document: incremental improvements in the survivorship from cpr occurred as more and more people were trained in cpr and as defibrillators became portable and were deployed in more locations . 
   finally , most people who had suffered from cardiac arrest did not survive to leave the hospital or did so in a neurological devastated state . in the early of 21 century , the survival rate of cardiac arrest outside of the hospital remained 78% . 
   about one - quarter of patients regained pulses after cpr , and about one - third of the patients with those initial successes survived hospitalization . the severe brain defect after cpr stimulated many investigations into the pathophysiology of , and treatments for , global brain ischemia . 
   for the protection of patient 's brain , mild hypothermia therapy has been proposed . in many animal experiments 
   for example , it can increase the survival rate and improve neurological function of animal . 
   besides , it reduces metabolic rate and the expression of some pro - apoptosis proteins . in clinical trials , 
   the effectiveness of hypothermia also has been proved . hence , 2010 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care recommended , comatose patients with out - of - hospital ventricular fibrillation cardiac arrest were cooled to 3234c for 12 or 24 h. however , recent years some other clinical trials showed that mild hypothermia can not improve the prognosis of patients after cpr . 
   therefore , we conducted a meta - analysis of all relevant published studies to evaluate the effectiveness and safety of mild hypothermia on patients with cardiac arrest . 
   studies were considered for inclusion if they met the following criteria : ( 1 ) all published randomized controlled trials ( rcts ) . ( 2 ) we included studies in adult patients who suffered from cardiac arrest and were successfully resuscitated . 
   ( 3 ) the intervention was therapeutic mild hypothermia , no matter how to lower the body temperature . 
   the temperature should remain between 32c and 34c . and the treatment for the control group was according to the standard treatment after cardiac arrest without hypothermia . 
   the secondary outcomes were adverse events , such as rearrest , renal failure , pulmonary edema and so on . 
   ( 5 ) the relative risks ( rrs ) with their corresponding 95% confidence intervals ( cis ) were reported . 
   studies were considered for exclusion if they met the following criteria : ( 1 ) we excluded studies on children and pregnant women . 
   ( 2 ) cardiac arrest patients under the treatment of mild hypothermia received other drugs in combination therapy . 
   ( 3 ) there was a history of central nervous system depressant drug medication prior to cardiac arrest . 
   an extensive literature search was conducted using electronic databases , manual searching , and correspondence with authors of included studies . 
   the cochrane library , pubmed , web of science , embase , cnki , and wan fang data were searched from the date of their establishment to october 2014 . 
   search terms used were  cooling ,   hypothermia ,   cpr ,   cardiac arrest  and  rct . 
   two reviewers independently reviewed the citations , abstracts , and full - text articles and determined the eligibility of all the studies identified in the initial search . 
   when the entire process was completed , the two cross - checked with each other . in cases of disagreements , a third reviewer was consulted . 
   the following details were extracted : authors , year of publication , sample size , interventions , and outcomes . 
   assessment of the quality of the included studies was performed using the methodology recommended by cochrane collaboration . 
   this method comprised assessments of the risk of potential bias in six domains : random sequence generation ( correct , incorrect or unclear ) , allocation concealment ( correct , incorrect or unclear ) , blinding of outcome assessment ( correct , incorrect or unclear ) , incomplete outcome data ( complete , incomplete or unclear ) , selective reporting ( yes , no or unclear ) , other bias ( yes , no or unclear ) , such as the baseline , source of funding , and academic biases . if all quality criteria were met , the trial was considered to have a low risk of bias ( score : a ) . 
   if one or more of the quality criteria were only partially met , the trial was considered to have moderate risk of bias ( score : b ) , and if one or more criteria not met , the trial was considered to have high risk of bias ( score : c ) . 
   statistical analysis was performed using review manager version 5.2 ( cochrane collaboration , oxford , uk ) software . 
   the heterogeneity of the qualitative analysis was assessed by chi - square test , and the significant level was set to p = 0.1 . 
   if p > 0.1 , i < 50% , the different rcts can be regarded as homogeneous . 
   if p < 0.1 , i  50% , the different rcts can be regarded as heterogeneity . 
   we used weighted mean deviation ( wmd ) and 95% ci to represent the continuous data . and 
   studies were considered for inclusion if they met the following criteria : ( 1 ) all published randomized controlled trials ( rcts ) . ( 2 ) we included studies in adult patients who suffered from cardiac arrest and were successfully resuscitated . 
