Running head: INTEGRATIVE REVIEW 1

Integrative Review

Keeley R. Dugan

Karen Mellott, PhD, MSN, RN

NUR 4122 – Nursing Research

Bon Secours Memorial College of Nursing

March 20, 2019

“I Pledge…”
INTEGRATIVE REVIEW 2

Abstract

Purpose: The purpose of this integrative review is to identify literature concerning

survival rates and neurological outcomes in patients being treated with therapeutic

hypothermia after suffering cardiac arrest.

Background: After cardiac arrest, the bulk of patients who had return of spontaneous

circulation (ROSC) continued to be in a comatose state and experienced injurious

consequences of rapid reperfusion. The use of therapeutic hypothermia has attributed to

the reduction of physiologic deficits from ROSC and improved survival rates.

Method: Online databases were used to target research articles appropriate for the

purpose of this paper. Design methods included retrospective prospective, observational

cohort studies within national databases and proposed data from sizeable patient

registries. The information from each article was used to develop evaluation of

therapeutic hypothermia on survival rates and neurological outcomes after cardiac arrest.

Limitations: Limitations included lack of therapeutic hypothermia protocol, inconsistent

control and treatment groups, the dependence on National registries, inherent biases, and

missing data such as unknown core body temperatures.

Results and Findings: Studies suggest that therapeutic hypothermia is not associated

with an increased survival rate and favorable neurological outcomes.

Implications: Implications specify the use of standardized protocols for all studies would

promote and improve understanding of the role therapeutic hypothermia plays in

decreasing mortality rates after cardiac arrest.

Recommendations: Recommendations include suggesting further research with

conduction of randomized trials with multi-centered controlled clinical trials.

INTEGRATIVE REVIEW 3

Integrative Review

The purpose of this integrative review is to analyze the effect of therapeutic

hypothermia on survival rates and favorable neurologic outcomes after cardiac arrest in

patients who had return of spontaneous circulation (ROSC). Cardiac arrest attributes to

the vast majority of patient morbidity and mortality in the United States. In-hospital

cardiac arrest (IHCA) affects approximately 209,000 patients each year, along with over

350,000 individuals experiencing out-of-hospital cardiac arrest (OHCA) in 2016

(American Heart Association, 2016). Unfortunately, between 70-90% of those who

experienced OHCA do not survive before reaching the hospital. Those who survive

experience physiological downfalls such as brain and nervous system interference as well

as psychological stressors (CDC, 2015).

The American Heart Association alongside the International Liaison Committee

of Resuscitation have addressed that therapeutic hypothermia post-cardiac arrest as the

standard of care for those cardiac arrest, comatose patients (Doshi et al., 2015).

Therapeutic hypothermia has been shown to reduce cerebral damage by decreasing the

oxygen demand on the brain, thus impeding the injurious activity cardiac arrest has on

the brain (Bae et al., 2015). The purpose of this integrative is to collect relevant, current,

and accurate information to the PICO question: does therapeutic hypothermia improve

neurological function and survival rate in patients who have experienced cardiac arrest?

Design and Research Methods

This integrative review is attentive to five research articles. The only method

utilized by the researcher was EBSCO Discovery Services. Key words such as

‘therapeutic hypothermia,’ ‘cardiac arrest,’ ‘neurological outcomes,’ and ‘survival’ were

INTEGRATIVE REVIEW 4

used to locate 1,760 relevant articles. The search was limited to studies having been

published within five years, full text, and peer-reviewed. Each article examined for this

integrative review relate back to the intended PICO question, “Does therapeutic

hypothermia improve neurological function and survival rate in patients who have

experienced cardiac arrest?”

The articles chosen were filtered based on the following inclusion criteria:

survival, favorable neurological outcomes, ROSC, adult patients, and each patient had to

be in an acute and/or critical care setting. These processes led to the selection of five

quantitative studies relevant to the association between therapeutic hypothermia after

cardiac arrest on survival rates and favorable neurological outcomes.

Findings and Results

The findings and results of the majority of the studies (four out of five)

acknowledged the need for further randomized clinical trials due to the assorted

limitations experienced during each of the studies (Chan et al., 2016; Kim et al., 2014,

Doshi et al., 2016; Pang et al., 2017). One of the five studies found a strong relationship

between favorable neurological outcomes after the use of therapeutic hypothermia in

victims of cardiac arrest (Bae et al., 2015). The major variable of each article was the

induction of therapeutic hypothermia and included many variables such as age,

comorbidities, gender, initial rhythm, ROSC, and OHCA (Bae et al., 2015; Doshi et al.,

2016; Kim et al., 2014) and IHCA as major contributing factors (Chan et al., 2016; Pang

et al., 2017). This integrative review focuses on the inclusion of OHCA, IHCA, and core

body temperature.
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Out-of-Hospital Cardiac Arrest (OHCA)

Three of the quantitative studies that were examined in this integrative review

suggested that studies comparing therapeutic hypothermia post-cardiac arrest, survival

rates, and favorable neurological outcomes requiring more intuition on those who

experienced and survived OHCA (Bae et al., 2015, Doshi et al., 2016, Kim et al 2014).

Doshi et al.’s (2016) research study focused on the usefulness of therapeutic hypothermia

and rate of survival for those who suffered OHCA and had a non-shockable rhythm (i.e.

aystole). This article utilized secondary analysis of OHCA patients listed in the Cardiac

Arrest Registry to Enhance Survival (CARES). The CARES data included 696 adults

who experienced OHCA with non-shockable rhythms between the years 2007 and 2012.

