Post on 21-Apr-2020
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 1
Assignment: State of Science Paper Two
Topic: Therapeutic Hypothermia to Improve Neurological and Survival Outcome in Adult Post
Cardiac Arrest Patients: A Systematic Review
Roshan Jan Muhammad
The Johns Hopkins University School of Nursing
“On my honor, I pledge that I have neither given or nor received any unauthorized assistance on
this assignment”. RJM
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 2
Abstract
Cardiac arrest (CA) and related mortality is one of the major health concerns in the United
States. The most evident cause of death among post CA patients is anoxic brain injury that
accounts for two third mortalities in these victims (Stub et al., 2011). The mechanism of brain
injury is triggered by ischemia during cardiac arrest and is further aggravated during reperfusion
phase when patient has return of spontaneous circulation (ROSC). Along with other measures,
mild therapeutic hypothermia (TH) is also proposed by International Liaison Committee of
Resuscitation (ILCOR), in order to prevent neurologic adversity and related mortality in CA
patients (Peberdy et al., 2010). However, despite international guidelines directing the
management of post CA patients, TH is used in less than 1% of CA patients in USA hospitals
because of statistical uncertainty of research findings (Kim et al. 2012). The purpose of this state
of the science paper is to determine the effect of TH on neurological and mortality outcome of
adult post CA patients compare to normo-thermia, in order to establish the basis for nursing
practice. Out of seventeen relevant articles found for the period of 2007-2012, ten were reviewed
for this paper that included; two Randomized Controlled Trial (RCT); one Quasi-Experiment
study; six retrospective observational studies and one prospective study. It is synthesized from
individual evidence summaries that here is evidence supporting the beneficial effect of
therapeutic hypothermia in reducing mortality and poor neurological outcomes in adult post CA
patients. However, much of these evidences are from observational studies (level III); in many
studies positive outcomes fail to reach statistical significance; and most studies in the review had
substantial risk of bias and had compromised validity. Therefore, a rigorous RCT is proposed as
nursing implication.
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 3
Key words: Therapeutic hypothermia (TH),Cardiac arrest (CA), return of spontaneous
circulation (ROSC), shockable rhythm (ventricular fibrillation or pulseless ventricular
tachycardia), non-shockable rhythm (Asystole or pulseless electrical activity), anoxic brain
injury, neurological outcome, mortality.
Introduction
According to American Heart Association (AHA), cardiac arrest (CA) is defined as “an
abrupt loss of heart function that is confirmed by the absence of circulation” (Beddingfield et al.,
2012). It is reported that out of hospital cardiac arrest (OHCA) affects up to 236,000 to 325,000
people in United States each year, with average survival to discharge rate of 7% (Roger et al.,
2011). On the other hand, In-hospital CA mortality rate of 67% is also a staggering figure
(Neumer et al., 2008). Though cardiac arrest causes global ischemia, but the brain is most
vulnerable to metabolic failure secondary to circulatory collapse during CA. According to
Neumer et al. (2008), neurological damage starts in 4-6 minutes after sudden cardiac arrest if
resuscitation is not attempted. However, immediate cardiopulmonary resuscitation and early
defibrillation increases the probability of return of spontaneous circulation (ROSC) and
perfusion. There is variability in definition of term “ROSC” in the literature. Nevertheless, it is
referred as sustained return of pulse or spontaneous circulation for the period ranging from 30
seconds to 20 minutes (Neumer et al., 2008).
While, ischemia is detrimental to the brain, evidences also suggest that reperfusion after a
brief episode of global ischemia, compliments initial hypoxic insult to the body, by causing
mitochondrial dysfunction. Pathophysiological responses during the early period of reperfusion
include calcium over load, abundance of reactive oxygen species and abrupt restoration of PH.
As a result, opening of non-specific mitochondrial permeability transition pore (mPTP) is
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 4
stimulated, leading to cell death (Cour et al., 2011). It is also known that ischemic event
perpetuate release of pro-inflammatory cytokines as a cascade of cellular events, thence,
compounding injury to the brain cells. Consequently, those who survive CA suffer serious
debilitating neurological complications or die due to post cardiac arrest syndrome. Nolan et al.
(2010) further emphasizes that the risk of poor neurological outcome post ROSC increases with
each degree increment in body temperature above 37C.
Mild therapeutic hypothermia (TH), that ranges between 32C-34C, is known to improve
neurological outcomes of post CA patients through various neuro-protective effects (Nolan et al.,
2010). TH prevents astroglial proliferation and blocks the cascade of pro inflammatory
mediators. It mitigates brain damage by reducing cerebral metabolic requirement; decreasing
cerebral edema, and intracranial pressure; inhibiting reperfusion injury; and limiting apoptosis
(Beddingfield et al., 2012). TH is a tri-phasic intervention which ideally include; induction,
maintenance and rewarming phase. Typically, induction phase is executed using conventional
ice packs on the groin, in armpit, and around the neck; intravenous ice-cold 0.9% normal saline
or ringers lactate infusion; and /or contemporary surface or internal cooling devices. This phase
often involves concomitant administration of opioids, hypnotics or neuromuscular blocking
agents to avoid shivering, as it has potential to aggravate neurological damage. Maintenance
phase usually lasts for 12-24 hours. Lastly, rewarming is done by using internal or external
thermal devices to ensure controlled rewarming at rate of 0.25C to 0.5C per hour (Nolan et
al., 2010).
For the first time, neuro-protective effects of TH in post CA patients got validation in
2002, when two independent randomized controlled trial by Bernard et al. (2002) and HACA
study group (2002) presented positive outcomes of TH in OHCA cases with an initial rhythm of
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 5
ventricular fibrillation (VF). Subsequently, in 2003, International Liaison Committee of
Resuscitation (ILCOR) recommended the use of TH in the treatment of adult post cardiac arrest
patients (Nolan et al., 2003). However, the recommendation was constraint to those CA victims
whose initial rhythm was shockable. Later, subsequent studies further supported the findings.
Nonetheless, most of them were observational.
In 2010, scientific statement released by American Heart Association on
Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, carried on with same
recommendation (Nolan et al., 2010). This time, the recommendation expanded the scope to
patients who sustained CA in-hospital and patients who had initial non-shockable rhythm.
Bernard (2012) reports that incidence of CA with PEA and Asystole as an initial rhythm is rising.
He further adds that, contrary to CA patient with shockable rhythm, this cohort has a relatively
poor prognosis. Meta-analysis conducted by Kim et al. (2012) also concluded that, though TH is
associated with reduced mortality for adult patients resuscitated from non-shockable rhythm,
most studies in the review had substantial risk of bias and the quality of evidence was very low.
Therefore, despite recommendations from expert panel, utilization of TH is still limited
and is only used for less than 1% of CA patients in USA hospitals (Kim et al. 2012). Major
barriers to wide spread use of TH are skepticism about quality of evidences, uncertainty about
eligibility, doubts about long term benefit, misconception of futility and lack of motivation. The
purpose of this state of the science paper was to determine if therapeutic hypothermia compared
with normo-thermia improves mortality and neurological outcomes in adult post cardiac arrest
patients with ROSC. In my future role of clinical nurse specialist, I envision myself as a change
agent advocating for evidence based practice. This review assisted me critically appraise related
evidences and synthesize conclusion about this crucial area of clinical practice. The paper
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 6
explored evidences pertinent to TH intervention in patients with both non-shockable and
shockable rhythm.
Search engines like PubMed, EMBASE, CINAHL and Cochrane were explored for the
period of 2007-2012 during search process. Database specific MeSH terms were used using
Boolean Operators. The search terms included; for PubMed ((“heart arrest”) OR
“cardiopulmonary resuscitation”) AND “hypothermia, induced”; for CINAHL (MM
“hypothermia, induced”) AND (MM “heart arrest”); for EMBASE ‘heart arrest’/exp OR
‘resuscitation’/exp AND ‘induced hypothermia’/exp; and for Cochrane “hypothermia”. The
search was truncated to randomized control trials, quasi-experimental studies and non-
experimental quantitative studies conducted on humans having ages above 18years. Publications
in language other than ‘English’ were excluded. The search retrieved total 271 articles, following
breakdown of PubMed (42), CINAHL (10), Cochrane (1), and EMBASE (218). After
eliminating duplication through ref works, the abstracts of all articles were reviewed based on
inclusion criteria. Finally, seventeen articles were found relevant, of which, ten were used for
this state of science paper. The following summary is synthesized from individual evidence
evaluation of all ten articles (Appendix B).
