the online version of this article ( doi:10.1007/s00134 - 016 - 4549 - 3 ) contains supplementary material , which is available to authorized users . about two - thirds of patients admitted to hospital   or an intensive care unit ( icu )   after cardiac arrest die before hospital discharge . most of these deaths are due to hypoxic - ischaemic brain injury [ 3 , 4 ] and result from active withdrawal of life - sustaining treatment ( wlst ) based on prognostication of survival with a poor neurological outcome [ 5 , 6 ] . however , in some resuscitated patients hypoxic - ischaemic brain injury can result in a total loss of clinical brain function , i.e. in brain death . despite being an unfavourable outcome for the individual patient , brain death creates opportunities for organ donation [ 4 , 8 ] , which may represent an additional benefit from cpr in terms of lives saved or improved . in fact , transplanted organs retrieved from brain - dead patients after cardiac arrest have a similar success rate as organs retrieved from patients who have died from other causes [ 810 ] . the 2015 american heart association guidelines for post - cardiac arrest care   recommend that all patients who are resuscitated from cardiac arrest but who subsequently progress to brain death should be evaluated for organ donation ( class i , level of evidence b ) . despite this , the prevalence of brain death following cardiac arrest is only rarely reported and it has never been systematically reviewed . knowing the epidemiology of brain death after cardiac arrest could help intensivists to organize a timely screening and identification of potential organ donors after resuscitation . the primary aim of the present systematic review is to measure the reported prevalence of brain death in adult patients resuscitated from cardiac arrest as compared to other causes of death . the secondary aim of this review is to measure the rate of organ donation in these patients . data reporting in this review is consistent with the preferred reporting items for systematic reviews and meta - analyses ( prisma ) statement . the review questions were formulated following the pico scheme ( population , intervention , comparator , outcome ) as follows : among adults who are admitted to hospital after successful resuscitation from cardiac arrest ( p ) , what is the prevalence of brain death at hospital discharge ( o)?among adults who develop brain death after successful resuscitation from cardiac arrest ( p ) , what is the rate of organ donation ( o ) ? 
  among adults who are admitted to hospital after successful resuscitation from cardiac arrest ( p ) , what is the prevalence of brain death at hospital discharge ( o ) ? among adults who develop brain death after successful resuscitation from cardiac arrest ( p ) , what is the rate of organ donation ( o ) ? in addition , a preliminary screening of the literature suggested potential differences in the epidemiology of brain death between patients resuscitated with extracorporeal cpr ( e - cpr ) as compared to patients resuscitated with conventional cpr ( c - cpr ) . all studies published as full - text articles in indexed journals which reported the prevalence of brain death in adult ( 18  years old ) patients resuscitated from cardiac arrest occurred either in - hospital ( in - hospital cardiac arrest , ihca ) or out - of - hospital ( out - of - hospital cardiac arrest , ohca ) were considered for inclusion . publication date was restricted to studies published after 2002 in order to better reflect current practice which includes targeted temperature management ( ttm ) [ 14 , 15 ] and post - resuscitation care bundles . reviews , case reports and studies published in abstract form were excluded . studies including patients with non - hypoxic causes of brain death or patients with hypoxic coma from causes other than cardiac arrest ( respiratory arrest , asphyxia , drowning , hanging ) were excluded . ( mesh ) or  cardiac arrest  ( mesh ) and  brain death  . isi web of science and the cochrane database of systematic reviews were searched using the search strings  cardiac arrest  and  brain death  . the reference lists of relevant studies were screened to identify other studies of interest . for each study included in the final analysis , the following data were extracted : patients age and sex ; location of cardiac arrest ( ihca or ohca ) ; witnessed status ; cause of cardiac arrest ; initial cardiac rhythm ; cpr technique ( c - cpr vs. e - cpr ) ; cardiac arrest duration , defined as the interval between collapse to either return of spontaneous circulation ( rosc ) or to the start of extracorporeal circulation ; hospital mortality ; mode of death ; rate and timing of brain death ; rate of organ donation . whenever possible , the authors of the original studies where contacted to retrieve missing data . the mean and standard deviations in individual studies were estimated from median and interquartile range , when needed , according to the method described by wan et al . . pooled estimates of continuous variables were made using the inverse variance method and reported as mean    standard error ( se ) . laird random effects model   was used to account for heterogeneity . for categorical variables , proportions with 95  % confidence intervals ( cis ) the heterogeneity of pooled data was estimated by calculating the q and i 
  statistics and it was regarded as significant when p  <  0.05 or i 
 >  50  % . statistical analyses were performed using medcalc software   version 16.4.1 ( medcalc software bvba , ostend , belgium ) , comprehensive meta - analysis version 2.2.064 ( biostat inc . , s.da . ) on the basis of the presence of limitations ( risk of bias ) , indirectness , inconsistency and imprecision according to the grading of recommendations assessment , development and evaluation ( grade ) criteria [ 2123 ] . given the observational nature of included studies , the quality of evidence was initially graded as low . inconsistency across studies was graded as serious when heterogeneity was significant ( p  <  0.1 or i 
 >  50  % ) . imprecision was graded as serious when either the lower or the upper bound of the cis was respectively less than or greater than 20  % of the point estimate of the prevalence . limitations of individual studies were assessed using a modified version of the quality assessment tool for observational cohort and cross - sectional studies delivered by the us national institutes of health , march 2014 version   ( esm table  1 ) . the review questions were formulated following the pico scheme ( population , intervention , comparator , outcome ) as follows : among adults who are admitted to hospital after successful resuscitation from cardiac arrest ( p ) , what is the prevalence of brain death at hospital discharge ( o)?among adults who develop brain death after successful resuscitation from cardiac arrest ( p ) , what is the rate of organ donation ( o ) ? 
  among adults who are admitted to hospital after successful resuscitation from cardiac arrest ( p ) , what is the prevalence of brain death at hospital discharge ( o ) ? among adults who develop brain death after successful resuscitation from cardiac arrest ( p ) , what is the rate of organ donation ( o ) ? in addition , a preliminary screening of the literature suggested potential differences in the epidemiology of brain death between patients resuscitated with extracorporeal cpr ( e - cpr ) as compared to patients resuscitated with conventional cpr ( c - cpr ) . all studies published as full - text articles in indexed journals which reported the prevalence of brain death in adult ( 18  years old ) patients resuscitated from cardiac arrest occurred either in - hospital ( in - hospital cardiac arrest , ihca ) or out - of - hospital ( out - of - hospital cardiac arrest , ohca ) were considered for inclusion . publication date was restricted to studies published after 2002 in order to better reflect current practice which includes targeted temperature management ( ttm ) [ 14 , 15 ] and post - resuscitation care bundles . reviews , case reports and studies published in abstract form were excluded . studies including patients with non - hypoxic causes of brain death or patients with hypoxic coma from causes other than cardiac arrest ( respiratory arrest , asphyxia , drowning , hanging ) were excluded . medline via pubmed was searched using the keywords  heart arrest  ( mesh ) or  cardiac arrest  ( mesh ) and  brain death  . isi web of science and the cochrane database of systematic reviews were searched using the search strings  cardiac arrest  and  brain death  . for each study included in the final analysis , the following data were extracted : patients age and sex ; location of cardiac arrest ( ihca or ohca ) ; witnessed status ; cause of cardiac arrest ; initial cardiac rhythm ; cpr technique ( c - cpr vs. e - cpr ) ; cardiac arrest duration , defined as the interval between collapse to either return of spontaneous circulation ( rosc ) or to the start of extracorporeal circulation ; hospital mortality ; mode of death ; rate and timing of brain death ; rate of organ donation . whenever possible , the authors of the original studies where contacted to retrieve missing data . the mean and standard deviations in individual studies were estimated from median and interquartile range , when needed , according to the method described by wan et al . . pooled estimates of continuous variables were made using the inverse variance method and reported as mean    standard error ( se ) . for categorical variables , proportions with 95  % confidence intervals ( cis ) were calculated using the freeman the heterogeneity of pooled data was estimated by calculating the q and i 
  statistics and it was regarded as significant when p  <  0.05 or i 
 >  50  % . statistical analyses were performed using medcalc software   version 16.4.1 ( medcalc software bvba , ostend , belgium ) , comprehensive meta - analysis version 2.2.064 ( biostat inc . the quality of evidence was independently and blindly assessed by two authors ( c.s . , s.da . ) on the basis of the presence of limitations ( risk of bias ) , indirectness , inconsistency and imprecision according to the grading of recommendations assessment , development and evaluation ( grade ) criteria [ 2123 ] . given the observational nature of included studies , the quality of evidence was initially graded as low . inconsistency across studies was graded as serious when heterogeneity was significant ( p  <  0.1 or i 
 >  50  % ) . imprecision was graded as serious when either the lower or the upper bound of the cis was respectively less than or greater than 20  % of the point estimate of the prevalence . limitations of individual studies were assessed using a modified version of the quality assessment tool for observational cohort and cross - sectional studies delivered by the us national institutes of health , march 2014 version   ( esm table  1 ) . the initial search on pubmed , isi web of science and the cochrane database of systematic reviews yielded 862 records , and 177 additional records were identified through forward search ( fig .  1 ) . after duplicate removal and abstract screening , 274 articles were considered for full - text analysis . among them , 248 were excluded because they did not fulfil inclusion criteria . the remaining 26 studies ( total 23,388 patients ) were included in our review . the overall quality of evidence was very low ( esm table  2).fig . 1flow chart of study selection 
  flow chart of study selection sixteen out of 26 studies included patients resuscitated using c - cpr [ 46 , 8 , 14 , 2636 ] while ten studies included patients resuscitated using e - cpr [ 3746 ] . the characteristics of these two patient subgroups are described in table  1.table  1patients characteristics in the included studiesauthor , year [ reference]ihca or ohcano . of patientsmales , n ( % ) age , year 
 vf / pvt , n ( % ) witnessed , n ( % ) ttm , n ( % ) 
 c - cpr 
 adrie , 2008 ohca246174 ( 70.7)55.2    17.662 ( 25.2)198 ( 80.5)71 ( 28.9)bernard , 2002 ohca7752 ( 67.5)66.5    9.777 ( 100)73 ( 94.8)48 ( 55.8)calderon , 2014 mixed7242 ( 58.3)59.0    1631 ( 43.1)n / a72 ( 100)dragancea , 2013 mixed159109 ( 68.6)67    13.797 ( 60.5)n / a159 ( 100)elmer , 2016 ohca42652740 ( 64.2)65 ( 5377)1835 ( 43)2809 ( 65.9)1858 ( 43.8)geocadin , 2006 mixed5841 ( 70.7)57.2    15n / an / an / agreer , 2013 mixed200124 ( 62)59.9    16.568 ( 34)n / a39 ( 19.5)grossestreuer , 2013 ohca194114 ( 58.8)57.0    1676 ( 40)n / a194 ( 100)lemiale , 2013 ohca1152842 ( 73.1)58.4    15.4654 ( 56.8)1054 ( 87.7)764 ( 66.3)mentzelopoulos , 2013 ihca268183 ( 68.3)63    18.245 ( 16.8)247 ( 92.2)68 ( 25.4)mulder , 2014 ohca154104 ( 67.5)59.0    1683 ( 53.9)154 ( 100)154 ( 100)nielsen , 2013 ohca939761 ( 81)64    12.6752 ( 80.1)839 ( 89.4)939 ( 100)peberdy , 2003 ihca14,7208390 ( 57)67.0    153680 ( 25)12,659 ( 86)n / arundgren , 2010 mixed9568 ( 71.6)65 ( 5074)57 ( 60)n / a95 ( 100)sivaraju , 2015 n / a10059 ( 59)62.3    16.233 ( 33)n / a100 ( 100)stammet , 2009 mixed4530 ( 66.7)56    1722 ( 48.9)n / a45 ( 100 ) 
 total c - cpr 

