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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


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.


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


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


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


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).


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;


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


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


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.


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-


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


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


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


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.


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.


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


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.


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cardiopulmonary, perioperative, and critical care; the council on clinical cardiology; and the

stroke council. Circulation, 118(23), 2452-2483.

doi:10.1161/CIRCULATIONAHA.108.190652

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


resuscitation; the american heart association emergency cardiovascular care committee; the

council on cardiovascular surgery and anesthesia; the council on cardiopulmonary,

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.


Pfeifer, R., Jung, C., Purle, S., Lauten, A., Yilmaz, A., Surber, R., . . . Figulla, H. R. (2011).

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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

Intensive Care Consortium. (2012). Mortality in out-of-hospital cardiac arrest patients has


decreased in the era of therapeutic hypothermia. Acta Anaesthesiologica Scandinavica,

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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patients resuscitated from non-shockable cardiac arrest. Emergency Medicine Journal :

EMJ, 29(2), 100-103. doi: 10.1136/emj.2010.105171

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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)


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)


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)


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



TH versus NT group


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



TH versus NT group


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



TH versus NT group


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



TH versus NT group


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



TH versus NT group


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



TH versus NT group


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



TH versus NT group


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



TH versus NT group


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


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



TH versus NT group


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



TH versus NT group


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


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



TH versus NT group


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


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



TH versus NT group


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.


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


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



TH versus NT group


prevent shivering. All TH patients received standard post

ROSC care.

Instruments used for outcome measurement Pittsburgh CPS for neurological

evaluation


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


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


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



TH versus NT group


Instruments used for outcome measurementPittsburgh CPCNA


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



TH versus NT group


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


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



TH versus NT group


Variables controlled NoneInstruments used for outcome measurement NA


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



TH versus NT group


effective in patients with both shockable and non-shockable rhythm.

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