Emergency Medial Services (EMS) logs were taken from the CARES files as well as

unidentified, randomized hospital information. Data was analyzed using chi-square tests

(%), propensity scores computed from a multiple logistic regression, model fit tests, and

the Wald test (Doshi et al., 2016). The analysis signified that therapeutic hypothermia

was not effective in increasing rates of survival for OHCA patients. This lead the authors

to conclude that further research is needed to offer a more conclusive information on

whether or not therapeutic hypothermia increases survival rates and favorable neurologic

outcomes.

Alongside Doshi et al.’s (2016) research, Bae et al.’s (2016) studies focused on

the association therapeutic hypothermia has by assessing location of ROSC and good

neurological outcomes post-OHCA. This was a quantitative, nationwide observational

study utilizing a non-experimental multivariable logistic regression analysis (Bae et al.,

2016). Data included in this study was limited to patient files drawn from the
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Cardiovascular Disease Surveillance (CAVAS) database. The database provided 11,007

OHCA patients with characteristics such as being 15 years or older, presumed cardiac

cause, survived to hospital admission from January 1, 2008 to December 31, 2013. Data

was analyzed using a Chi-Square test, Mann-Whitney U test and multivariate logistic

regression. This research study concluded that a positive correlation between therapeutic

hypothermia and favorable neurological outcomes exist after OHCA. Along with

favorable neurologic outcomes, location of ROSC was a noteworthy authority indicating

the efficacy of therapeutic hypothermia.

Lastly, Kim et al.’s (2014) research studied 86 adult OHCA patients who

remained comatose after ROSC treated with therapeutic hypothermia. This quantitative

prospective observational study aimed to determine if there is a correlation between the

duration of resuscitation efforts and good neurological outcomes in patients after OHCA

and therapeutic hypothermia. Data was collected from January 2008 to September 2012

and included patients treated at a tertiary care teaching hospital. Each patient’s electronic

medical record was screened by professional research assistants of the hospital and

information such as location of cardiac arrest, time between the start of CPR, the time of

sustained ROSC, witnessed arrest, and whether CPR was begun by a bystander (Kim et

al., 2014). Data analysis included the use of Kruskal-Wallis, Chi-squared or Fisher’s

exact test, and univariate and multivariate analyses by logistic regression to assess the

relationship between duration of resuscitation efforts and favorable neurological

outcomes.

In-Hospital Cardiac Arrest (IHCA)

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Two of the five quantitative research studies concluded that the induction of

therapeutic hypothermia post-cardiac arrest had limited information regarding IHCA

patients and the associated survival rate and favorable neurological outcomes (Chan et

al., 2016; Pang et al., 2017). In Chan et al.’s (2016) research study, measures were taking

to weigh the association between therapeutic hypothermia and survival rates and

favorable neurologic outcome among IHCA patients only. This quantitative, retrospective

cohort study included 26,183 IHCA patients pulled from the Get-With-The-Guidelines

(GWTG) Resuscitation registry along with Medicare files that were successfully

resuscitated from IHCA. This study examined the independent variable of therapeutic

hypothermia in IHCA patients compared to a control group of those not treated with

hypothermia. Data was collected based on hospital research staff using multiple methods:

centralized collection of cardiac arrest flow sheets, hospital paging system logs, as well

as routine code cart checks and tracing pharmacy drug records (Chan et al., 2016). To

analyze the association of therapeutic hypothermia with survival rates and neurological

outcomes, propensity score analyses were developed along with a multivariable logistic

regression to approximate the likelihood of inducting therapeutic hypothermia post-

IHCA. Compared to those not treated with therapeutic hypothermia, analyses determined

that therapeutic hypothermia used for post-IHCA treatment was associated with lower

rates of survival and favorable neurologic outcomes. Researches indicated that faster

response times with IHCA may limit the efficacy of reperfusion injury associated with

anoxic brain injury, but the need for further randomized clinical trials was addressed.

To evaluate the efficacy of therapeutic hypothermia in patients under

extracorporeal life support (ECLS) following cardiac arrest, Pang et al.’s (2017) study
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was similarly composed of 225 patients being treated with therapeutic hypothermia post-

IHCA between July 2003 and January 2016 that received CPR for greater than ten

minutes. This quantitative, retrospective review evaluated patient demographics, ECLS

related complications, in hospital mortality and neurologic outcomes. Patients who

remained unconscious after ROSC were selected randomly and treated with therapeutic

hypothermia for the first 24 hours of ECLS. Data was analyzed using standard deviations,

two-tailed t-tests, Mainn Whitney U-test, logistic regression analyses, Kaplan-Meier

survival curves, and Fisher’s exact test (Pang et al., 2017). Analyses of the data indicated

that patients treated with therapeutic hypothermia post-IHCA had a significant increase in

favorable neurologic outcomes. The researchers noted that therapeutic hypothermia is

proved to be particularly useful when evaluating the risks and benefits for those receiving

ECLS.

Core Body Temperature

Out of the five research articles, three support the association of core body

temperature range (32oC to 34oC) in carrying out effective therapeutic hypothermia (Bae

et al., 2015; Chan et al., 2016; Pang et al., 2017). In Pang et al.’s (2017) study,

researchers evaluated the involvement of specific measures such as therapeutic

hypothermia in relation to favorable outcomes in patients also under ECLS after IHCA.