Overall Summary of Evidences
Studies Descriptions
Of ten articles appraised, two included RCTs (Tiainen et al., 2007; Kim et al., 2007); one
was quasi-experimental study (Granja et al., 2011); six were retrospective observational studies
(Reinikainen et al., 2012; Prior et al., 2010; Pfeifer et al., 2011; Testori et al., 2011; Stub et al.,
2011; Van der et al., 2011); and one had prospective observational design (Storm et al., 2012).
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 7
All were of good quality except for Kim et al.’s (2007) study that was rated poor. All the studies
included hypothermia in the treatment arm; however, there was variability in control/comparison
groups. Amongst ten studies, two had control group of normo-thermia with controlled
hyperthermia (Tiainen et al., 2007; Pfeifer et al., 2011); two utilized normo-thermia group
without hyperthermia control (Testori et al., 2011; Van der et al., 2011); whereas, five studies
(Granja et al., 2011; Reinikainen et al., 2012; Prior et al., 2010; Storm et al., 2012; Stub et al.,
2011) did not provided information about hyperthermia control in comparison group. All
observational studies had used historical controls for the comparison. Overall, these studies
enrolled 10,912 patients, 7472 in the treatment arm and 3396 in the comparison group, out of
which, 9275 patients were in two registry based multicenter-retrospective observational studies
only. Out of these ten studies, three studies inducted CA patients with shockable rhythms; two
included CA patients from non-shockable rhythms; and remaining five studies enrolled CA
survivors from both shockable and non-shockable rhythms. Remaining key facts about the study
design and the results are summarized in Appendix A.
Effect of Therapeutic Hypothermia on Survival Outcomes Post Cardiac Arrest
Out of ten studies, nine showed mortality benefit of TH in post CA patients. However,
findings of only five studies (Reinikainen et al., 2012; Prior et al., 2010; Testori et al., 2011; Stub
et al., 2011; Van der et al., 2011) could reach statistical significance, and all of them were
observational studies with historical controls. In addition, all statistically significant results were
observed against normo-thermia group in which hyperthermia was either not prevented or not
monitored/reported.
Discharge outcomes of intervention group in CA patients with shockable versus non-
shockable rhythm is also important to analyze. All three studies (Tiainen et al., 2007;
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 8
Reinikainen et al., 2012; Stub et al., 2011) with inclusion of CA patients with shockable rhythm
had better survival rate at discharge, and two of them reached statistically significant conclusion
as well. On the contrary, two studies (Testori et al., 2011; Storm et al., 2012) that had enrolled
CA patients with non-shockable rhythm, only one showed beneficial effect and significant
results. Synthesis of remaining four studies (Granja et al., 2011; Prior et al., 2010; Pfeifer et al.,
2011; Van der et al., 2011) that had inducted both shockable and non-shockable rhythms is
equivocal. Though all of them reported reduced mortality rate, nonetheless, only two had
significant results. Of those two, only one that presented separate analysis concluded substantial
favorable outcome in patients with shockable rhythm versus non-shockable rhythm. Overall
evidences, though of lower quality, are more favorable for CA victims with shockable rhythms.
Nevertheless, clinical benefits of non-statistically significant, yet inconsistent positive results
cannot be disregarded for the non-shockable group as well. However, in lieu of threats to internal
validity, that is described latter in the paper, findings should be generalized with great caution.
Effect of Therapeutic Hypothermia on Neurological Outcomes Post Cardiac Arrest
Of eight studies that evaluated neurological status post treatment, all endorsed protective
neurological effect of TH in the treatment group. Nevertheless, only four could render
statistically significant conclusion (Prior et al., 2010; Pfeifer et al., 2011; Testori et al., 2011;
Stub et al., 2011), all being lower level of evidence (LOE III) and with historical controls. It is
important to note that three out of four studies had comparable group with no pyrexia preventive
measures.
Separate analysis of the findings pertinent to shockable and non-shockable rhythms is
also critical. TH attributed to positive outcomes in both studies done on CA patients following
shockable rhythm, but, only one produced statistically conclusive results. Similar outcome
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 9
pattern emerged from two studies that included CA patients with non-shockable rhythm.
Conversely, four studies that enrolled CA patients with all rhythms, despite positive outcomes in
all, only two produced statistically substantial results, mostly in VF/VT patients.
Limitations
All the studies included in the analysis had vast differences in terms of study deign, rigor,
and methodology. Therefore, aforementioned, results must be viewed in consideration of study’s
limitations. Selection bias, lack of control over confounding variables, inadequate
standardization of treatment, sample size limitation and influence of history as a threat to
internal, external and statistical validity of the studies are discussed here to guide conclusion.
Selection Bias
Of ten studies reviewed, five included the samples having a particular type of rhythm in
CA patients. Additionally, non-random sampling, exclusion of critical patients, elimination of
fatality cases within 24 or 48 hours of CA from the study, and the use of subgroup for the
analysis, are few critical elements that contribute to selection bias. As a consequence, study
sample may not be true representative of all CA patients. Therefore, the findings cannot be
generalized to all CA patients.
Lack of Control over Confounding Variables
Overall the studies reviewed have presented suboptimal control over following critical
confounding variables that compromises internal validity of the studies.
Fever is common after CA. It is responsible for release of excitatory neurotransmitters
that is responsible for neuronal cell death, and unfavorable neurologic outcome in a variety of
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 10
experimental models of brain injury (Laptook et al., 2008). Natale, et al. (2000) documents that
fever in CA victim is independently associated with worse outcome compared to patients with
normothermia. In this systematic review, we found that only Tiainen et al. (2007) and Pfeifer et
al. (2011) had controlled hyperthermia in their comparison group and both the studies showed
positive but not statistically significant outcomes in TH group. It is interesting to note that in
Van der et al’s. (2011) study, median temperature in the treatment arm was inclined toward
lower threshold of normo-thermia (35.5C) in most patients instead of hypothermia, and that
study also showed positive yet statistically inconclusive results. Thus, it can be extrapolated that
lower threshold normo-thermia with fever control measures may produce the comparable results
as of TH. It is consistent with the conclusion of Stub et al.’s (2011) study that pyrexia prevention
can be used as a minimum recommendation if TH is contraindicated or not feasible.
Arterial Hyperoxia (PaO2 >300mmHg) is another potential confounder that is labeled as
a predicator of mortality in patients with CA compared with normoxia and hypoxia (Kilgannon et
al., 2010). Additionally, Mean arterial pressure (MAP) is also listed as an important covariate
for poor outcomes in CA victims. Stub (2011) reports that hemodynamic instability (MAP <
65mmHg), that is common after effect of CA, is also associated with poorer survival and
neurological outcomes. Furthermore, Nielson et al. (2011) has reported that sustained
hyperglycemia (blood glucose >8 mmol/L for >4 hrs) is associated with high mortality in post
CA patients who were treated with TH. During this review, it was found that only Tiainen et al.
(2007); Kim et al. (2007); and Prior et al. (2010), demonstrated reasonable control over these
variables through exclusion or regression analysis. Though all three studies have shown positive
impact but, only Prior et al. (2010) has documented significant outcomes. It is plausible that poor
outcomes in normo-thermia group are secondary to lack of control over this extraneous variable.
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 11
In recent years, TH with Percutaneous Coronary Intervention (PCI) is also surfacing as
efficacious approach to attain better outcomes in comatose survivors of OHCA. Stub et al’s.
(2011) study used this synergy intervention and concluded statistically significant results. But,
Stub did not present multivariate analysis to statistically adjust the effect modification or
confounding effect of PCI on the association of TH and outcomes.
Overall, except for Tiainen et al. (2007), no other studies have presented adequate control
or statistical adjustment of above mentioned covariates and his research also revealed non-
statistically significant positive results.
Inadequate Measures to Standardize Treatment
All observational studies in particular, by virtue of their design, had huge variability in
treatment implementation. Burns and Groove (2009) emphasizes that treatment standardization is
crucial every time it is executed to detect a true difference. Inconsistency in treatment
implementation reduces the likelihood of detecting the true difference. In studies reviewed,
researchers did not report measures of central tendency and variability for induction time for TH
(Tiainen et al., 2007 ; Kim et al., 2007; Reinikainen et al., 2012; Storm et al., 2012; Stub et al.,
2011; Van der et al., 2011); temperature achieved against target goal in TH group (Kim et al.,
2007 ; Granja et al., 2011; Reinikainen et al., 2012; Prior et al., 2010; Storm et al., 2012; Stub et
al., 2011); duration of cooling (Kim et al., 2007; Reinikainen et al., 2012; Pfeifer et al., 2011;
Testori et al., 2011; Storm et al., 2012; Stub et al., 2011;Van der et al., 2011); and rewarming
rate. Nordmark et al. (2009) reports that neurochemical changes indicating cerebral ischemia and
excitoxicity are found both after CA and during the re-warming phase that perpetuate
neurological sequel. Thus, delayed induction and rapid rewarming might decrease the neuro-
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 12
protective effects of TH. Due to gaps in information, best parameters of TH execution cannot be
established.
