Relation of Smoking Status to Outcomes After

Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest

Tanush Gupta, MDa, Dhaval Kolte, MD, PhDa, Sahil Khera, MDa, Wilbert S. Aronow, MDb,
Chandrasekar Palaniswamy, MDb, Marjan Mujib, MD, MPHa, Diwakar Jain, MDb, Sachin Sule, MDa,
Ali Ahmed, MD, MPHc, Sei Iwai, MDb, Paul Eugenio, MDb, Seth Lessner, MDb,
William H. Frishman, MDb, Julio A. Panza, MDb, and Gregg C. Fonarow, MDd,*
In-hospital cardiac arrest (IHCA) is common and is associated with poor prognosis. Data
on the effect of smoking on outcomes after IHCA are limited. We analyzed the Nationwide
Inpatient Sample databases from 2003 to 2011 for all patients aged 18 years who underwent cardiopulmonary resuscitation (CPR) for IHCA to examine the differences in
survival to hospital discharge and neurologic status between smokers and nonsmokers. Of
the 838,464 patients with CPR for IHCA, 116,569 patients (13.9%) were smokers. Smokers
were more likely to be younger, Caucasian, and male. They had a greater prevalence of
dyslipidemia, coronary artery disease, hypertension, chronic pulmonary disease, obesity,
and peripheral vascular disease. Atrial brillation, heart failure, and diabetes mellitus with
complications were less prevalent in smokers. Smokers were more likely to have a primary
diagnosis of acute myocardial infarction (14.8% vs 9.1%, p <0.001) and ventricular
tachycardia or ventricular brillation as the initial cardiac arrest rhythm (24.3% vs 20.5%,
p <0.001). Smokers had a higher rate of survival to hospital discharge compared with
nonsmokers (28.2% vs 24.1%, adjusted odds ratio 1.06, 95% condence interval 1.05 to 1.08,
p <0.001). Smokers were less likely to have a poor neurologic status after IHCA compared
with nonsmokers (3.5% vs 3.9%, adjusted odds ratio 0.92, 95% condence interval 0.89 to
0.95, p <0.001). In conclusion, among patients aged 18 years who underwent CPR for
IHCA, we observed a higher rate of survival in smokers than nonsmokersconsistent with
the smokers paradox. Smokers were also less likely to have a poor neurologic status
after IHCA. 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;114:169e174)
Smoking is the leading preventable cause of morbidity
and mortality in the United States.1 Although cigarette
smokers have higher rates of acute myocardial infarction
(AMI) than nonsmokers, multiple studies have shown a
lower mortality rate after AMI in smokers.2,3 This phenomenon, termed the smokers paradox,4,5 has largely
been attributed to younger age of and fewer co-morbidities
in smokers.6,7 However, some studies have shown that the
association between smoking and improved survival after
AMI persists even after adjustment for these variables.8,9
Smoking has also been found to be associated with lower
risk-adjusted in-hospital mortality in patients with acute
heart failure and patients with acute ischemic stroke.10,11
Although smoking is a well-dened risk factor for cardiac
a
Department of Medicine and bDivision of Cardiology, New York
Medical College, Valhalla, New York; cDepartment of Medicine, Division
of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama; and dDepartment of Medicine, Division of Cardiology,
David Geffen School of Medicine, University of California at Los Angeles,
Los Angeles, California. Manuscript received March 7, 2014; revised
manuscript received and accepted April 15, 2014.
This paper was presented at the American College of Cardiology 63rd
Annual Scientic Session in Washington, DC on March 29, 2014.
Drs. Gupta and Kolte have contributed equally to this study.
See page 173 for disclosure information.
*Corresponding author: Tel: (310) 206-9112; fax: (310) 206-9111.
E-mail address: gfonarow@mednet.ucla.edu (G.C. Fonarow).

0002-9149/14/$ - see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjcard.2014.04.021

arrest,12 data on the effect of smoking on outcomes after inhospital cardiac arrest (IHCA) are limited. Given potential
physiological similarities of IHCA with AMI, acute heart
failure, and acute ischemic stroke, it is possible that a history
of smoking may be associated with improved outcomes after
cardiopulmonary resuscitation (CPR) of IHCA. The primary
objective of this study was to examine the association of
smoking status with outcomes after IHCA using the
Nationwide Inpatient Sample databases from 2003 to 2011.
Methods
Data were obtained from the 2003 to 2011 Nationwide
Inpatient Sample databases. The Nationwide Inpatient
Sample, sponsored by the Agency for Healthcare Research
and Quality as a part of Healthcare Cost and Utilization
Project, is the largest publicly available all-payer inpatient
care database in the United States. It contains dischargelevel data from approximately 8 million hospital stays
from about 1,000 hospitals designed to approximate a 20%
stratied sample of all community hospitals in the United
States. Criteria used for stratied sampling of hospitals
include hospital ownership, patient volume, teaching status,
urban or rural location, and geographic region. Discharge
weights are provided for each patient discharge record,
which were used to obtain national estimates.
We used the International Classication of Diseases,
Ninth Revision, Clinical Modication (ICD-9-CM) codes
www.ajconline.org

170

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

Figure 1. Flowchart depicting methods used to select the study population.