   ( 3 ) the intervention was therapeutic mild hypothermia , no matter how to lower the body temperature . 
   the temperature should remain between 32c and 34c . and the treatment for the control group was according to the standard treatment after cardiac arrest without hypothermia . 
   the secondary outcomes were adverse events , such as rearrest , renal failure , pulmonary edema and so on . 
   ( 5 ) the relative risks ( rrs ) with their corresponding 95% confidence intervals ( cis ) were reported . 
   studies were considered for exclusion if they met the following criteria : ( 1 ) we excluded studies on children and pregnant women . 
   ( 2 ) cardiac arrest patients under the treatment of mild hypothermia received other drugs in combination therapy . 
   ( 3 ) there was a history of central nervous system depressant drug medication prior to cardiac arrest . 
   an extensive literature search was conducted using electronic databases , manual searching , and correspondence with authors of included studies . 
   the cochrane library , pubmed , web of science , embase , cnki , and wan fang data were searched from the date of their establishment to october 2014 . 
   search terms used were  cooling ,   hypothermia ,   cpr ,   cardiac arrest  and  rct . 
   two reviewers independently reviewed the citations , abstracts , and full - text articles and determined the eligibility of all the studies identified in the initial search . 
   when the entire process was completed , the two cross - checked with each other . in cases of disagreements , a third reviewer was consulted . 
   the following details were extracted : authors , year of publication , sample size , interventions , and outcomes . 
   assessment of the quality of the included studies was performed using the methodology recommended by cochrane collaboration . 
   this method comprised assessments of the risk of potential bias in six domains : random sequence generation ( correct , incorrect or unclear ) , allocation concealment ( correct , incorrect or unclear ) , blinding of outcome assessment ( correct , incorrect or unclear ) , incomplete outcome data ( complete , incomplete or unclear ) , selective reporting ( yes , no or unclear ) , other bias ( yes , no or unclear ) , such as the baseline , source of funding , and academic biases . if all quality criteria were met , the trial was considered to have a low risk of bias ( score : a ) . if one or more of the quality criteria were only partially met , the trial was considered to have moderate risk of bias ( score : b ) , and if one or more criteria not met , the trial was considered to have high risk of bias ( score : c ) . 
   statistical analysis was performed using review manager version 5.2 ( cochrane collaboration , oxford , uk ) software . 
   the heterogeneity of the qualitative analysis was assessed by chi - square test , and the significant level was set to p = 0.1 . 
   if p > 0.1 , i < 50% , the different rcts can be regarded as homogeneous . 
   if p < 0.1 , i  50% , the different rcts can be regarded as heterogeneity . 
   we used weighted mean deviation ( wmd ) and 95% ci to represent the continuous data . and 
   a total of 1613 potentially relevant studies were identified from the following databases in our initial articles search : two hundred and twenty - six from pubmed , 412 from embase , 161 from cochrane library , 292 from web of science , 245 from cnki , 237 from wan fang data . after screening the titles or abstracts , 
   the full text of the remaining 60 studies was retrieved and assessed for eligibility . of the retrieved studies , 
   54 studies were excluded because of other type of publications ( review , case report , retrospective studies , prospective studies ) . finally , a total of six studies met the inclusion criteria [ figure 1 ] . 
   the six rcts included 531 adult patients who suffered from cardiac arrest and were successfully resuscitated . 
   the original articles compared the therapeutic effect under different conditions ( hypothermia or normothermia ) . 
   characteristics of the rcts included in the meta - analysis rcts : randomized controlled trials , vf : ventricular fibrillation , ca : cardiac arrest . 
   ( 1 ) all of the six studies mentioned  random ,  but only three studies described the method of generating a random sequence correctly . 
   ( 2 ) only two studies showed us they use a sealed envelope to conduct allocation concealment . 
   ( 3 ) six studies mentioned blinding in which five studies were double - blind . 
   ( 4 ) all of the six studies described the case of which quit or lost to follow - up . 
   the number of quit or lost to follow - up of each study were < 20% of the total number . 
   the methodological quality of the rcts included in the meta - analysis rcts : randomized controlled trials 
   . the survival rate of patients who suffered from cardiac arrest and were successfully resuscitated is one of the primary outcomes which we concerned . 
   all of the six studies reported the survival rate in which three studies reported survival rate at hospital discharge ( subgroup 1 ) , the other three studies reported survival rate after 6 months ( subgroup 2 ) . 
   there was no heterogeneity from the outcome in subgroup 1 ( p = 0.50 , i = 0 ) and subgroup 2 ( p = 0.32 , i = 12% ) . 
   the pooled results showed [ figure 2 ] no significant difference in the survival rate at hospital discharge between treatment group and control group ( rr = 1.35 , 95% ci : 0.872.10 , p = 0.18 ) . 