Instrument and Measurement Issues
Core temperature monitoring was of essence in the study. Reinikainen et al. (2012); Stub
et al. (2011) and Van der et al. (2011) did not report the monitoring instrument used in their
studies. Nonetheless, Kim et al. (2007) and Testori et al. (2011) have reported inconsistent use of
instrument that might have compromised the precision of measurements. One the other hand,
instrument used for neurological evaluation, and it methodology is critical to appraise
aforementioned presented synthesis. Though all studies used Pittsburgh Cerebral Perfusion
Scale, Prior et al. (2010); Pfeifer et al. (2011); Storm et al. (2012); and Stub et al. (2011)
assigned ratings to the patients through clinical chart review instead of direct evaluation. The
remaining researchers, who used in person evaluation, only Tiainen et al. (2007) and Testori et
al. (2011) used blinded assessor to prevent bias. Additionally, time to assessment was also
variable among all the studies. All researchers have presented neurological outcomes at
discharge except for Tiainen and Testori, who did appraisal at 3 month and 6 months. As a
consequence, patients who might have recovered in long run, could not be captured in all
remaining studies that might have under-estimated the outcomes.
Statistical validity
According to Burns and Groves (2009), low powered studies increases the likelihood of
concluding non-statistically significant result between groups when actually there is difference.
Despite the fact, only Reinikainen et al. (2012) and Van der et al.’s (2011) have used large
sample size, concluding non-significant and significant findings respectively, causing
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 13
ambivalence. Besides that, none of the studies, including level I and II trails, reported power
analysis thus, adequacy of sample size cannot be ascertained and non-statistically significant
findings remain inconclusive and dubious.
History as a Threat to Validity
Peri-cardiac arrest factors like duration and quality of BLS and ACLS and general post
resuscitation care are important determinants of CA outcomes. Revised cardiopulmonary
resuscitation guidelines published from ILCOR, in 2003, was a break through. It recommended
several key changes to reduce no flow (time from collapse to BLS) and low flow time (time from
collapse to ROSC); and ameliorate post ROSC care. It can be deduce that promising results in
CA victims after this period can be due to bundle effect of these recommendations. And
therefore, significant results of Reinikainen et al. (2012); Prior et al. (2010); Testori et al.’s
(2011); Storm et al.’s (2012); Stub et al.’s (2011); Van der et al.’s (2011) studies, that utilized
historical controls from before this period can be challenged by rival hypothesis.
Conclusion
This state of the science paper concludes that there is reasonable evidence that TH is
effective for adult comatose post CA victim with ROSC. Nevertheless, favorable evidences are
more inclined towards CA with shockable rhythm and all studies with statistically significant
conclusion are of lower level and lack adequate rigor. Therefore, causality cannot be established
and TH can be concluded as a sole and independent predictor of positive outcome in CA
patients. However, keeping in view that outcomes in CA patients are generally very poor, non-
statistically significant survival and neurological benefits might be of clinical importance.
Despite this consideration, clinical implication of TH in this patient population is highly
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 14
restricted. It is because, there are several questions still unanswered due to study limitations and
in-adequate information, such as, who would be the beneficiaries; what is the best induction time
and duration of cooling, what is most therapeutic depth of cooling and rate of rewarming. As a
consequence, it limits translation of this research synthesis into practice. Therefore, Randomized
Control Trial with adequate rigor and with better control over confounding variables needs to be
conducted, that draws more definite conclusion, determines causal relationship, produces
unbiased results for patients with both shockable and non-shockable rhythms, and adequately
answers the key questions related to treatment implementation. Besides, that also proclaims the
long term survival and neurological benefit of the treatment. Thus, based on the learning from
this synthesis, following study is proposed for future nursing implication.
Implications for Nursing Research
Research Question
To evaluate if therapeutic hypothermia (32-34C) has positive survival and neurological
benefit compare to lower threshold normo-thermia(36C) in adult post CA patients with
shockable and non-shockable rhythm.
Study Design
Multicenter randomized Controlled trial.
Setting.
ICU settings of at least 3 tertiary care hospitals would be used to conduct the study.
Variables
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 15
Independent variables. Hypothermia and lower threshold normo-thermia would be
independent variables in the study.
Dependent variables. There are 2 dependent variables in the study. First is ‘survival
outcome’ that would be monitored at discharge, one month, three months and six months period
through hospital data base and follow up through telephone by blinded assessor. Second variable
is ‘neurological outcome’, which would also be followed at the same duration as of survival
outcome. Evaluation would be carried out by blinded assessor through in person evaluation of
patients. We would use 2 valid and reliable instruments to prevent mono-opertaion bias that
include: Pittsburgh Cerebral Perfusion Category (CPC) and Modified Rankin Scale (MRS).
Standard definition would be used to dichotomize the neurological outcome as ‘good’, that is
CPC < 2 and MRS < 3.
Inclusion Criteria
All patients over 18 years of age, who are resuscitated from OHCA or in-hospital CA
with presumed cardiac causes and who remain unconscious (GCS <8) one hour after ROSC
would be included in the study. It is aligned with landmark RCT’s (HACA, 2002 & Bernard et
al., 2002) and Tiainen et al.’s (2007) clinical trial.
Exclusion Criteria
We would follow the exclusion criteria similar to most of the RCTs reported so far. The
criteria include pregnancy; coagulopathy; intracranial hemorrhage and stroke; CPC > 2;
cardiogenic shock (i.e., MAP systolic blood pressure less than 80 mmHg) refractory to pressors;
and terminal disease before cardiac arrest.
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 16
Sample Size and Sampling Methodology
To ensure that study is adequately powered to detect the difference in the outcomes
between groups, sample size would be calculated to attain 80% power at 5% level of
significance. However, effect size would be extrapolated from meta-analysis of high or good
quality randomized control trial on related theme. As we intend to conduct neurological
evaluation at discharge, 3 months and 6 months, potential sample attrition would also be
considered while calculating the sample size. Patients would be randomly assigned to treatment
and controlled arm. Nature of the study is such that the care providers cannot be kept blinded,
nevertheless, person conducting neurological evaluation and the statistician would be blinded.
Method
The hypothermia protocol would be developed following recommendations from
American Association and ILCOR to ensure standardization of treatment. Prior to the start of
therapy, baseline information would be obtained that is peri-cardiac arrest, baseline vital signs,
lab investigation, clinical evaluation and acute physiology and chronic health evaluation
(APACHE) score to be used later for multivariate analysis. Thereafter, TH would be introduced
using intravenous cold saline and temperature would be monitored via urinary catheter. The
intervention would be phased out in 4 steps. (a)‘Induction phase’ would be within 4 hours of
ROSC. (b) ‘Maintenance phase’ would last for 24 hours from individual patients’ indication time
after achieving temperature end point. (c) ‘Rewarming phase’ would have end point of 37 C
with rate adjusted for 8 hours duration. (d) ‘Post hypothermia phase’ would include maintenance
of temperature 37 C + 0.5 C to prevent detrimental effect of pyrexia for 72 hours from CA in
both the groups. All confounding variables listed in the limitation section would be monitored
throughout 72 hours.
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 17
In consideration of presumed certainty about deleterious effect of hyperthermia,
temperature for control group is determined as lower threshold normo-thermia to prevent
potential sweep to hyper thermic range. In order to do so, close monitoring and aggressive
quality control measures would be undertaken to maintain temperature at cut off range and to
prohibit hyperthermia in control group. Besides that, both the groups would receive comparable
treatment for shivering and seizures prevention; glycemic control (i.e., 8-10 mmol/L); MAP
maintenance (above 65 mmHg, through fluids and vassopressors); and hypoxia/hyperxia
prevention. This would control key confounding variables related to treatment that were poorly
controlled in previous studies.
Statistical Analysis.
Analysis would essentially include comparison of the groups for basic characteristics
using t test for continuous variable and Chi-square for categorical variables. Main outcome
analysis would be pursued as follows.