99.60 or 99.63 to identify all patients aged
18 years who

underwent CPR for IHCA (n 838,464; Figure 1). This
approach has been used in previous studies using administrative databases to accurately identify patients with
IHCA.13,14 Smokers were then identied using ICD-9-CM
codes V15.82 or 305.1 (n 116,569). Patients who did
not have either of these ICD-9-CM codes were considered
as nonsmokers (n 721,895). Previous study has shown
that these ICD-9-CM codes have a sensitivity of 100%, a
specicity of 32%, and an accuracy of 66% to identify
smokers in a general patient population with little evidence
of documentation bias.15
Our primary outcome of interest for this study was survival to hospital discharge. We used poor neurologic status
(dened as coma [ICD-9-CM code 780.01], persistent
vegetative state [ICD-9-CM code 780.03], or brain death
[ICD-9-CM code 348.82]) as the secondary outcome.
Baseline patient characteristics used included demographics (age, gender, and race), primary expected payer,
weekday versus weekend admission, median household income for patients zip code, 29 Elixhauser co-morbidities as
dened by the Agency for Healthcare Research and Quality,
other clinically relevant co-morbidities (dyslipidemia,
known coronary artery disease, family history of coronary
artery disease, previous myocardial infarction, previous
transient ischemic attack or stroke, previous percutaneous
coronary angioplasty, previous coronary artery bypass
grafting, previous cardiac arrest, family history of sudden
cardiac death, carotid artery disease, dementia, and atrial
brillation), primary diagnosis of AMI, and initial cardiac
arrest rhythm.16,17 A list of ICD-9-CM and Clinical Classications Software codes used to identify co-morbidities is
provided in Supplementary Table 1. Hospital characteristics
such as hospital region (Northeast, Midwest, South, and
West), number of beds (small, medium, and large), location
(rural and urban), and teaching status were also included.

We initially compared baseline patient and hospital

characteristics between the 2 groups using Pearsons
chi-square test for categorical variables and Student t test for
continuous variables to identify signicant univariate associations. Multivariate logistic regression was used to
compare outcomes between the 2 groups. The regression
model adjusted for demographics, primary expected payer,
weekday versus weekend admission, median household income, all Elixhauser co-morbidities, other clinically relevant
co-morbidities (dyslipidemia, known coronary artery disease, family history of coronary artery disease, previous
myocardial infarction, previous transient ischemic attack or
stroke, previous percutaneous coronary angioplasty, previous coronary artery bypass grafting, previous cardiac arrest,
family history of sudden cardiac death, carotid artery disease, dementia, and atrial brillation), primary diagnosis of
AMI, and initial cardiac arrest rhythm.
Statistical analysis was performed using IBM SPSS
Statistics 20.0 (IBM Corp., Armonk, New York). We used a
2-sided p value of <0.05 to assess for statistical signicance
for all analyses. Categorical variables are expressed as
percentage and continuous variables as mean  SD. Odds
ratio (OR) and 95% condence interval (CI) are used to
report the results of logistic regression.
Results
From 2003 to 2011, of the 838,464 patients with CPR for
IHCA, 116,569 patients (13.9%) were smokers. Smokers were
more likely to be younger, Caucasian, and male (p <0.001).
They were also more likely to have dyslipidemia, coronary
artery disease, family history of coronary artery disease, previous myocardial infarction, previous transient ischemic attack
or stroke, previous percutaneous coronary angioplasty, previous coronary artery bypass grafting, previous cardiac arrest,
alcohol abuse, deciency anemia, chronic blood loss anemia,
chronic pulmonary disease, depression, drug abuse, hypertension, liver disease, metastatic cancer, obesity, peripheral
vascular disease, psychoses, pulmonary circulation disorders,
and solid tumor without metastasis (p <0.001 for all).
Dementia, atrial brillation, heart failure, coagulopathy,
diabetes mellitus with complications, hypothyroidism, lymphoma, uid and electrolyte disorder, other neurologic disorders, paralysis, chronic renal failure, valvular disease, and
weight loss were less prevalent in smokers (p <0.001 for all).
Smokers were more likely to be admitted to large nonteaching
hospitals (p <0.001). They were also more likely to have a
primary diagnosis of AMI and ventricular tachycardia or
brillation as the cardiac arrest rhythm (Table 1).
The primary outcome of the study was survival to hospital
discharge. Smokers had a higher rate of survival to hospital
discharge after IHCA than nonsmokers (28.2% vs 24.1%,
unadjusted OR 1.24, 95% CI 1.22 to 1.26, p <0.001). Survival to hospital discharge remained signicantly higher in
smokers even after adjusting for baseline demographics,
hospital characteristics, co-morbidities, primary diagnosis of
AMI, and the initial cardiac arrest rhythm (adjusted OR 1.06,
95% CI 1.05 to 1.08, p <0.001; Table 2).
Poor neurologic status was used as the secondary
outcome of interest. Smokers had a signicantly lower rate
of poor neurologic status after IHCA compared with