Patients randomly selected to receive therapeutic hypothermia with a target body

temperature of 34oC. Body temperature was monitored with nasopharyngeal and

tympanic temperature gauges and maintained a internal temperature of 34oC for 24 hours.

After the initial 24 hours post-IHCA, warming methods were initiated to raise body

temperature to 36.5oC at 0.5oC per hour. This study revealed that core body temperature
INTEGRATIVE REVIEW 9

consistently kept between 32oC to 34oC for 24 hours is significantly associated with

increased favorable neurological outcomes and increaser survival rates.

In Bae et al.’s (2015) study, measures were taken to maintain an internal body

temperature between 32oC to 34oC for the initial 12 hours after ROSC. Results concluded

that 23% of those treated with therapeutic hypothermia attained favorable neurological

outcomes. In those who did not receive therapeutic hypothermia, only 15% of patients

achieved favorable neurological outcomes.

Chan et al.’s (2016) study was composed of an optional data element of core body

temperature that was applied to 346 of 26,183 patients that were treated with therapeutic

hypothermia. The median lowest core body temperature that was achieved was 33.1oC.

Analyses of the 346 patients that had recordings of core body temperatures showed that

therapeutic hypothermia was meaningfully associated with a negative correlation of

survival rates.

Discussion and Implications for Practice

Each of the five articles included in this integrative review appraise the

involvement of therapeutic hypothermia treatment after cardiac arrest, assessing patient

survival rates and favorable neurologic outcomes with relevance to the associated PICO

question. Four of the articles utilize a large patient sample (up to 26, 183 patients) to

examine the effectiveness of therapeutic hypothermia, with one of the articles utilizing a

small (86 patients) selection of patients from a selected registry. Each of these articles

evaluated different factors and variables that contributed to the outcome of therapeutic

hypothermia (. Of the five articles, two associated therapeutic hypothermia with negative

patient outcomes or had insignificant data (Chan et al., 2016; Doshi et al., 2015).
INTEGRATIVE REVIEW 10

However, three of the articles included associated therapeutic hypothermia with a

meaningful correlation of increased survival and favorable neurologic outcomes (Bae et

al., 2015; Kim et al., 2014; Pang et al., 2017). Although all five articles used did not have

identical conclusive findings, each article adequately provides information to support the

PICO question.

The use of therapeutic hypothermia is divisive among medical providers as well

as hospital systems in relation to a lack of universal protocol. Continuing research studies

present diverse findings related to the efficacy of post-cardiac arrest treatment by

providing further information regarding predicting factors, limitations, contraindications,

and implications for medical practice. Health care professionals are able to use the data

concluded in these research studies to contemplate and develop more nationalized

protocols along with more appropriate standardization for the induction of therapeutic

hypothermia (Bae et al., 2015). The inclusion of State and National guidelines, courses,

and certifications should be established by considering the data from previous studies so

there is an available standardization of care. A more accurate standardization of care and

national protocols would make for more accurate clinical trials on the value of

therapeutic hypothermia and its relationship to survival rates and neurologic outcome.

Limitations

Limitations encountered during this integrative review included limited

experience of the researcher. The accuracy of the information provided could be

misrepresented due to the lack of knowledge as well as a lack of clinical exposure, which

can limit the understanding of the content. Basing article selection on a five year time

frame along with information based on application to advanced practice can limit the
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information available along with the understanding of each article. The perimeters were

already implemented before the conduction of this non-exhaustive integrative review.

Limitations identified in the five articles included lack of detailed data regarding

therapeutic hypothermia protocol, unidentified core body temperatures, using National

registries as a source of sampling, unequal control and treatment groups, potential bias in

the data collection process, and finally, incomplete information as a result of registry

guidelines.

Conclusion

The evidence concluded from this integrative review signifies that there is slight

association between increased survival or favorable neurologic outcomes after cardiac

arrest with the use of therapeutic hypothermia. In patients who remained comatose post-

cardiac arrest and endured ROSC, treatment of therapeutic hypothermia was determined

based upon several factors: location of induction, initial heart rhythm (asystole versus

ventricular fibrillation), and core body temperature. The conduction of larger,

randomized clinical trials is necessary to offer more understanding and information on

the efficacy of therapeutic hypothermia and the role it plays in survival rates and

favorable neurologic outcomes. Findings of this integrative review relate to the PICO

question, “Does therapeutic hypothermia improve neurological function and survival rate

in patients who have experienced cardiac arrest?” by indicating that there is no

correlation between the use of therapeutic hypothermia and increased survival rates and

favorable neurologic outcome.

INTEGRATIVE REVIEW 12

References

American Heart Association. (2016). CPR & first aid: Emergency cardiovascular care.

Retrieved from

https://cpr.heart.org/AHAECC/CPRAndECC/ResuscitationScience/UCM_477263

_AHA-Cardiac-Arrest-Statistics.jsp%5BR=301,L,NC%5D

Bae, K. S., Sang, D. S., Ro, Y. S., Song, K. J., Lee, E. J., Lee, Y. J., Suh G. J., & Kwak,

Y. H. (2015). The effect of mild therapeutic hypothermia on good neurological

recovery after out-of-hospital cardiac arrest according to location of return of

spontaneous circulation: A nationwide observational study. Resuscitation.