‘Survival outcome at discharge’ would be carried out by using uni-variate logistic
regression. To eliminate the potential effect of confounder or effect modifier, multi-variate
logistic regression will be performed, adjusted for covariates like no flow time, low flow time,
initial rhythm, blood glucose level, arterial oxygen level, and MAP, pyrexia, gender, age and
acuity level based on (APACHE II) score. Additionally, ‘survival outcome at 6 months’ would
be determined using cox regression analysis both unadjusted and adjusted for above listed
variables. ‘Neurological outcome at discharge, 3 months and 6 months’ would be evaluated
through Chi- square to compare proportion of good and bad neurological outcomes between the
groups. Post hoc stratified analysis will also be conducted to present the outcomes based on
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 18
shockbale and non-shockable rhythm of cardiac arrest. For all the tests, the effect estimates will
be provided considering 95% confidence interval and ∝0.5 (2 tailed).
Stake Holders
The nature of the study demands involvement of multidisciplinary team that include
administration of hospital CPR committee; chair of ICU committee; neurologist; nurse manager
of the units; clinical nurse specialists; nurses and medical residents on the floor; patients and
their proxy; and statistician . We would also involve experts in the field from ILCOR to provide
consultancy.
THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 19
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of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline.
Circulation, 115(24), 3064-3070. doi: 10.1161/CIRCULATIONAHA.106.655480
Kim, Y. M., Yim, H. W., Jeong, S. H., Klem, M. L., & Callaway, C. W. (2012). Does therapeutic
hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial
rhythms?: A systematic review and meta-analysis of randomized and non-randomized
studies. Resuscitation, 83(2), 188-196. doi:10.1016/j.resuscitation.2011.07.031
Laptook A, Tyson J, Shankaran S, et al.: Elevated temperature after hypoxic-ischemic
encephalopathy: risk factor for adverse outcomes. Pediatrics 2008; 122:491–499
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Natale JE, Joseph JG, Helfaer MA, et al.: Early hyperthermia after traumatic brain injury in
children: Risk factors, influence on length of stay, and effect on short-term neurologic
status. Crit Care Med 2000; 28:2608–2615
Neumar, R. W., Nolan, J. P., Adrie, C., Aibiki, M., Berg, R. A., Bottiger, B. W., . . . Vanden
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and prognostication. A consensus statement from the international liaison committee on
resuscitation (american heart association, australian and new zealand council on
resuscitation, european resuscitation council, heart and stroke foundation of canada,
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Nolan, J. P., Morley, P. T., Vanden Hoek, T. L., Hickey, R. W., Kloeck, W. G., Billi, J., . . .
International Liaison Committee on Resuscitation. (2003). Therapeutic hypothermia after
cardiac arrest: An advisory statement by the advanced life support task force of the
international liaison committee on resuscitation. Circulation, 108(1), 118-121.
doi:10.1161/01.CIR.0000079019.02601.90
Nolan, J. P., Neumar, R. W., Adrie, C., Aibiki, M., Berg, R. A., Bbttiger, B. W., . . . Council on
Stroke. (2010). Post-cardiac arrest syndrome: Epidemiology, pathophysiology, treatment,
and prognostication: A scientific statement from the international liaison committee on
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perioperative, and critical care; the council on clinical cardiology; the council on stroke (part
II). International Emergency Nursing, 18(1), 8-28. doi:10.1016/j.ienj.2009.07.001
Nordmark, J., Rubertsson, S., Mortberg, E., Nilsson, P., & Enblad, P. (2009). Intracerebral
monitoring in comatose patients treated with hypothermia after a cardiac arrest. Acta
Anaesthesiologica Scandinavica, 53(3), 289-298. doi: 10.1111/j.1399-6576.2008.01885.x
Peberdy, M. A., Callaway, C. W., Neumar, R. W., Geocadin, R. G., Zimmerman, J. L., Donnino,
M., . . . Kronick, S. L. (2010). Part 9: Post-cardiac arrest care: 2010 american heart
association guidelines for cardiopulmonary resuscitation and emergency cardiovascular
care. Circulation, 122(18 Suppl 3), S768-86.
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Pfeifer, R., Jung, C., Purle, S., Lauten, A., Yilmaz, A., Surber, R., . . . Figulla, H. R. (2011).
Survival does not improve when therapeutic hypothermia is added to post-cardiac arrest
care. Resuscitation, 82(9), 1168-1173. doi: 10.1016/j.resuscitation.2011.05.024
Prior, J., Lawhon-Triano, M., Fedor, D., Vanston, V. J., Getts, R., & Smego, R. A.,Jr. (2010).
Community-based application of mild therapeutic hypothermia for survivors of cardiac
arrest. Southern Medical Journal, 103(4), 295-300. doi: 10.1097/SMJ.0b013e3181d3cedb
Reinikainen, M., Oksanen, T., Leppanen, P., Torppa, T., Niskanen, M., Kurola, J., & Finnish
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THERAPEUTIC HYPOTHERMIA POST CARDIAC ARREST 23
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56(1), 110-115. doi: 10.1111/j.1399-6576.2011.02543.x; 10.1111/j.1399-6576.2011.02543.x
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10.1097/CCM.0b013e3181fd6aef
Appendix A
Summary of Evidences
1st
Author
Study design
/Control/LOE
Sample
TH vs NT
Type of CA rhythm
Site of CA
Cooling device
Induction time from
ROSC
Target temp in TH
group /Mean temp
Cooling duration
Mean temp in
NT group
Survival Outcome
TH vs NT
Neurological Outcome
TH vs NT
Tiainen (2007)
Randomized prospective
trial(I B)
N = 70TH = 36NT= 34
Shockable *OHCA External device
NA 32-34C/33+1C
24hrsMean NA
^NTMean NA
[SO] ( 28 vs 22, p = 0.226) 93% vs 78%, no P valueCognitive outcome:
Intact or subtle deficit67% vs 44%, NS
Kim (2007)
Randomized controlled
trial(I C)
N = 97TH = 49NT = 48
All rhythms
*OHCA SC and CS
NA 32-34C/Mean NA
NA ×NTMean NA
[SO] VF group: 66% vs 45%, p= NS
Non VF group:6% vs 20%, p = NS
Adjusted OR for survival = 0.91, 95% CI=0.28 to 2.96
Awakening in VF patients:
69% vs 45%, P = 0.15Awakening in Non-VF
patients:9% vs 23%, P = 0.13
Granja (2011)
Before and after(II B)
N = 130TH = 55NT =75
All rhythms
IN and **OHCA
SC and CS
4+2.25hrs 32-34C/Mean NA
15.1+4.1hrs
×NTMean NA
[SO] 60% vs 39% ,P= 0.16 26 vs 21 patients, NS
Reinikainen 2012
Retrospective observational
with HC(III B)
N = 3958TH = 3072NT = 886
Shockable OHCANA
NA NA 32-34C/Mean NA
NA ×NTMean NA
[M]51.1% vs 57.9%, P< 0.001Adjusted OR = 0.54, 95 % CI=
0.45-0.64, P < 0.001)
NA
Prior(2010)
Retrospective cohort with
HC(III B-/C)
N = 456TH = 44NT = 368
All rhythms
IN and **OHCA
SC 2.8hrs (0.2-7.8
32-34C/Mean NA
9-28hrs ×NTMean NA
[SO] Within TH group:Shockable vs non shockable
61% vs 24%, P < 0.05
43% vs 13%, P < 0.001
Pfeifer(2011)
Retrospective observational
with HC(III B)
N = 210TH = 143NT = 67
All rhythms
IN and **OHCA
SC and CS
4-6hrs 32-34C/33+1C
24hrsMean NA
^NTMean NA
[SO] All patients:48.2% vs 44.8%, P = 0.659
For shockable :26.4% vs 28.6%, P = 0.807
For non-shockable:70.4% vs 56.4%, P = 0.149)
Better in VF patient within TH group (p < 0.001)
Appendix A
Testori,(2011)
Retrospective cohort with
HC(III B)
N = 374TH =135NT= 239
Non Shockable
*OHCA SC and CS
1.4hrs 32-34C/33+1C
24hrsMean NA
^^NTMean NA
[SO] Adjusted OR = 0.56, 95% CI, 0.34 – 0.93
Adjusted OR = 1.84, 95% CI, 1.08 – 3.13
Storm (2012)
Prospective observational
with HC(III B)
N = 175TH = 87NT = 88
Non Shockable
IN and **OHCA
SC and CS
NA 32-34C/Mean NA
24hrsMean NA
×NTMean NA
[SO] Adjusted HR 0.98, 95% CI = 0.53-1.5, p = 0.63
27.5% vs 18.2%, P = 0.175
Stub (2011)
Retrospective observational
with HC(III B)
N = 125TH = 81NT = 44
Shockable **OHCA SC and CS
NA 32-34C/Mean NA
NA ×NTMean NA
[SO] 64% vs 39%, p <0.01Unadjusted Odds ratio 2.7,
95% CI = 1.1 – 6.4 , P = 0.02
57% vs 29%, p < 0.01
Van der (2011)
Retrospective observational
with HC(III B)
N = 5317TH= 3770NT = 1547
All rhythms
**OHCA NA NA 33-36.4C NA ^^NTMean NA
[M] 65% vs 72%, p = NAAdjust OR= 0.8, 95% CI= 0.65
– 0.98, p = 0.29
NA
LOE= Level of evidence; CA=Cardiac arrest; ROSC=Return of spontaneous circulation; SO=Survival Outcome; M=Mortality Outcome; All rhythms= VT/VF/PEA/Asystole; TH=Therapeutic hypothermia; Shockable =VT/VF; Non Shockable=PEA/Asystole; NT=Normothermia; ^ hyperthermia controlled; ^^ hyperthermia not controlled; × hyperthermia information NA; *OHCA=Out of hospital cardiac arrest(witnessed); **OHCA=Out of hospital cardiac arrest(witnessed and un witnessed);IN=In-hospital; NS=Not significant; NA=Not available/assessed; SC=Surface cooling; CS=cold saline/fluids; HR=hazard ratio; HC=Histori
Johns Hopkins Nursing Evidence-Based Nursing Practice
Individual Evidence Summary Tool
EBP Question: In adult post cardiac arrest patients, who have return of spontaneous circulation, does therapeutic hypothermia compared with normothermia, improve mortality and neurological outcomes.