Coronary Artery Disease/Smoking and Outcomes After IHCA

Table 1
Baseline demographics, co-morbidities, and hospital characteristics of
patients
18 years of age with in-hospital cardiac arrest
Variable

Age, mean  standard

deviation (years)
Women
Caucasian
African-American
Hispanic
Asian or Pacic Islander
Other
Primary expected payer
Medicare
Medicaid
Private insurance
Uninsured
Other
Weekend admission
Median household income
(percentile)
0e25th
26the50th
51ste75th
76the100th
Co-morbidities*
Dyslipidemia
Coronary artery disease
Family history of coronary
artery disease
Prior myocardial infarction
Prior transient ischemic
attack/stroke
Prior percutaneous
coronary intervention
Prior coronary bypass
Prior cardiac arrest
Family history of sudden
cardiac death
Carotid artery disease
Dementia
Atrial brillation
AIDS
Alcohol abuse
Deciency anemia
Rheumatoid arthritis/
collagen vascular
diseases
Chronic blood loss anemia
Congestive heart failure
Chronic pulmonary disease
Coagulopathy
Depression
Diabetes mellitus
(uncomplicated)
Diabetes mellitus
(complicated)
Drug abuse
Hypertension
Hypothyroidism
Liver disease
Lymphoma

Non-Smokers

Smokers

(n 721,895)

(n 116,569)

67.8  16.3

63.7  14.2

<0.001

46.9%
62.6%
20.7%
10.1%
3.3%
3.3%

36.2%
72.8%
15.8%
6.8%
2.0%
2.6%

<0.001
<0.001

65.8%
9.8%
17.6%
4.8%
2.0%
23.7%

55.3%
11.9%
21.8%
8.0%
3.1%
23.9%

31.3%
25.6%
23.1%
20.0%

30.7%
26.9%
24.5%
17.9%

15.8%
25.6%
0.5%

28.7%
36.1%
2.7%

<0.001
<0.001
<0.001

4.8%
1.9%

9.3%
3.8%

<0.001
<0.001

2.8%

6.9%

<0.001

5.2%
0.2%
<0.1%

7.4%
0.5%
<0.1%

<0.001
<0.001
0.140

0.8%
6.5%
23.5%
0.3%
4.2%
20.5%
2.4%

1.5%
3.4%
19.6%
0.4%
12.2%
21.4%
2.3%

<0.001
<0.001
<0.001
0.010
<0.001
<0.001
0.829

2.0%
36.3%
23.0%
13.5%
5.0%
22.1%

1.6%
30.6%
42.0%
11.6%
8.1%
22.4%

<0.001
<0.001
<0.001
<0.001
<0.001
0.077

7.8%

5.2%

<0.001

2.3%
49.2%
8.5%
4.1%
1.4%

6.4%
56.4%
8.3%
5.3%
1.0%

<0.001
<0.001
0.009
<0.001
<0.001

Table 1
(continued)
Variable

p Value

<0.001

0.207
<0.001

171

Fluid and electrolyte

disorder
Metastatic cancer
Other neurological
disorders
Obesity
Paralysis
Peripheral vascular disease
Psychoses
Pulmonary circulation
disorders
Renal failure (chronic)
Solid tumor without
metastasis
Peptic ulcer (non-bleeding)
Valvular disease
Weight loss
Hospital characteristics
Number of beds
Small
Medium
Large
Urban location
Teaching hospital
Region
Northeast
Midwest
South
West
Ventricular tachycardia/
brillation
Primary diagnosis of acute
myocardial infarction