89(2016). 120-136, http://dx.doi.org/10/1016/j.resuscitation.2015.01.024

Chan, P. S., Berg, R. A., Tang, Y., Curtis, L. H., & Spertus, J. A. (2016). Association

between therapeutic hypothermia and survival after in-hospital cardiac arrest.

JAMA, 316(13), 1375-1382. Doi: 10.1001/jama.2016.14380

Center for Disease Control. (n.d.). Cardiac arrest: An important public health issue.

Retrieved from https://www.cdc.gov/dhdsp/docs/cardiac-arrest-infographic.pdf

Doshi, P., Patel, K., Banuelos, R., Darger, B., Baker, S., Chambers, K. A., Thangam, M.,

Gates, K. (2015). Effect of therapeutic hypothermia on survival to hospital

discharge in out-of- hospital cardiac arrest secondary to nonschockable rhythms.

Academic Emergency Medicine, 2015(23). 15-20. Doi: 10.1111/acem.12847

Kim, W. Y., Giberson, T. A., Uber, A., Berg, K., Cocchi, M. N., Donnino, M. W. (2014).

Neurologic outcome in comatose patients resuscitated from out-of-hospital

cardiac arrest with prolonged downtime and treated with therapeutic

hypothermia. Resuscitation, 85(2014). 1042-1046.

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http://dx.doi.org/10.1016/j.resuscitation.2014.04.005

Pang, P. Y. K., Wee, G. H. L., Huang, M. J., Hoo, A. E. E., Sheriff, I. M. T., Lim, S. L.,

Lim, C. H. (2017). Therapeutic hypothermia may improve neurological

outcomes in extracorporeal life support for adult cardiac arrest. Heart, Lung, and

Circulation, 2016 (26), 817-824. http://dx.doi.org/10.1016/j.hlc.2016.11.022

 INTEGRATIVE REVIEW 14

Article Reference Bae, K. S., Sang, D. S., Ro, Y. S., Song, K. J., Lee, E. J., Lee, Y. J., Suh, G. J.,

& Kwak, Y. H. (2015). The effect of mild therapeutic hypothermia on

good neurological recovery after out-of-hospital cardiac arrest

according to location of return of spontaneous circulation: A nationwide

observational study. Resuscitation. 89(2016). 120-136,

http://dx.doi.org/10/1016/j.resuscitation.2015.01.024

Problem Background/Problem Statement: Mild therapeutic hypothermia (MTH) has

Statement / been known to be associated with good neurological recovery after out-of-
hospital cardiac arrest (OHCA). Prehospital return of spontaneous circulation
(P-ROSC) is associated with better hospital outcomes than ROSC at emergency
Background /
department (ED-ROSC). The study aims to examine the association between
MTH by location of ROSC and good neurological recovery after OHCA.
Research Question/Specific Aim/Purpose: To investigate the effect of MTH
Research Question- on favorable neurological outcome in comatose adult patients after an out-of-
Specific Aim or hospital cardiac arrest according to the location of ROSC.
Purpose / Significance Statement: Out of hospital cardiac arrest (OHCA) is recognized
as a worldwide, serious public health problem. This study was conducted to
Significance provide further research on whether mild therapeutic hypothermia was
statement beneficial on neurological outcome.
Conceptual or Not discussed.
Theoretical
Framework
Method Design / Method: Quantitative; non-experimental multivariable logistic regression
Philosophical analysis
Underpinnings Philosophical Underpinnings: N/A.
Sample / Sample: 11,007 EMS-assessed OHCA patients 15 years of age or older with
Setting / presumed cardiac cause and survived to hospital admission from January 1,
Ethical 2008-December 31, 2013. All cases were confirmed by medical record review.
Considerations Patients who died prior to hospital admission as well as patients who had non-
cardiac etiology were excluded. Patients with unknown neurological status due
to incomplete medical record were also excluded. Adequacy of the sample size
cannot be determined due to the study design and lack of power analysis. Cases
unnecessary to be cooled might be in the MTH group and cause bias for the
effect of MTH. An inter-rater agreement issue could be raised because the
authors did not test the agreement among medical records reviewers.
Setting: All EMS assessed OHCA patients who are 15 years or older pulled
from the Cardiovascular Disease Surveillance (CAVAS) database in Korea.
Ethical Considerations: The Institutional Review Board of the Seoul National
University Hospital approved of this study in 2013.
 INTEGRATIVE REVIEW 15