Key terms: Therapeutic hypothermia (TH), Normo-thermia(NT),Return of spontaneous circulation (ROSC), Cardiac arrest (CA), Intracranial hemorrhage (ICH), Out of hospital cardiac arrest (OHCA), Systolic blood pressure (SBP), Ventricular fibrillation (VF), Ventricular tachycardia (VT), Glasgow coma scale (GCS), Mini mental state examination (MMSE), Cerebral perfusion category (CPC/CPC), Systolic blood pressure (SBP), Simplified acute physiology score (SAPS). Not available (NA), Not significant (NS), Hemodynamic (HD), cerebrovascular accident (CVA), Basic life support (BLS), Diabetes Mellitus (DM), Chronic Obstructive pulmonary disease (COPD), Acute physiology and chronic health evaluation (APACHE)
Definition: ROSC (return of spontaneous pulse that is sustained for at least 20 minutes), No flow time (Time from collapse to start of BLS), low flow time (Time from start of life support until restoration of ROSC).
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
1Tiainen (2007)
Design: Randomized prospective study
Study Duration: March 1997 and June 2000
Control Group: Normo-thermia<38 C
Intervention Details Target temperature: 33 + 1C Induction phase: NA TH initiation site : Hospital TH phase: 24 hrs Rewarming phase: Passive, at rate of
0.5 C per hour over 12 hours. Cooling device : External device
(TheraKool Kinetic Concept) Variables controlled: Both groups
received standard ICU protocol
Setting :Helsinki university hospital
Inclusion criteria Age: 18-75 Initial rhythm: VF/Non-
perfusing VT Cardiac origin of arrest Site of CA: OHCA
(witnessed) No flow time: 5-15mins Low flow time <60mins ROSC definition: No
timeline defined. GCS < 9
Survival Outcomes Survival to discharge, at 3 and
6 months (n= 50, 28 vs 22, P = 0.226)
Neurophysiological Outcomes at 3 months Neurophysiological outcomes
at 3 months in 45 of 50 survivors (27 versus 18). Good neurological outcome was observed in(93% versus 78%, no P value)
Cognitive outcome:1. Severe deficit (15% versus
28%, NS)2. Moderate deficit (19% verse
28%, NS)
Significant delay in publication.Sampling issues There is no evidence if the groups
were similar in terms of their acuity level at the time of CA that could mask the improvement.
Single center study. Patient population of the hospital may not be representative of entire CA population.
Treatment issuesMean and SD values for TH induction time, time to target temperature and mean temperature in control group not provided. Thus, consistent application of TH is difficult to ascertain.
No evidence if controls were applied beyond 32 hrs of CA. Neurological sequel can be observed within 72 hrs from CA.
I B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
treatment. Sedation and shivering/seizure
prevention for 32 hours MAP > 80 mmHg Normoglycemia < 10mmol/L HOB elevation > 30 Neuropsychologist was blinded Procedural and monitoring
controls. Both groups are statistically
comparable for age, gender, education, BLS, ACLS time, GCS, blood glucose, type of initial rhythm, acute MI, ischemia, neuron-specific enolase, temperature on admission and coronary interventions.
More than one test for neuro evaluation to prevent monooperation bias.
Instruments used for outcome measurement Temperature monitoring technique:
Urinary bladder catheter. Comprehensive neurophysiological
examination. Pittsburgh CPC Cognitive assessment Wechsler Adult
intelligence scale-revised (WAIS-R) Learning and memory domain
assessment: Wechsler memory scale revised (WMS-R) and auditory verbal learning test (AVLT).
Executive functioning assessment: Modified stroop test, trial making test, verbal fluency task, timed calculation
Exclusion Criteria Pregnancy Temp < 30 C O2 sat < 85% for > 15
mins MAP < 60 for > 30
mins Response to verbal
commands after ROSC. Terminal illness leading
to arrest. Coagulopathy Factors that makes
follow-up unlikely
Sample Size N = 70 TH group= 36 Control group= 34 Randomization: Yes,
technique not mentioned
Power analysisNA
3. Intact or subtle deficit (67% versus 44%, NS)
Learning and memory domain: NS
Executive functioning deficit: NS
Q-EEG NS.
P 300 was significantly higher in TH.P300 correlated with CPC class (r = -0.37, P <0.016)
Instrument and measurementNoneAnalysis and results
Randomization process detail not mentioned
Neurophysiological and cognitive outcomes were favorable in TH group but could not reach statistical significance may be because of sample size, sample mortality at 30 days, and further sample attrition for specific neurological exam at 6 months. Power analysis not done to support sample size and minimize threat of type II error.Treatment induction time and time to target temperature from CA is not provided. Thus, it is difficult to comment if delay in initiating or reaching optimal target temperature were contributor to NS results.P value for neurological outcomes is not provided for statistical conclusion.
In both groups there were few patients with ischemic stroke that could have masked the neurological recovery from CA.Generalizability is limited due to: Probably inadequate sample size. It only included patients with VF
(witnessed) arrest. Results cannot be generalized to CA patients with non-shock able rhythm.
Stringent exclusion criteria to control potential confounders has improved the study validity but has limited generalizability even within VF group who do not share same clinical
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
task Quantitative electroencephalogram
(Q-EEG) Auditory P300
Statistical significance : 0.05 (one or 2 tail not mentioned)
characteristics. Absolute recommendations related to
induction time cannot be drawn.
2 Kim(2007)
Design: Randomized controlled trial
Study Duration: Nov 2004 to February 2006
Control Group : Normo-thermia
Intervention Details: Standard care plus hypothermia. Target temperature: 32-34C Induction phase: Soon after
resuscitation TH initiation site : Out of hospital TH phase: Continuation of pre
hospital cooling was left at admitting physician discretion during hospitalization
Rewarming phase: Not provided Cooling device: 2 L of NS at 4 C at
pre hospital and surface cooling in hospital.
Variables controlled: Groups comparable for age, gender,
witnessed CA, CPR before paramedic’s arrival, HR, systolic, blood gases, O2 saturation, BP, and pressors at arrival and 12 hours of
Setting :Seattle, involving 7 paramedic units and 7 acute care hospitals.
Inclusion criteria Age: ≥ 18 years Initial rhythm: All
rhythms Non traumatic CA
(witnessed) Site of CA: Out of
hospital
Exclusion Criteria Traumatic cardiac arrest Following commands
post ROSC Temperature < 34 C Re-arrest during
treatment
Sample Size Enrolled N = 125 TH group= 63 Control group= 62 Randomization: Yes,
Survival Outcome at discharge
VF group: 66% versus 45% (P= NS)Non VF group: 6% versus 20% (P = NS)
Field those who received field cooing alone OR for survival to discharge = 1.92 (95% CI= 0.46 to 8.0) adjusted for hospital cooling and interaction terms.
For those received hospital cooling alone OR for survival to discharge = 0.91 (95% CI=0.28 to 2.96) adjusted for field cooling and interaction terms.
Neurophysiological Outcomes at hospital
Awakening in VF patients: 69% versus 45%, P = 0.15
Sampling Issues 65 eligible patients were not
randomized and enrolled in the study. And 23 cases were not considered for screened for eligibility. It is plausible that these patients differ from those enrolled in the study.
28 patients enrolled in the study could not survive up to admission.