Non-Smokers

Smokers

p Value

(n 721,895)

(n 116,569)

48.7%

45.9%

<0.001

3.8%
11.5%

4.7%
9.5%

<0.001
<0.001

7.5%
3.7%
9.1%
3.1%
4.7%

11.2%
2.3%
13.6%
4.5%
5.5%

<0.001
<0.001
<0.001
<0.001
<0.001

24.8%
2.9%

17.3%
4.2%

<0.001
<0.001

<0.1%
5.9%
10.2%

<0.1%
4.8%
8.8%

0.533
<0.001
<0.001

10.0%
24.7%
65.3%
90.7%
44.7%

9.2%
23.9%
66.9%
90.5%
41.5%

20.3%
18.8%
37.6%
23.3%
20.5%

13.2%
20.7%
38.6%
25.5%
24.3%

<0.001

9.1%

14.8%

<0.001

<0.001

0.111
<0.001
<0.001

AIDS acquired immunodeciency syndrome.

* Co-morbidities (including the 29 Elixhauser co-morbidities) were
extracted from the database using International Classication of Diseases,
Ninth Edition, Clinical Modication diagnosis or Clinical Classication
Software codes.

Number of beds categories are specic to hospital location and teaching

status, available at http://www.hcup-us.ahrq.gov/db/vars/hosp_bedsize/
nisnote.jsp.

nonsmokers (3.5% vs 3.9%, unadjusted OR 0.88, 95% CI

0.85 to 0.91, p <0.001). When adjusted for baseline demographics, hospital characteristics, co-morbidities, primary
diagnosis of AMI, and the initial cardiac arrest rhythm,
smoking status was associated with a signicantly lower
likelihood of having a poor neurologic status after IHCA
(adjusted OR 0.92, 95% CI 0.89 to 0.95, p <0.001;
Table 2).
Discussion
The term smokers paradox was rst introduced
>25 years ago after observations that despite the increased
prevalence of acute coronary syndromes, the mortality rate

172

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

Table 2
Outcomes after in-hospital cardiac arrest in non-smokers and smokers
Outcome

Survival to hospital discharge

Poor neurological status

Non-Smokers

24.1%
3.9%

Smokers

28.2%
3.5%

p Value

<0.001
<0.001

Odds Ratio (95% CI)

Unadjusted

Adjusted*

1.24 (1.22e1.26)
0.88 (0.85e0.91)

1.06 (1.05e1.08)
0.92 (0.89e0.95)

CI condence interval.
* Adjusted for age, sex, race, primary payer status, weekday versus weekend admission, median household income, hospital characteristics (bed size,
location, teaching status, and region), co-morbidities, primary diagnosis of acute myocardial infarction, and ventricular tachycardia or brillation as the cardiac
arrest rhythm.

after AMI was lower in smokers than in nonsmokers.2,18

This was partly explained by the younger age and fewer
co-morbidities in patients with AMI who were current
smokers. The magnitude of this paradoxical associated
protective effect of smoking was reduced after adjustment
for age and co-morbidities; however, some of these studies
showed an independent residual association even after
adjustment for these factors. Similar results were later
replicated in randomized control trials such as the International Tissue Plasminogen Activator/Streptokinase Mortality Trial19 and the Global Utilization of Streptokinase and
Tissue Plasminogen Activator for Occluded Coronary Arteries trial.6 In an analysis of 297,458 patients with AMI
included in the National Registry of Myocardial Infarction
2, crude in-hospital mortality rate among smokers was 50%
lower than in nonsmokers. Smokers were on average
14 years younger than nonsmokers. The mortality rate in
smokers was lower by 14% even after adjustment for age
and baseline clinical risk factors.3 Multiple other observational studies and registry analyses have supported the existence of this paradox in patients with AMI.4 In addition,
analyses have found similar associations of smoking status
with improved outcomes in patients hospitalized with acute
heart failure and patients with acute ischemic stroke.10,11
Our current analysis of a large, contemporary, real-world,
multi-institutional cohort of patients included in the
Nationwide Inpatient Sample database is the largest study to
date to examine the effect of smoking status on outcomes
after IHCA. Despite being younger, smokers had greater
prevalence of previous myocardial infarction and cardiac
arrest and were more likely to have undergone coronary
reperfusion in the past. They were also more likely to have
AMI at the time of admission to the hospital and have
ventricular tachycardia or brillation at the time of IHCA.
Although the higher survival rate after CPR for IHCA in
smokers was partly attenuated after adjustment for baseline
differences, there was a residual association even after risk
adjustment. Smokers also had signicantly lower rates of
poor neurologic status after IHCA.
Our results are consistent with a recent, single-center
observational study that assessed the association between
smoking and survival with a good neurologic outcome in
181 patients with cardiac arrest treated with mild therapeutic
hypothermia. Smokers had higher survival to hospital
discharge with good neurologic outcome compared with
nonsmokers (50% vs 28%, p 0.003). Even after adjustment for age, initial rhythm, time to return of spontaneous
circulation, bystander CPR, and time to initiation of