Major Variables The independent variable of the study is mild therapeutic hypothermia and was
Studied (and their a case receiving hypothermia procedure regardless of procedure method. The
definition) primary outcome was survival with favorable neurological outcomes at
discharge after cardiac arrest. Other variables included sex, age, location of
arrest, witnessed status, bystander CPR, residence in metropolitan, response
time interval, scene time interval, transport time interval, initial
electrocardiogram, pre-hospital defibrillation, level of ED, reperfusion therapy,
and location of any ROSC.
The major variables are clearly defined and described in the article.
Measurement Tool Measurement Tool: Scores were determined and coded via medical record
/ Data Collection reviewers of Korean CDC. Study population was divided into 2 group based off
Method application of
Data Analysis Study patients were divided into 2 groups based on the application of MTH
(MTH group and non-MTH) and location of ROSC (P-ROSC group and ED-
ROSC group). These two types of baseline characteristics were compared using
the chi-square test for categorical variables and the Mann-Whitney U test for
continuous variables. Multivariable logistic regression analyses for the primary
outcome with (interaction model) or without (simple model) the interaction
term between MTH and location of ROSC were performed to adjust for
potential confounders. Statistical analyses were performed with SAS software
version 9.3. A 2-sided value of p<0.05 was regarded as statistically significant.
Validity/reliability could not be determined due to the study design. The types
of statistical tests use are appropriate for the design.
Findings / MTH had association with good neurological outcome. The effect of MTH on
favorable neurological outcome differed by location of ROSC. If the patient
Discussion was a pre-hospital ROSC, there were unidentified benefits of MTH and
neurological outcome. If the patient was Emergency Department-ROSC, there
was a significant association between MTH and good neurological outcome.
The researchers related findings to external knowledge (suggesting regardless
of location of ROSC, MTH is beneficial), disagreeing that there was a
significant association between MTH and good neurological outcome.
However, MTH did not have positive effects on good neurological outcome in
pre-hospital ROSC group as opposed to significant benefit in ED-ROSC group.
Appraisal/Worth MTH is significantly associated with good neurological recovery in OHCA
to practice survivors, with more being those with ED-ROSC. To date, optimal
hypothermia protocols remain unclear. The authors acknowledge that more
study is needed and that their study can add one evidence on “who” will be the
target of MTH to current practice. Limitations included: all potential
confounders were not adjusted, hospital EDs do not have the same protocol for
post resuscitation care and hypothermia interventions, no measurement of exact
time for ROSC, clinical neurological outcomes measured from discharge
abstract or medical record not physician, no collection of data concerning
important variables that might influence neurological state on discharge,
selection bias, inter-rater agreement could be raised due to failure to test
agreement among medial record reviewers, and the EMS system characteristics.
Implications included that shorter time to ROSC decreases benefits of MTH on
 INTEGRATIVE REVIEW 16

cerebral resuscitation. I would use this study to support a change in nursing

practice.

Article Chan, P. S., Berg, R. A., Tang, Y., Curtis, L. H., & Spertus, J. A. (2016).
Reference
Association between therapeutic hypothermia and survival after in-

hospital cardiac arrest. JAMA, 316(13), 1375-1382. Doi:

10.1001/jama.2016.14380

Problem Statement / Problem Statement/background: Therapeutic hypothermia is used for

patients following both out-of-hospital cardiac arrest and in-hospital cardiac
Background / arrest. However, randomized trials on its efficacy for the in-hospital setting do
not exist, and comparative effectiveness data are limited. To evaluate the
Research Question-
association between therapeutic hypothermia and survival after in-hospital
Specific Aim or cardiac arrest.
Purpose / Research Question-Specific Aim or Purpose: Is therapeutic hypothermia
associated with better survival outcomes for patients with in-hospital cardiac
Significance arrest?
statement
Significance Statement: To evaluate the association between therapeutic
hypothermia and survival after in-hospital cardiac arrest.
Conceptual or The theoretical framework recognized is based on the factors that impact
Theoretical survival for patients who experienced in-hospital cardiac arrest along with the
Framework
role induction of therapeutic hypothermia has on the outcomes of patients who
experienced in-hospital cardiac arrest.
Method Method/Design: Non-experimental, quantitative cohort study
Design/Philosophic Philosophical Underpinnings: N/A.
al Underpinnings
Sample / Sample/Setting: 26,183 patients successfully resuscitated from in-hospital
cardiac arrest that were pulled from the Get-With-The-Guidelines-
Setting /
Resuscitation Registry and Medicare files. Patients must have been on
Ethical mechanical ventilation, had return of spontaneous circulation, and had to be the
Considerations first episode of in-hospital cardiac arrest with first use of therapeutic
hypothermia. Sample size adequacy cannot be determined due to a lack of
power analysis. Indication bias could have been introduced due to the variable
assessment of comatose patients and the potential for sicker patients to receive
therapeutic hypothermia.
Ethical Considerations: The institutional review board of the Mid America
Heart Institute waived the requirement for informed consent as data were de-
identified.
Major Variables Major Variables: The independent exposure variable was active induction of
Studied (and their therapeutic hypothermia, as documented within the Get-With-The-Guidelines-
definition)
Resuscitation registry. The primary outcomes were in-hospital survival (to
hospital discharge) and the secondary outcome was favorable neurological
survival (survival to hospital discharge with cerebral performance category
 INTEGRATIVE REVIEW 17

score of 1 or 2 – no neurological disability). All variables are clearly defined

and described well in the article.