   however , there was significant difference in the survival rate after 6 months ( rr = 1.23 , 95% ci : 1.021.48 , p = 0.03 ) 
   . summarized the above six studies , no heterogeneity among them ( p = 0.60 , 
   i = 0 ) , and the pooled results showed hypothermia does improve the survival rate ( rr = 1.25 , 95% ci : 1.051.49 , p = 0.01 ) . 
   the neurological function of patients who suffered from cardiac arrest and were successfully resuscitated is another primary outcome which we concerned . in clinical , cerebral performance category ( cpc ) 
   the cpc scale ranges from 1 to 5 , with 1 representing good cerebral performance ( conscious , alert , capable of normal life ) or minor disability which do not significantly compromise cerebral or physical function , 2 moderate cerebral disability ( function is sufficient for independent activities of daily life ) , 3 severe cerebral disability , dependent on others for daily life support , 4 coma or vegetative state ( not conscious , unaware of surroundings , no cognition ) , and 5 brain death . included studies considered cpc 12 as good neurological recovery and cpc 35 as bad neurological recovery . hence , these data can be converted to dichotomous data . all of the six studies reported the neurological function in which three studies reported neurological function at hospital discharge ( subgroup 3 ) , the other three studies reported neurological function after 6 months ( subgroup 4 ) . 
   there was no heterogeneity from the outcome in subgroup 3 ( p = 0.30 , i = 18% ) and subgroup 4 ( p = 0.23 , 
   the pooled results showed [ figure 3 ] no significant difference in the neurological function at hospital discharge between treatment group and control group ( rr = 1.53 , 95% ci : 0.952.45 , p = 0.08 ) . however , there was significant difference in the neurological function after 6 months ( rr = 1.33 , 95% ci : 1.081.65 , p = 0.007 ) 
   . summarized the above six studies , no heterogeneity among them ( p = 0.38 , i = 6% ) , the pooled results showed hypothermia does improve the neurological function ( rr = 1.37 , 95% ci : 1.131.66 , p = 0.001 ) 
   . summary of data on neurological function for mild hypothermia versus normothermia . in the included studies , only four studies mentioned rearrest . 
   meta - analysis [ figure 4 ] demonstrated mild hypothermia does not influence the incidence of rearrest ( rr = 1.19 , 95% ci : 0.871.61 , p = 0.27 ) . 
   the result [ figure 5 ] showed no significant difference between treatment group and control group ( rr = 0.88 , 95% ci : 0.481.61 , p = 0.68 ) . 
   other adverse events such as pulmonary edema , pneumonia , bleeding , showed the same results ( data not shown ) . because only a single article mentioned the above adverse events , we did not put them into meta - analysis . 
   most studies at the top of the funnel plot , it meant the studies ci is narrow and their precision is high . to evaluate the influence of any single study on the pooled rr and ci 
   we omitted two high - risk studies from the overall analysis , the pooled rr ( 95% ci ) ranged from 1.25 ( 1.051.49 ) to 1.21 ( 1.011.45 ) for studies reporting the rrs by survival rate and from 1.37 ( 1.131.66 ) to 1.30 ( 1.061.59 ) for studies reporting the rrs by neurological function . 
   funnel plot compares log relative risk ( rr ) versus the standard error of log rr for survival rate and neurological function (  : at hospital discharge ;  : at 6 months ) . 
   a total of 1613 potentially relevant studies were identified from the following databases in our initial articles search : two hundred and twenty - six from pubmed , 412 from embase , 161 from cochrane library , 292 from web of science , 245 from cnki , 237 from wan fang data . after screening the titles or abstracts , 
   the full text of the remaining 60 studies was retrieved and assessed for eligibility . of the retrieved studies , 
   54 studies were excluded because of other type of publications ( review , case report , retrospective studies , prospective studies ) . finally , a total of six studies met the inclusion criteria [ figure 1 ] . 
   the six rcts included 531 adult patients who suffered from cardiac arrest and were successfully resuscitated . 
   the original articles compared the therapeutic effect under different conditions ( hypothermia or normothermia ) . 
   characteristics of the rcts included in the meta - analysis rcts : randomized controlled trials , vf : ventricular fibrillation , ca : cardiac arrest . 
   ( 1 ) all of the six studies mentioned  random ,  but only three studies described the method of generating a random sequence correctly . 
   ( 2 ) only two studies showed us they use a sealed envelope to conduct allocation concealment . 
   ( 3 ) six studies mentioned blinding in which five studies were double - blind . 
