuscitation neurologic outcome.
Our study support observations that epinephrine administration during advanced cardiac life support may improve
the rate of return of spontaneous circulation but not the rate
of survival to hospital discharge.4e6 However, there are
important differences between our report and previously
published data. Two previous studies were observational,
retrospective, cohort studies similar to ours but differed in
that the analysis of epinephrine use was dichotomized,
rather than leaving epinephrine as a continuous variable.6,7
Additionally, one study did not include modern postresuscitation care, namely therapeutic hypothermia and
coronary intervention, in the analysis of outcome. Three
other studies evaluated cumulative epinephrine dose and
long-term outcome,8e10 but none of these studies included
postresuscitation interventions in the analysis. Finally, we
used CART analysis, which has a number of advantages
over other analytic methods including multivariate logistic
regression. CART is inherently nonparametric, and no assumptions are made regarding the underlying distribution of
values of the predictor variables. Additionally, CART can
handle missing data by repeated sampling techniques, as
well as data that are highly skewed or multimodal and
categorical predictors with either ordinal or nonordinal
structure.
It is generally believed that blood lactate concentration
after resuscitation from cardiac arrest is predictive of
outcome. However, published studies yield conicting results, most likely due to methodological study differences.
Muller et al11 demonstrated a weak correlation between
admission lactate levels and cardiac arrest duration and that
the initial lactate level was poorly predictive of neurologic
outcome. Donnino et al12 and Starodub et al13 demonstrated

Coronary Artery Disease/Neurologic Outcome After Cardiac Arrest

1027

Table 4
Association of patient characteristics of epinephrine administration in the eld (n 184)
Variable

Age (years)
Male gender
Shockable arrest rhythm
Witnessed arrest
Bystander CPR
Field ROSC
Time to resuscitation (minutes)
Lactate (mmol/L)
Survival to hospital discharge
Survival with GCS of 14 or 15

Epinephrine (n 160)

No Epinephrine (n 24)

N (median)

% IQR

N (median)

% (IQR)

65
79
48
117
67
121
22
5.8
56
27

55e77
50
30
74
42
76
18e32
3.0e9.9
35
17

60.5
18
18
23
17
24
13.5
2.9
19
16

52e68
75
75
96
71
100
9e18
1.8e4
79
67

that lactate clearance rather than the initial lactate level was
a better predictor of survival to hospital discharge. Two
studies have demonstrated that median initial lactate levels
are lower in patients with a good neurologic outcome14 or
who survive15 and that outcome is related to estimated arrest
duration but variably related to arrest rhythm. Adrie et al14
included epinephrine dose as a study variable and found it
to be insignicant when included in the multivariate analysis, whereas Oddo et al15 did not include epinephrine. It is
not surprising that we and others identied the admission
lactate level as a potential predictor of eventual outcome
because restoration of cerebral function depends on alleviating global ischemia, and lactate levels reect the degree of
ischemia during arrest and resuscitation. Thus, a lower
lactate level may indicate that cerebral perfusion was relatively well maintained. In our study, we demonstrated a
lactate cut point value of 5 mmol/L, which approximates the
median value of 3.1 mmol/L in patients with a good
neurologic outcome reported by Adrie et al, but is much
lower than the median of 8 mmol/L reported in survivors by
Oddo et al. After adjusting for epinephrine administration,
the initial lactate level was no longer predictive in our nal
multivariate logistic regression analysis and CART.
Oddo et al did not show that initial rhythm, witness
status, and bystander CPR were important variables when
therapeutic hypothermia was included in the analysis.15
Our study also failed to demonstrate that arrest-related
variables that constitute the chain of survival for OHCA
were important predictors of good neurologic outcome at
discharge.
Our study has a number of limitations: the study population is from a single center, limiting the generalizability. The
study design is a retrospective cohort review and is subject to
the biases that are inherent in a retrospective analysis. Our
study sample is of modest size for this kind of epidemiologic
study, with 184 patients and 43 subjects achieving the desired
outcome. However, our sample size is greater than that of
Oddo et al15 (n 77) and approximates the derivation (n
130) and validation (n 210) sets of Adrie et al.14 Although
we used a partitioning approach to our modeling, our results
should be viewed as exploratory and warrant validation in
larger populations. Our institution is a teaching hospital with
percutaneous coronary intervention capability and a large ED
volume. Specically, in this study population, 115 patients

OR (95% CI)

p-Value

(0.1e0.9)
(0.1e0.4)
(0.1e0.9)
(0.1e0.8)

0.1 (0.1e0.4)
0.1 (0.1e0.4)

0.3
0.03
<0.0001
0.02
<0.01
<0.01
<0.0001
<0.001
<0.0001
<0.0001

0.3
0.1
0.1
0.3

(63.2%) received hypothermia and 20 (11%) underwent


percutaneous coronary intervention, both of which have been
shown to increase the likelihood of survival to hospital
admission after OHCA.16 Although there is some evidence
that earlier epinephrine administration may be of benet,17,18
we did not assess timing of epinephrine administration.
Neurologic outcome at the time of discharge was used in our
analysis, rather than long-term outcome. However, Phelps
et al19 has shown that Cerebral Performance Category at the
time of hospital discharge is a useful marker or measure of
long-term outcome.
Acknowledgment: Drs. Kaji and Niemann had full access
to all the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Disclosures
The authors have no conicts of interest to disclose.
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2014 Elsevier