Measurement Tool / Measurement Tool/Data Collection Method: Data collection consisted of

trained hospital personnel within the Get-With-The-Guidelines-Resuscitation
Data Collection
Method
registry attempting to identify all patients without DNR orders with a cardiac
arrest who undergo cardiopulmonary resuscitation. Cases are identified by
hospital research staff through multiple methods: centralized collection of
cardiac arrest flow sheets, reviews of hospital paging system logs, and routine
checks of code carts and pharmacy tracer drug records. Baseline differences
between patients treated and not treated with therapeutic hypothermia were
evaluated using X2 tests for categorical variables and student’s t-tests for
continuous variables. Due to the design of the study, validity and reliability
were threatened.
Data Analysis Data Analysis: All analyses were performed using a SAS version 9.2 and R
version 2.10.0 statistical software. Baseline differences between patients
treated and not treated with therapeutic hypothermia were evaluated using X2
tests for categorical variables and student’s t-tests for continuous variables.
Propensity score analyses were constructed to evaluate the association between
therapeutic hypothermia and survival outcomes. A multivariable logistic
regression model was constructed to estimate a patient’s likelihood to being
treated with therapeutic hypothermia after in-hospital cardiac arrest. These
types of statistical analyses are appropriate for the type of quantitative,
correlational study.
Findings / Findings: 417 (27.4%) patients that underwent therapeutic hypothermia
survived to discharge. Therapeutic hypothermia was associated with a lower
Discussion
likelihood of in-hospital survival. A lower proportion of patients treated with
therapeutic hypothermia group died during the first day than in the non-
hypothermia group. Therapeutic hypothermia was associated with a lower
likelihood of favorable neurological survival for all rhythms.
Discussion: Therapeutic hypothermia was not associated with higher rates of
survival to hospital discharge or favorable neurological survival in patients
with in-hospital cardiac and was associated with potential harm. These findings
are true for both shockable and non-shockable rhythms. Follow up extension of
one year still showed no survival advantage with therapeutic hypothermia.
Appraisal/Worth to Appraisal/Worth to Practice: Use of therapeutic hypothermia for those with
practice in-hospital cardiac arrest is associated with a low likelihood of survival to
hospital discharge and no favorable neurological outcomes. These findings
associate a need for randomized clinical trials to assess the efficacy of
therapeutic hypothermia for in-hospital cardiac arrest. Limitations of the study
included only reporting male patients, variability of neurological assessments
threatening accuracy of neurological outcomes, missing data, possibility of
residual confounding, possibility of null findings for therapeutic hypothermia
representing poor implementation due to a lack of data collection on protocols
and treatment, potential influence on the study’s results due to the possibility of
differential misclassifications being present that could favor the non-
 INTEGRATIVE REVIEW 18

hypothermia treated group, and unknown variations among results due to the
fact that Get-With-The-Guidelines-Resuscitation registry does not include
every single hospital in the nation. Implications for practice focus on the
characteristics of in-hospital cardiac arrests as the main factors for therapeutic
hypothermia efficacy as well as the study’s potential indication bias and
misclassification as the main factors warranting more randomized clinical trials
to be conducted.

Article Reference Doshi, P., Patel, K., Banuelos, R., Darger, B., Baker, S., Chambers, K.

A., Thangam, M., Gates, K. (2015). Effect of therapeutic hypothermia

on survival to hospital discharge in out-of- hospital cardiac arrest

secondary to nonschockable rhythms. Academic Emergency Medicine,

2015(23). 15-20. Doi: 10.1111/acem.12847

Problem Statement Problem Statement/Background: Therapeutic hypothermia has been shown

/ to improve neurologic outcome and survival in out-of-hospital cardiac arrest
Background / (OHCA) following return of spontaneous circulation (ROSC) and current
guidelines recommend therapeutic hypothermia for all comatose survivors of
Research Question-
OHCA. However, recommendations for nonschockable rhythms are not as
Specific Aim or
strongly supported.
Purpose /
Significance/Purpose: To provide further evidence on the use of therapeutic
Significance
hypothermia in nonschockable rhythms.
statement
Conceptual or Not discussed.
Theoretical
Framework
Method Design / Method/Design: Qualitative multivariate analysis, retrospective study
Philosophical Underpinnings: A 2012 systematic review and meta-analysis
Philosophical to determine whether therapeutic hypothermia is associated with improved
Underpinnings outcomes in OHCA survivors with a nonschockable rhythm revealed that the
two randomized controlled trials whose data were available included only 44
patients, and of the nonrandomized trials, the study with the largest group of
OHCA patients with nonschockable rhythms included 534 patients, but only
28 patients received therapeutic hypothermia.
Sample / Sample/Setting: Individuals were eligible for study inclusion if they were
adult patients with ROSC following OHCA secondary to nonshockable
rhythms between 2007 and 2012 and had definitive information regarding the
implementation or no implementation of therapeutic hypothermia in the
Setting / hospital. The Cardiac Arrest Registry to Enhance Survival (CARES) was used
and included every 911 activated cardiac arrest event in Houston, Texas. Of
Ethical the 9,479 OHCA patients in the registry, 696 met the inclusion criteria and 335
Considerations had been treated with therapeutic hypothermia. Sample size was not adequate
 INTEGRATIVE REVIEW 19