   ( 4 ) all of the six studies described the case of which quit or lost to follow - up . the number of quit or lost to follow - up of each study were < 20% of the total number . 
   the methodological quality of the rcts included in the meta - analysis rcts : randomized controlled trials . 
   the survival rate of patients who suffered from cardiac arrest and were successfully resuscitated is one of the primary outcomes which we concerned . 
   all of the six studies reported the survival rate in which three studies reported survival rate at hospital discharge ( subgroup 1 ) , the other three studies reported survival rate after 6 months ( subgroup 2 ) . 
   there was no heterogeneity from the outcome in subgroup 1 ( p = 0.50 , i = 0 ) and subgroup 2 ( p = 0.32 , i = 12% ) . 
   the pooled results showed [ figure 2 ] no significant difference in the survival rate at hospital discharge between treatment group and control group ( rr = 1.35 , 95% ci : 0.872.10 , p = 0.18 ) . 
   however , there was significant difference in the survival rate after 6 months ( rr = 1.23 , 95% ci : 1.021.48 , p = 0.03 ) 
   . summarized the above six studies , no heterogeneity among them ( p = 0.60 , i = 0 ) , and the pooled results showed hypothermia does improve the survival rate ( rr = 1.25 , 95% ci : 1.051.49 , p = 0.01 ) . 
   the neurological function of patients who suffered from cardiac arrest and were successfully resuscitated is another primary outcome which we concerned . in clinical , cerebral performance category ( cpc ) 
   the cpc scale ranges from 1 to 5 , with 1 representing good cerebral performance ( conscious , alert , capable of normal life ) or minor disability which do not significantly compromise cerebral or physical function , 2 moderate cerebral disability ( function is sufficient for independent activities of daily life ) , 3 severe cerebral disability , dependent on others for daily life support , 4 coma or vegetative state ( not conscious , unaware of surroundings , no cognition ) , and 5 brain death . included studies considered cpc 12 as good neurological recovery and cpc 35 as bad neurological recovery . 
   all of the six studies reported the neurological function in which three studies reported neurological function at hospital discharge ( subgroup 3 ) , the other three studies reported neurological function after 6 months ( subgroup 4 ) . 
   there was no heterogeneity from the outcome in subgroup 3 ( p = 0.30 , i = 18% ) and subgroup 4 ( p = 0.23 , i = 31% ) . 
   the pooled results showed [ figure 3 ] no significant difference in the neurological function at hospital discharge between treatment group and control group ( rr = 1.53 , 95% ci : 0.952.45 , p = 0.08 ) . 
   however , there was significant difference in the neurological function after 6 months ( rr = 1.33 , 95% ci : 1.081.65 , p = 0.007 ) 
   . summarized the above six studies , no heterogeneity among them ( p = 0.38 , i = 6% ) , the pooled results showed hypothermia does improve the neurological function ( rr = 1.37 , 95% ci : 1.131.66 , p = 0.001 ) . 
   meta - analysis [ figure 4 ] demonstrated mild hypothermia does not influence the incidence of rearrest ( rr = 1.19 , 95% ci : 0.871.61 , p = 0.27 ) . 
   the result [ figure 5 ] showed no significant difference between treatment group and control group ( rr = 0.88 , 95% ci : 0.481.61 , p = 0.68 ) . 
   other adverse events such as pulmonary edema , pneumonia , bleeding , showed the same results ( data not shown ) . because only a single article mentioned the above adverse events , we did not put them into meta - analysis . 
   most studies at the top of the funnel plot , it meant the studies ci is narrow and their precision is high . to evaluate the influence of any single study on the pooled rr and ci , we performed a sensitivity analysis . 
   we omitted two high - risk studies from the overall analysis , the pooled rr ( 95% ci ) ranged from 1.25 ( 1.051.49 ) to 1.21 ( 1.011.45 ) for studies reporting the rrs by survival rate and from 1.37 ( 1.131.66 ) to 1.30 ( 1.061.59 ) for studies reporting the rrs by neurological function . 
   funnel plot compares log relative risk ( rr ) versus the standard error of log rr for survival rate and neurological function (  : at hospital discharge ;  : at 6 months ) . 
   as the cpr technology became more and more mature , a growing number of patients with cardiac arrest were saved . 
   in the half past century especially the last 10 years , hypothermia is the only method that approved by a large amount of clinical trials which can improve the prognosis of patients . 