Treatment issues.Treatment controls were poor for RCT. End point for temperature not defined
before study. Highly inconsistent administration of
treatment. 8 subjects did not receive pre-hospital cooling at all, and only 12 received full 2L of cold fluid.
Once at hospital, patients were treated as per hospital protocol. There was some crossover of subjects from control to TH group and vice versa. 60 of 97 patients received hospital cooling regardless of field cooling.
All hospitals had variable protocols. Duration of hospital cooling, induction timing, mean temperature during hospital, rewarming details not provided to ensure consistency.
1 C
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
hospitalization.
Other controls during intervention for both group
Sedation and seizures prevention MAP > 80 mmHg Normoglycemia < 10mmol/L HOB elevation > 30
Instruments used for outcome measurement Temperature monitoring technique:
Esophageal temperature sensor in field and/or tympanic temperature probe in hospital temperature
Statistical significance : 0.05
over phone while patient still in field, Balanced block of 4
Survived up to admission N = 97 TH group= 49 Control group= 48
Power analysisNone
Awakening in Non-VF patients: 9% versus 23%, P = 0.13
Random and inconsistent use of pancuronium and midazolam for shivering control in TH group for shivering control.
Instrument and measurement Inconsistent instrument used for
temperature monitoring in field and in hospital
No valid instrument used for neuro outcomes, instead “awakening” was used as a parameter, and that too was assessed through charts.
Analysis and results The study mainly focuses on outcomes
of pre hospital cooling. Discharge and neurological evaluation was on sub sample.
No power analysis performed. Sample size not adequate to render conclusion on effect of TH on survival of neurological outcome.
No indication if pyrexia was prevented in controlled group that could have attributed to poor outcome. And mean SBP, blood gases, O2 saturation, were not compared for the entire duration of treatment. These variables can be potential confounders.
Several missing entries of temperature in the record. Researcher does not specify how missed data was handled.
Results of awakening in non-shockable group and adjusted OR for hospital cooling is inconsistent with all other studies.
Generalizability
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
Limited because of serious threats to internal and statistical validity.
3 Granja 2011
Design: Before and after
Study Duration: 2004-2009 (Before, Oct 2004-Mar 2006) and (After, April 2006-Sep 2009)
Control Group : Normo-thermia
Intervention Details Target temperature: 32-34 C Induction phase: 4hrs (SD + 2.25) TH initiation site : ICU TH phase: Target 12-24hrs, mean 15
hrs (SD + 4.11hrs) Rewarming phase: Passively, for 5hrs
(SD + 2.33 hrs) Cooling device : Cold normal saline
infusion (4C at 30ml/hr) and surface cooling
Variables controlled: Shivering control measures in TH
group Groups were comparable for age,
gender, reason for admission, no flow time, type of initial rhythm.
Instruments used for outcome measurement Pittsburgh CPC scale for neurological
evaluation. Esophageal temperature probe
Statistical significance : 0.05
Setting :General ICU at urban general hospital
Inclusion criteria Age: >18 Initial rhythm: All
rhythms Origin of arrest: All Site of CA: In and out
of hospital (witnessed and non-witnessed)
Exclusion Criteria Esophageal temperature
less than <32 Traumatic brain injury Status epileptics Pregnancy Refractory hypotension
SBP < 80 Bleeding diathesis Incomplete data in file Conscious after CA.
Sample Size N = 130 TH group= 55 Control group= 75 Randomization: None
Power analysisNot done
Survival to discharge
Survival outcome in TH group is better but NS
60% versus 39% (P = 0.16)
Neurophysiological Outcomes after 6 months.
CPC evaluated only on 56 patients 28 in each group.
26 versus 21 patients presented favorable neurological outcomes (P = NS)
Sampling issuesNon randomized sampling can lead to selection bias.Treatment issues Study does not inform if control and
TH groups were handled in a similar way; if pyrexia was restricted in control group; and if MAP, glycemic control, oxygenation parameters were same in both.
Treatment is elaborated but quality control measures for standardization of intervention is not mentioned in the article.
Instrument and measurement issues Mean temperature attained in
intervention and control group is not provided.
Person conducting neurological evaluation was not blinded that can potentially add bias.
Analysis and results Power analysis is not conducted to
support adequacy of sample size. NS findings might be due to type II error secondary to small sample.
As per mean duration of TH treatment 50% of patient were cooled for less than 15 hrs. short duration might have contributed to NS results
Sample attrition at 6 months for neurological leaves a very small sample size. Thus, results are prone to type II error.
II B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
Date was collected retrospectively and monitoring controls cannot be assured.
Not all potential confounders or effect modifiers listed above were adequately controlled.
Generalizability Is limited because of threat to
statistical validity due to low sample size and lack of control on potential confounders.
4 Reinikainen (2012)
Design: Retrospective observational study
Study Duration: 2000-2008, (pre hypothermia era, 2000-2002) and hypothermia era (2003-2008)
Comparison group : Normothermia Historical control
Intervention Details Target temperature: 32-34C Induction phase: NA TH initiation site : NA TH phase: 24 hours mostly Rewarming phase: NA Cooling device : NA Variables controlled: NA
Instruments used for outcome measurementNA
Statistical significance : Not
Setting :Finnish intensive care settings (20 hospitals).
Inclusion criteria Age: 18+ Initial rhythm: VF or
non perfusing VT. Cardiac origin of arrest: Site of CA: OHCA No flow time 5-15
minuets Low flow time < 60
minutes
Exclusion Criteria In-hospital CA
Sample Size N = 3958 TH group= 3072 Non TH group= 886 Randomization: None
Power analysis
Hospital mortality51.1% versus 57.9% (P < 0.001)
Hypothermia was associated with a decreased risk mortalityOR = 0.54 (95 % CI= 0.45-0.64, P < 0.001) adjusted for the SAPS II score and gender.
This effect was consistent for both young and older patients...
Neurophysiological Outcomes
Not assessed
Sampling issues Huge variation in number of patients
in the groups (3702 versus 886). Selected population of CA with
shockable rhythms is included that is not representative of all CA patients.
Information not available on peri arrest factors like no flow, low flow time, witnessed and non-witnessed status of CA. It cannot be commented if groups were comparable at baseline.
Treatment issues Mean temperature in groups, induction
time, optimal temperature, duration of TH and rewarming phase details not provided in the study. It is difficult to determine how well treatment was executed.
Instrument and measurement issues Instrument used for temperature
monitoring is not mentioned. Core versus shell temperature monitoring results are different.
Analysis and results issues Level of significance not mentioned.
Tight glycemic control practices were
III B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
mentioned NA also widely adopted during TH period that could have confounded the true association between TH and outcomes which is not controlled in the analysis.
New resuscitation guidelines were published in 2003 that might have intensified resuscitation practice and post ROSC care in general during interventions period of the study, attributing to positive results. This is not acknowledged in the study.
Mean temperature in control group is also not provided. And there is no indication if pyrexia in pre TH group was controlled that could have adversely effected the outcomes in that group.
Power analysis not providedGeneralizability Findings can be generalized with
caution to CA patient with OHCA with shockable rhythm only
In absence of treatment related details it is difficult to extrapolate exact recommendations about treatment details like induction time, optimal temperature, duration of TH and rewarming phase. Thus, translation of research into practice seems obstructed.
5Prior(2010)
Design: Retrospective cohort study with historic controls
Study Duration: 2002-2004
Setting :3 community hospitals in Scranton, Pennsylvania
Survival to discharge
Within TH group:Survival of patients in VF/VT
Sampling Assignment to groups was not
random that pose selection bias. Sample size in TH group is very less
III B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
Comparison Group : Normo-thermia Historical controlIntervention Details Target temperature: 32 C to 34 C Induction phase: Target < 4 hrs
Mean 2.8 hrs (range 0.2 -7.8) from ROSC
Target achieved in mean 7.2 hrs (range 0.8 to 15.1 hrs)
TH initiation site : In hospital TH phase: 24hrs (range 9 to 28 hours) Rewarming phase: Passive Cooling device : surface cooling Ice
and cooling blankets Variables controlled:
Shivering measures for TH group
Glycemic control in TH group Hyperthermia controlled after
rewarming in TH group only
Instruments used for outcome measurement Bladder temperature technique Pittsburgh CPC scale for neurological
evaluation
Statistical significance :0.05
Inclusion criteria Age: >18 years Initial rhythm: All
rhythms Cardiac origin of arrest: Site of CA: Out of
hospital and in hospital (witnessed and non-witnessed)
GCS: Coma
Exclusion Criteria Pregnancy cardiogenic shock SBP of less than 90 mm
Hg despite epinephrine infusion)
Non CA cause of coma
Sample Size N = 456 TH group = 44 Control group = 368 Randomization: None
Power analysisNA
group is higher than in non-shockable rhythm61% versus 24%, P = < 0.05
Good Neurophysiological Outcomes at discharge
43% versus 13% (P < 0.001)
Patients with a good CPC score were less likely to achieve goal temperature within 8 hours (P <0.05) and were cool longer than 24 hrs (P < 0.02)
compare to control.Treatment issues Huge variation in induction and TH
maintenance time as range is wide. Treatment applied inconsistently as
4.4% of temperature readings were above 34 C and 16.4% below 32C.