and was only included individuals in one state. Attrition rate was not
discussed.
Ethical Considerations: the institutional review board at the University of
Texas Health Science Center at Houston approved the study.
Major Variables Independent Variables: active induction of therapeutic hypothermia
Studied (and their Dependent Variables: age, sex, race, incident location (home, health care
definition) facility, etc.), witnessed arrest, bystander initiated CPR, first monitored
rhythm, survived to discharge
Primary Outcome: survival to hospital discharge
Measurement Tool Measurement Tool: Information pulled from CARES files.
/ Data Collection Method: Secondary analysis of CARES. CARES is an
emergency medical services (EMS) web-based registry for OHCA, in which
Data Collection review of EMS logs is coupled with selected, anonymized extraction of
Method hospital information.
Data Analysis Categorical demographic and baseline variables were compared between
groups using chi-square tests and reported as count (%). Only continuous
variable was age. Individuals were matched using propensity scores computed
from a multiple logistic regression on whether therapeutic hypothermia was
received. Association between therapeutic hypothermia and survival to
discharge was assessed by performing multiple conditional logistic regression
of matched pairs. The model fit was assessed by the likelihood ratio chi-square
test and final covariates by the Wald test.
Findings / Based on multiple logistic regression analysis of the 260 matched pairs, there
is no association between therapeutic hypothermia and survival to discharge
Discussion (36.5% with therapeutic hypothermia and 27.7% without). Whether the cardiac
arrest was witnessed was the only variable that had a statistically significant
association with survival to discharge. The researches observed significant
differences in the age of patients, as well as differences in location of cardiac
arrest and hospital location. Previous large prospective trials evaluating the
effect of therapeutic hypothermia in OHCA survivors were limited to
shockable rhythms and were thus unable to answer the question of efficacy in
patients with initial nonshockable rhythms.
Appraisal/Worth to Limitations: Major limitation of the study was that it was a retrospective and
practice relied on registry. The accuracy of the data entry ha snot been assessed or
verified. 59% of OHC survivors with nonshockable rhythms during the study
period were excluded because no information regarding therapeutic
hypothermia was provided by the treating hospital. There is missing
information regarding the target temperature and how long the target
temperature was maintained. Unavailable information in the CARES registry
was another limitation as well as neurological function was not included as
secondary outcomes. No information on patient comorbidities were available.
Implications: In clinical practice, therapeutic hypothermia does not seem to
be associated with improved survival in this cohort. Significant baseline
difference between groups, most notably the group who received therapeutic
hypothermia was younger, more likely to have arrest occur at home, and more
likely to be treated in tertiary care setting. However, there was no difference
 INTEGRATIVE REVIEW 20

noted in survival between the two groups.

The study fails to show a survival benefit from use of therapeutic hypothermia
and indicates the need for prospective studies to answer the study question
with greater clarity.

Article Reference Kim, W. Y., Giberson, T. A., Uber, A., Berg, K., Cocchi, M. N., Donnino, M.

W. (2014). Neurologic outcome in comatose patients resuscitated from

out-of-hospital cardiac arrest with prolonged downtime and treated

with therapeutic hypothermia. Resuscitation, 85(2014). 1042-1046.

http://dx.doi.org/10.1016/j.resuscitation.2014.04.005

Problem Statement Problem statement: Previous reports have shown that prolonged duration of
/ resuscitation efforts in out-of-hospital cardiac arrest (OHCA) is associated with
poor neurologic outcome.
Background: This has recently been questioned with advancements in post-
Background /
cardiac arrest care including the use of therapeutic hypothermia (TH). Only
two randomized trials have shown that TH is comatose survivors of cardiac
arrest reduces mortality and improves neurologic outcome.
Research Question- Aim of Study: The aim of this study was to determine the rate of good
Specific Aim or neurologic outcome based on the duration of resuscitation efforts in OHCA
Purpose / patients treated with TH.
Significance: This study was conducted to determine the relationship between
Significance downtime and neurologically intact survival in comatose adult OHCA patients
statement treated with TH and to evaluate the rates of survival at prolonged downtimes.
Conceptual or Framework: Previous reports have shown that prolonged duration of
Theoretical resuscitation effort in cardiac arrest is more likely to result in unfavorable
Framework neurologic outcomes; however, most studies concluding this information were
conducted before TH was the standard of care, so outcomes in patients
requiring prolonged resuscitation treated with TH is inconclusive.
Method Study Type: Quantitative prospective, observational study.
Design/Philosophic Philosophical underpinnings: N/A
al Underpinnings
Sample / Sample Size: 86
Sampling Strategy: study consisted of adult OHCA comatose patients with
Setting / sustained ROSC treated with comprehensive post-arrest care including TH
between January 2008 and September 2012.
Ethical Attrition Rate: Not discussed.
Considerations Bias: Selection bias may have occurred if individual clinicians opted not to use
TH for a patient with a longer down time, although this is nor part of the
criteria for TH as used at their hospital.
Setting: Urban tertiary care teaching hospital (cardiac arrest center) with 650
inpatient beds.
 INTEGRATIVE REVIEW 21