therapeutic hypothermia, a history of smoking was independently associated with increased odds of neurologically
intact survival at the time of hospital discharge (OR 3.54,
95% CI 1.41 to 8.84, p <0.01).20
The association between smoking and increased survival
with lower likelihood of poor neurologic status after IHCA
can potentially be explained by the phenomenon of ischemic
conditioning. First described by Murry et al,21 it is the
practice of applying brief intermittent episodes of nonlethal
ischemia and reperfusion to confer protection against a
sustained episode of lethal ischemia and reperfusion.22
Although reperfusion is essential to maintain viable tissue
after a period of sustained ischemia, the actual process of
reperfusion itself paradoxically induces injury, partly
attenuating its benets.23 Murry et al,21 in their seminal
experimental study, made an observation that subjecting the
canine myocardium to four 5-minute cycles of nonlethal
ischemia and reperfusion (induced by alternate occlusion
and reperfusion of the circumex coronary artery) immediately before a sustained episode of lethal myocardial
ischemia (40 minutes of circumex coronary artery occlusion) and reperfusion for 4 days paradoxically reduced the
size of the resultant myocardial infarction to 25% of that
observed in untreated control hearts. Multiple subsequent
clinical studies have validated the benet of ischemic conditioning in attenuating ischemia-reperfusion injury.24e27
Smoking has been shown to be associated with a chronic
reduction in tissue perfusion and oxygenation.28,29 It is
possible that diffuse hypoxia induced by smoking creates an
ischemic preconditioned state, thus blunting the lethal effects of reperfusion injury that follows a catastrophic
ischemic event such as IHCA. Whether this association is
driven by inadequate adjustment with residual measured or
unmeasured confounding, or whether it may in addition be
due to differences in pathophysiological processes in
smokers versus nonsmokers with IHCA, remains to be
established. This apparent smokers paradox should not be
interpreted as a rationale for cigarette smoking. There is
substantial evidence of the harmful nature of smoking, and
therefore intensive efforts to encourage smoking cessation
as a primary and secondary preventive measure for cardiac
arrest, myocardial infarction, and stroke should remain a
very high priority.
Being a retrospective observational study, this analysis of
the administrative Nationwide Inpatient Sample database
has its limitations. It has a potential for selection bias and
unrecognized miscoding of diagnostic and procedure codes,
which may have led to underestimation or overestimation of

Coronary Artery Disease/Smoking and Outcomes After IHCA

CPR and/or IHCA events, smoking status, and other comorbidities based on ICD-9-CM coding. However, these 2
limitations may be, at least partially, compensated by the
large size of the database and the ability to obtain nationwide estimates using the discharge weights provided. The
amount of smoking exposure could not be determined
because of unavailability of individual patient charts or
medical records. Duration and severity of the main disease
leading to IHCA as well as co-morbid conditions are not
collected in this database and could not be adjusted for.
These may have contributed to residual confounding. The
database does not provide information on the quality of
resuscitation, time delay between the onset of IHCA and
CPR, and time to debrillation, which might be different
among various hospitals. The database does not include
information on the medications used. There is no information available on patients advance directives; it is possible
that some of the patients had do-not-resuscitate orders after
surviving the initial episode of IHCA, which could have
affected survival rates in both the groups. Lastly, outcomes
in the database are limited to in-hospital events, and causes
of IHCA are not differentiated.
This large observational study examined the effect of
smoking status on outcomes after CPR for IHCA. The
present study demonstrates that smokers have a higher
survival rate and a lower likelihood of having a poor
neurologic status after IHCA than nonsmokers. Although it
is difcult to denitively explain this paradoxical association between smoking and higher survival rates after IHCA,
it is plausible that the phenomenon of ischemic preconditioning may play a role. Further prospective studies are
needed to conrm our observations and to elucidate the
mechanisms underlying this paradox in patients with IHCA.

7.

8.

9.

10.
11.

12.
13.
14.
15.
16.
17.

Disclosures
The authors have no conicts of interest to disclose.
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