Comparative analysis not provided for TH and control groups for key characteristics like demographic, acuity level, no flow and low flow time, duration of resuscitation, type of initial rhythm, MAP, O2 Saturations.
TH and controls were not treated similarly Inclusion and exclusion criteria were
not applied to controls. Thus groups might not be homogenous
Seizure, pyrexia and glycemic control not applied to controls
Instrument and measurement Definition of good neurological
outcome was set different for controls versus TH group. CPC was not used for neuro evaluation in controls group.
CPC score was assigned through chart review and the assessor was not blinded.
Analysis and results Pyrexia and glycemic control was not
observed in control group that could be the explanation of poor outcome in this group.
General post CA ROSC care also
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
improved under new guidelines during intervention period. Favorable outcomes might be attributable to that.
Power analysis is not done and groups are not equal.
Survival to discharge analysis does not include comparison of TH with control group. It only includes comparison of outcomes among VT/VF and non shockable patients within TH group.
Comparison of neurological outcomes in VT/VF versus non shockable rhythms is not provided. It is difficult to conclude if all benefited equally.
Groups were not homogenous so results in favor of TH might be due to specific characteristics in control group patients.
Generalizability Lack of homogeneity, decrease sample
size in TH group, inconsistent treatment of TH and control group, different operational definition of neurological outcome for TH versus control group, threatens the study validity. Results should be generalized with extreme caution.
6Pfeifer(2011)
Design: Retrospective study
Study Duration: 2003-2010
Comparison Group: Normo-thermia(< 38C )
Setting :Single center registry
Inclusion criteria Age: 18+ Initial rhythm: All
Mortality rate at 30 days from CA
TH group did not have any mortality benefit even if they were comparatively young and
SamplingThere are several factors potentiating selection bias. Non randomized assignment of
individuals to group. On duty doctor decided for TH or
III B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
Historical control
Intervention Details Target temperature: 33 + 0.5 C Induction phase:4-6 hrs of CA TH initiation site : In hospital TH phase: 24 hrs Rewarming phase: Passive and active
(0.3 C per hour) Cooling device : Surface or
intravascular cooling method Variables controlled:
Shivering control measures in TH Pyrexia control in both Standard ICU care in both
Instruments used for outcome measurement Bladder temperature probe Pittsburgh CPC
Statistical significance :O.05
rhythms Non trauma cardiac
arrest. Site of CA: In and out
of hospital (witnessed and non-witnessed)
Low flow time: < 60 mins
Hypoxia time < 15 mins in non-witnessed CA.
Exclusion Criteria Regained consciousness
within 1hr of CA. TH induction time more
than 6 hrs from ROSC Refractory
hemodynamic instability without vasopressors.
Sample Size N = 210 TH group= 143 Control group= 67 Randomization: None
Power analysisNA
less severely illAll patients:48.2% versus 44.8% (P = 0.659)For VF patients :26.4% versus 28.6% (P = 0.807)For non-shockable:70.4% versus 56.4% (P = 0.149)
Statistically significant survival outcomes was observed in only those who had hypoxia time < 6 minutes, low flow time < 20 mins and VF as a primary rhythm. (p = 0.044)
Comparison of patients with good and poor CPC score within TH group
Patients with good neurological outcome in TH group were young (58.6 versus 64.6, P= 0.014), more often had VF as primary rhythm (P < 0.001), had lower SAP II score (P = 0.04), had shorter duration of CPR (P < 0.001) and were cooled for
control based on inclusion that could have led to selection bias.
Only those patients who survived 48 hours after CA in the groups were apprised in the analysis. Those who survived and included in analysis might be less critical and different in particular characteristics then those who were not.
HT group has more patients than control
The groups were not comparable. Patients in control group were significantly older, and had higher acuity level (high SAP score) and had more patients with in-hospital CA that goes in favor of TH group.
There is no information if groups were comparable in no flow and low flow time.
Treatment issues Mean temperature in control group is
not available to verify if claim of pyrexia control was actually achieved in all patients.
Instrument and measurement issues CPC scores were assigned through
documents review, telephone interview with patients and discharge letters, instead of clinical examination. Further, assessor was not blinded that could have added bias to neurological results.
Analysis and results Power analysis is not performed.
Inadequate power might have led to
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
longer period (P = 0.003) after adjusted for SAP, no flow/low flow time, duration of CPR.
Neurological outcome in comparison with control group NA
NS findings due to risk of type II error.
There is no evidence if potential confounder like hyperglycemia, MAP, O2 saturation were controlled through exclusion criteria, group comparison or regression analysis.
Neurological evaluation is presented for TH group only, comparison with control group is not provided.
Generalizability is limited due to: Statistical validity is questioned as
power analysis is not performed and findings may be prone to type II error.
Single center study.7 Testori
(2011)Design: Retrospective cohort study registry based
Study Duration: 1992-2009
Comparison Group : Normothermia Historical control
Intervention Details Target temperature: 33 C + 1 C Induction phase:
1.4 hrs (IQR 0.71 to 2.33) from ROSCTarget achieved in 2.9 hrs (IQR 1.48 to 4.11)
TH initiation site : TH phase: 24 hrs Rewarming phase: NA Cooling device : Surface, invasive or
combined cooling techniques
SettingSingle tertiary care setting
Inclusion criteria Age: 18+ Initial rhythm in CA:
Non-shockable Cardiac origin of arrest:
Non traumatic Site of CA: Out of
hospital (witnessed)
Exclusion Criteria GCS > 8 CPS > 2 before CA Temp <30 C CVA associated CA
Sample Size N = 374
Survival at 6 months
Mortality rate was significantly lower in TH groupOR = 0.56 (95% CI, 0.34 – 0.93)adjusted for age, gender, cause of CA, bystander BLS (Y/N), no flow time, low flow time, history of DM, COPD, epinephrine doses, GCS on admission
Neurophysiological Outcomes at six months
Neurological outcomes were better in TH group OR = 1.84 (95% CI, 1.08 – 3.13) adjusted for potential confounder listed
Sampling issuesSeveral factors might have caused selection bias. 667 eligible patients with CA who
died in initial 24 hours were excluded during registry review and only survivors (374patients) beyond 24 hrs were included in analysis. This might have excluded pool of most critical patients from the study.
There is no indication in the study if those who were not included in the study differed in particular characteristics from those included.
Non randomized assignment to TH and normo-thermiagroup.
Cooling decision was at discretion of on call doctor, who might not have cooled patients with expected bad outcomes.
374 patients for the period of 1992-
III B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
Variables controlled All TH patients received standard
sedation and muscle relaxant to prevent shivering.
Instruments used for outcome measurement
Infrared tympanic thermometer, esophageal probe, or foleys catheter
Pittsburgh CPS for neurological evaluation
Statistical significance :0.05
TH group= 135 Control group= 239 Randomization: None
Power analysisNA
above. 2009 is a very small sample Groups were unequal.
Above factors are threats to internal validity.Treatment related issues No quality control measures to ensure
treatment standardization over the period.
Instrument and measurement issues 3 separate temperature monitoring
devices were used. Different cooling devices were used Collection of data from registry thus
had missing data. There is no specification how CPC
evaluation was performed. CPC validity is not tested for
retrospective application.Analysis and results Power analysis is not done Because of retrospective observational
study, several confounders like MAP, oxygenation status, patient’s acuity level, glucose level, hyperthermia, baseline GCS post CA were not controlled.
Groups were not treated equally. Patients in comparable group had a trend towards hyperthermia which may have contributed to the poor outcome in the group that threatens statistical validity.
There is no specification how missed temperature recordings were handled.
GeneralizabilityFindings should be generalized with
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
caution because: Exclusion of post CA fatalities within
24 hours limits the sample to relatively stable patients who may not be true representative of actual population of CA with initial non-shockable rhythm.
Out of hospital, witnessed cardiac arrest patients were enrolled that limits generalizability to in hospital and non-witnessed CA patients who may be more critical.
Single center study.8 Storm
(2012)Design: Prospective observational study.