Adequacy: The sample size is relatively small and could lead to insufficient
results.
Ethical: The hospital Institutional Review Board approved this study.
Major Variables Dependent Variable: Neurologic outcome and survival rate
Studied (and their Independent Variable: Duration of resuscitation efforts in OHCA treated
definition) with TH.
The variables are clearly defined and described in the article.
Measurement Tool Measurement tools: Demographic and clinical characteristics during
/ downtime were assessed using one-way ANOVA or Kruskal-Wallis, Chi-
squared or Fisher’s exact test. Data Collection: All patients presenting with
Data Collection OHCA were screen by trained research assistants via the hospitals electronic
Method medical record system. Patient demographic information including age, sex,
race, and past medical history were recorded at the time of enrollment.
Downtime was measure from the time from the recognition of cardiac arrest to
the time of sustained ROSC.
Validity/Reliability: Not Discussed.
Data Analysis Univariate and multivariate analyses were performed using logistic regression
to evaluate the association between downtime and neurological outcome.
These are appropriate for the design of the study.
Findings / Findings: Downtime was significantly different in good neurologic outcome
and bad neurologic outcome groups. Longer downtime is associated with
Discussion worse outcome neurologically in OHCA patients, but comatose patients who
have been successfully resuscitated and treated with TH have neurologically
intact survival rates of 23% even with prolonged downtime.
Significance: The author’s do not mention statistical significance.
Relation to Literature: In previous studies, prolonged downtime was
associated with poor neurologic outcomes without the use of TH. The results
of this study showed that downtime is a major determinant of recovery with
good neurologic outcome even after TH.
Appraisal/Worth to Further Research: The authors recognize a need for further randomized
practice controlled trials.
Limitations: Small sample size, observational design, single-center study,
results may not be able to be generalized to other settings, potential selection
bias, data including non-sustained ROSC, and 11.4% of patients receiving TH
had early withdrawal of aggressive care.
Implications for Practice: Although longer downtime is associated with
worse outcome in OHCA, the authors found that comatose patients who have
been successfully resuscitated and treated with TH have neurologically intact
survival rates of 23% even with prolonged downtime.

Article Reference Pang, P. Y. K., Wee, G. H. L., Huang, M. J., Hoo, A. E. E., Sheriff, I. M.

T., Lim, S. L., Lim, C. H. (2017). Therapeutic hypothermia may

improve neurological outcomes in extracorporeal life support for adult

 INTEGRATIVE REVIEW 22

cardiac arrest. Heart, Lung, and Circulation, 2016 (26), 817-824.

http://dx.doi.org/10.1016/j.hlc.2016.11.022

Problem Statement Problem Statement/Background: Extracorporeal cardiopulmonary

/ resuscitation (E-CPR) shows survival benefit over conventional CPR in in-
hospital cardiac arrest (IHCA) of cardiac origin. Amongst patients resuscitated
with extracorporeal life support (ECLS) the rate of neuro favorable survival
Background /
remains low.
Knowledge gaps: Limited data exists on patients receiving therapeutic
hypothermia during ECLS; investigated outcomes & prognostic factors in
Research Question- these patients.
Specific Aim or Research Question/Importance of Study: Despite advances in resuscitative
Purpose / care, the survival rate after cardiac arrest remains poor at <20%. This study
Significance was conducted to evaluate the impact of peri-resuscitative variables and
statement adjunct measures such as therapeutic hypothermia on early outcomes in
patients receiving ECLS for refractory cardiac arrest at a tertiary referral
center.
Conceptual or Not discussed.
Theoretical
Framework
Method Design / Type of study: Quantitative retrospective review
Philosophical Philosophical Underpinnings: N/A
Underpinnings
Sample / Sample Size: 225 consecutive adult patients treated with ECLS between July
2003 and January 2016.
Strategy: Patients who experienced in hospital cardiac arrest were treated at
the National Heart Centre Singapore and were treated with therapeutic
Setting / hypothermia and received venoarterial ECLS. This study focused exclusively
on patients receiving E-CPR for refractory cardiac arrest, with conventional
Ethical CPR ongoing for more than 10 minutes.
Considerations Adequacy: Small sample size contributes to inadequacy of results.
Attrition Rate: Not discussed.
Bias: Inherent biases in data collection were inevitable. The proportion of
patients receiving therapeutic hypothermia in this study was relatively small
and could have limited statistical power.
Setting: National Heart Center Singapore
IRB Approval: Approval was granted to this study by the local institutional
review board.
Major Variables Independent Variable: induction of therapeutic hypothermia/E-CPR
Studied (and their Dependent Variable: age, gender, BSA, comorbidities, CPR/ECLS data,
definition) complications
Clearly Operationalized: Yes; each variable was clearly described and put
into an easy to read table.
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Measurement Tool Measurements used: Continuous variables expressed as either means with
/ standard deviation or median with interquartile range, and were compared
using two-tailed t-test or Mann-Whitney U-test respectively. Categorical
Data Collection variables expressed as percentages and analyzed with x2 or Fisher’s exact test.
Method For factors that trended towards significance (p<0.10) logistic regression
analyses were conducted. Survival function was presented using Kaplan-Meier
survival curves. All two-tailed p-values <0.50 were taken as significant.
Data Analysis Type of test used: Patient demographics, ECLS-related complications, in-
hospital mortality and neurological outcomes were analyzed. Statistical
analyses performed with the Statistical Package for Social Science, version 17.
Appropriate?: Yes
Findings / Findings: 35 patients (44.3%) were successfully weaned off ECLS of which
21 (26.6%) survived to hospital discharge. Among the 21 survivors, 16
Discussion patients (76.2%) had good neurological recovery; 6 patients (42.(%) in the
hypothermia group compared to 10 (15.4) in the normothermia group.
Statistically Significant: The use of therapeutic hypothermia during ECLS
was associated with significantly improved neurological outcomes.
Appraisal/Worth to Further research needed?: Yes
practice Limitations: Limitations of the study include the fact that it is a retrospective
observational study, the proportion of patients receiving therapeutic
hypothermia was relatively small and could have limited statistical power, and
it was conducted at a single ECLS center.
Implications for practice: The final results of this study may provide further
insights regarding the efficacy of therapeutic hypothermia. Prospective
randomized trial or a multi-centered study may enable more substantive
conclusions regarding the prognostic factors identified in this study.