   meta - analysis can evaluate the effectiveness and safety of hypothermia which results are quite credible . in this study , we used meta - analysis to integrate these different independent researches , in order to get more reliable analysis about the efficacy of mild hypothermia for the treatment of patients with cardiac arrest . for patients rescued from cardiac arrest , we pay most attention to their prognosis . 
   the data of three studies were measured at hospital discharge , the other three were measured after 6 months . in order to avoid the heterogeneity first we analyzed the data by subgroups . 
   the mild hypothermia therapy can not improve survival rate and neurological function at hospital discharge . 
   we speculated the possible reasons are as follows : ( 1 ) whole - body hypothermia influences all organ systems , and any potential benefit should be balanced against possible side effects ; ( 2 ) in clinical treatment , combination hypothermia with many other drugs may bring about some unknown influences , for example it will reduce the rate of drug metabolism and so on ; ( 3 ) hypothermia revives neurons is a long and slow process , for some other reasons patients die before neurons recovery . 
   the pooled results showed us that mild hypothermia does improve survival rate and neurological function of patients with cardiac arrest . 
   for example : hypothermic blanket , ice packs , cold saline intravenous infusion and so on . 
   however , some other studies or meta - analysis hold the view that early initiation of rapid cooling can not improve the prognosis . 
   the possible mechanisms include : ( 1 ) hypothermia can reduce cerebral oxygen consumption and energy metabolism ; ( 2 ) it can reduce reactive oxygen species generation and release of excitatory amino acids ; ( 3 ) it also can preserve the integrity of the blood - brain barrier , regulate the gene expression of inflammatory protein and apoptotic proteins and reduce cell death . 
   although there are many advantages of mild hypothermia , we should not ignore the side effects . 
   in the included six studies , the main adverse events were re - arrest , renal failure , pulmonary edema and so on . 
   hence , we drew a conclusion mild hypothermia therapy for cardiac arrest patients is safe . 
   however , the study also suffers from several limitations : ( 1 ) the number of trial and the study size may be inadequate . 
   therefore , the precision of the outcome parameters obtained is generally low ; ( 2 ) another potential limitation of this meta - analysis is clinical and methodological heterogeneity . according to the six studies , we knew cardiac arrest patients with different first recorded cardiac rhythm are included . besides , the time from start of cooling to target temperature was different , the duration of keeping hypothermia was different and the methods of cooling body temperature were also different in these studies . 
   all of the above factors would lead to inaccurate results . in this meta - analysis 
   , we conducted a subgroup analysis according to different situations , although there was almost no heterogeneity . 
   but in order to get more accurate results , further research should include high - quality studies to analyze the impact of different cooling measures or different hypothermia duration on the survival rate and neurological function . in conclusions , 
   this meta - analysis demonstrated mild hypothermia can not improve survival rate and neurological function of patients at hospital discharge . 
   the pooled results showed mild hypothermia does improve prognosis of patients . and it does not influence the incidence of adverse events compared with the control group .
summary: background : therapeutic hypothermia has been recommended for the treatment of cardiac arrest patients who remain comatose after the return of spontaneous circulation . 
   the aim of this study was to evaluate the effectiveness and safety of mild hypothermia on patients with cardiac arrest by conducting a meta-analysis.methods:the relevant trials were searched in cochrane library , pubmed , web of science , embase , cnki and wan fang data from the date of their establishment to october 2014 . 
   thereafter , the studies retrieved were screened based on predefined inclusion and exclusion criteria . 
   data were extracted , and the quality of the included studies was evaluated . 
   a meta - analysis was conducted using the cochrane collaboration review manager 5.2 software.results:six randomized controlled trials involving 531 cases were included , among which 273 cases were assigned to the treatment group and the other 258 cases to the control group . 
   the meta - analysis indicated that mild hypothermia therapy after cardiac arrest produced significant differences in survival rate ( relative risk [ rr ] = 1.23 , 95% confidence interval [ ci ] : 1.021.48 , p = 0.03 ) and neurological function ( rr = 1.33 , 95% ci : 1.081.65 , p = 0.007 ) after 6 months compared with normothermia therapy . 
   however , no significant differences were observed in the survival to the hospital discharge ( rr = 1.35 , 95% ci : 0.872.10 , p = 0.18 ) , favorable neurological outcome at hospital discharge ( rr = 1.53 , 95% ci : 0.952.45 , p = 0.08 ) and adverse events.conclusions:the meta - analysis demonstrated that mild hypothermia can improve the survival rate and neurological function of patients with cardiac arrest after 6 months . on the other hand , regarding the survival to hospital discharge , favorable neurological outcome at hospital discharge , and adverse events , our meta - analysis produced nonsignificant results .