Study Duration: 2002-2010
Comparison Group : Normo-thermia Historical control
Intervention Details Target temperature: 33 C Induction phase:
Time from ROSC: NATarget achieved in 3 to 5.33hrs
TH initiation site : Hospital TH phase: 24 hrs Rewarming phase: Controlled at 0.25
C per hour. Cooling device: Surface and invasive
cooling devices.
Variables controlled All TH patients received standard
sedation and muscle relaxant to
Setting: University hospital Charite Berlin
Inclusion criteria Age: 18+ Initial rhythm in CA:
Non-shockable Cardiac origin of arrest:
Non traumatic Site of CA: Out and In
hospital
Exclusion CriteriaNA
Over all Sample Size N = 387 TH group= 201 Control group= 186 Randomization: NA
Study presents sub analysis of patients with
Survival at dischargeCox regression showed NS improvement in TH groupHazard ratio 0.98, 95% CI = 0.53-1.5, p = 0.63 adjusted for APACHIE score, low flow time, ICU stay.
90 days Kaplan Meier analysis revealed NS results (log rank test P = 0.82
Neurophysiological Outcomes at discharge
TH was not associated with significantly improved neurological outcomes in TH group27.5% versus 18.2% (P = 0.175)
Sampling issues 175 patients for the duration of 8 years
seems to be small. The study does not specify how patients were excluded.
Treatment related issuesThe treatment execution might have differed over the prolong study period.Instrument and measurement issues There is no information how
temperature was monitored Temperature monitoring devices used
is not specified thus instrument validity cannot be ensured.
Analysis and results Mean temperature in control group is
not provided. Power analysis not conducted. NS
result may be due to inadequate sample and type II error.
Details not provided if control group also received standard post ROSC treatment (excluding hypothermia) as of TH group. Thus, several
III B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
prevent shivering. All TH patients received standard post
ROSC care.
Instruments used for outcome measurement Pittsburgh CPS for neurological
evaluation
Statistical significance :0.05
non-shockable rhythm N = 175 TH group= 87 Control group= 88
Power analysisNA
TH group had decreased low flow time.
confounders like MAP, oxygenation status, patient’s acuity level, glucose level, and hyperthermia could have confounded the results that are not controlled during regression analysis.
Neurological evaluation is provided at the time of discharge only. Thus, improvement at 90 days or 6 months was not captured in the results.
GeneralizabilityMay be limited because of Single center study Probably inadequately powered
study.9 Stub
(2011)Design: Retrospective observational study
Study Duration: 2002-2009
Comparison Group : Normo-thermia Historical control
Intervention Details Target temperature: 32-34C Induction phase:
From ROSC NATarget achieved in NA
TH initiation site : NA TH phase: NA Rewarming phase: NA Cooling device: Surface and
intravenous cooling interventions.
Variables controlledStandard ROSC care for both groups
SettingAlfred hospital
Inclusion criteria Age: 18+ Initial rhythm in CA:
VF/VT Only cardiac origin of
arrest: Site of CA: Out of
hospital (witnessed and non-witnessed)
Exclusion Criteria GCS All non-cardiac causes
of CA (stroke, drug over dose, trauma)
Sample Size N = 125 TH group= 81
Survival at discharge64% versus 39% (p <0.01)
Survival rate was significantly better in TH groupUnadjusted Odds ratio 2.7, 95% CI = 1.1 – 6.4 , P = 0.02
Neurophysiological Outcomes at discharge57% versus 29% (p < 0.01)
Sampling issues During intervention period, the
institution simultaneously introduced coronary artery disease evaluation and the need for coronary intervention as standard post CA ROSC care along with TH. The study is prone to selection bias because it limits participant who had CA of cardiac origin as they wanted to examine impact of 2nd intervention on survival outcome as well.
Non randomization of patients to TH versus control group
Treatment related issues Intervention details like induction
time, TH duration, mean temperature in TH and control group, rewarming strategies, cooling devices used etc. is not provided in the article.
Instrument and measurement Hospital records were used for data
III B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
Instruments used for outcome measurementPittsburgh CPCNA
Statistical significance :0.05
Control group= 44 Randomization: None
Power analysisNA
collection. CPC scores were assigned through
chart review instead of clinical evaluation.
CPC validity is not tested for retrospective application.
Analysis and results m ust be interpreted with caution because of serious threats to internal validity. Effect of coronary intervention was
not adjusted during statistical analysis and only univariate analysis is presented.
Significantly high number of patients in TH group also received coronary interventions like angiography (p < 0.01) and PTCA (p = 0.03). Keeping in view this potential confounder and in absence of adjusted analysis, TH cannot be labeled as sole predictor of positive outcome.
New resuscitation practices were also adopted during treatment period like compression to ventilation ration and uninterrupted compression. Moreover, duration of resuscitation was short in treatment group that could perhaps have attributed to favorable results in TH group.
CPC scores to ascertain neurological outcomes were assigned through chart review. Thus, precision of data is doubtful.
Power analysis not conducted.GeneralizabilityCan be limited because of following
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
threats to internal validity due to: OHCA patients, with VF/VT as initial
rhythm and with cardiac origin of CA were included who may not be representative of all CA patients with VF/VT as an initial rhythm
Inadequate information about the treatment seriously compromises the recommendations.
Single center study10
Van der (2011)
Design: Retrospective multicenter observational study.
Study Duration: 1999-2009 Historical control
Before Implementation Group :Minimum temperature 35.5 C (IQR 34.3 C – 36.5 C)Maximum temperature 37.8 C (IQR 36.8 C – 38.5 C)After implementation group Temperature:Minimum temperature 33 C (IQR 32 C – 35.4 C)Maximum temperature 36.4 C (IQR 35.1 C –37.6 C) Induction phase:
Time from ROSC:Target achieved
TH initiation site : TH phase: 12 – 24 hrs Rewarming phase: NA Cooling device : NA
Setting: 59 ICUs of Netherland
Inclusion criteria Age: 18+ Initial rhythm in CA:
Both shockable and non shockable
Site of CA: In and Out of hospital
Exclusion Criteria CA in ICU GCS > 8 post ROSC CA patients in initial 3
months of implementation period.
Cardiothoracic and burn patients.
Over all Sample Size N = 5317 TH group = 3770 Control group= 1547 Randomization: NA
Survival outcomes at discharge
Mortality of CA patients before and after treatment period65% versus 72%, p = NA
Odd ration for hospital mortality for CA patients after mild therapeutic hypothermia isOR= 0.8, 95% CI= 0.65 – 0.98, p = 0.29 adjusted for SAP score, age, gender, in and out of hospital CA, and propensity score.
Propensity score is the probability of a patient to be part of before or after implementation group.
Patients with in hospital CA has significantly high mortality compare to OHCA
Sampling issues Data was extracted from registry Non random selection of ICUs.Treatment related issues All institutions had their own TH
protocol therefore treatment standardization could not be maintained. Thus, there was a wide variation range of minimum and maximum temperature and IQR in TH group. Moreover, maximum temperature in the group is almost close to normothermia.
Mean induction time, optimal temperature time, duration of TH, cooling devices used in not mentioned in the article.
Instrument and measurement Instrument used for temperature
monitoring is not specified. Consistency in findings cannot be assured.
Result and analysis Due to wide variation in temperature
end point in TH group, it cannot be ascertain whether hypothermia or
III B
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
Variables controlled NoneInstruments used for outcome measurement NA
Statistical significance :0.05
Power analysisNA
OR = 1.16, p = 0.26
Neurophysiological Outcomes at discharge NA
lower threshold normo-thermiawith controlled pyrexia was associated with positive outcomes
41% of patients in pre implementation group had experienced pyrexia during first 24 hrs that could have contributed to poor outcome in control group.
In post implementation group, practices like pyrexia prevention, glycemic control, coronary interventions and general post ROSC care had improved because of new guidelines. These covariates could have contributed to improved outcomes but were not controlled in the study.
Researcher could not get information on, mean no flow and low flow timings. Systematic difference in these variables among group might have attributed to the results.
The researcher does not inform the neurological outcomes of patients
Generalizability is restricted Inadequate information about
treatment details and wide variation in target temperature in TH group restrict any absolute recommendation for future.
Findings cannot be generalized to in- patients CA setting because mortality outcomes are not significant in that group.
Survival outcomes are not provided as per type of initial CA rhythm. Thus, we are not sure if the treatment is
Appendix B
#Author & Date
Study DesignAnd
Key elements
Sample, Sample Size, & Setting
Study findings that help answer the EBP question
TH versus NT group
Limitations LOE & Quality
effective in patients with both shockable and non-shockable rhythm.