 22,744 

 13,833 ( 60.8 ) 

 60.9    0.86 

 7572 ( 33.3 ) 

 18,033 ( 82.6 ) 

 4601 ( 57.8 ) 

 e - cpr 
 avalli , 2012 mixed4233 ( 78.6)64.8    11.728 ( 66.7)42 ( 100)42 ( 100)fagnoul , 2013 mixed2414 ( 58.3)48 ( 3855)10 ( 41.7)22 ( 91.7)17 ( 70.8)lamhaut , 2013 ohca76 ( 85.7)42    165 ( 71.4)7 ( 100)7 ( 100)le guen , 2011 ohca5146 ( 90.2)42    1532 ( 62.7)51 ( 100)51 ( 100)massetti , 2005 mixed4023 ( 57.5)42    15n / an / an / amegarbane , 2007 mixed175 ( 29.4)47 ( 2757)017 ( 100)17 ( 100)megarbane , 2011 mixed6651 ( 77.3)46 ( 3955)30 ( 45.5)66 ( 100)66 ( 100)pozzi , 2016 ohca6850 ( 73.5)43.7    11.432 ( 47.1)68 ( 100)68 ( 100)rousse , 2015 ohca3223 ( 71.9)43.2    14.319 ( 59.4)32 ( 100)32 ( 100)thiagarajan , 2009 n / a297195 ( 65.7)52 ( 3564)n / an / an / a 
 total e - cpr 

 644 

 466 ( 72.4 ) 

 47.6    1.44 
 * 
 156 ( 50.8 ) * 

 305 ( 99.3 ) * 

 300 ( 97.7 ) * 

 overall 

 23,388 

 14,299 ( 61.1 ) 

 57.5    0.74 

 7728 ( 33 ) 

 18,338 ( 82.9 ) 

 4901 ( 59.2 ) 
 total percentages are referred to studies with available data 
 c - cpr conventional cardiopulmonary resuscitation , e - cpr extracorporeal cardiopulmonary resuscitation , ihca in - hospital cardiac arrest , n / a not available , ohca out - of - hospital cardiac arrest , ttm targeted temperature management , vf / pvt ventricular fibrillation / pulseless ventricular tachycardia *  p  < 0.0001 vs. c - cpr 
 mean    standard deviation or median ( interquartile range ) 
 pooled estimate of the mean    se 
  patients characteristics in the included studies total percentages are referred to studies with available data 
 c - cpr conventional cardiopulmonary resuscitation , e - cpr extracorporeal cardiopulmonary resuscitation , ihca in - hospital cardiac arrest , n / a not available , ohca out - of - hospital cardiac arrest , ttm targeted temperature management , vf / pvt ventricular fibrillation / pulseless ventricular tachycardia *  p  <  0.0001 vs. c - cpr 
 mean    standard deviation or median ( interquartile range ) 
 pooled estimate of the mean    se eleven out of 26 studies ( 42.3  % ) included only patients resuscitated from ohca , two ( 7.7  % ) included only patients resuscitated from ihca , 11 studies ( 42.3  % ) included both ihca and ohca patients while in two studies ( 7.7  % ) the location of cardiac arrest was not specified . the cause of arrest was cardiac in three studies ( 11.5  % ) , cardiac or respiratory in 17 studies ( 65.4  % ) , while in six studies ( 23.1  % ) the cause of arrest was not specified . patients had a mean age of 57.5 ( 0.74 ) years and 14,299 ( 61.1  % ) were male . patients resuscitated with e - cpr were significantly younger than those resuscitated with c - cpr ( 47.6 vs. 60.9  years ; p  <  0.001 ) . the first recorded rhythm was shockable in 7728 ( 33.0  % ) patients ( 7572/22,686 [ 33.3  % ] c - cpr patients vs. 156/307 [ 50.8  % ] e - cpr patients ; p  <  0.001 ) . the overall duration of cardiac arrest was 42.4    1.5  min ( 19/26 studies ; table  2 ) . patients resuscitated with e - cpr had a significantly longer duration of arrest than those resuscitated with c - cpr ( 94.7    2.9 vs. 24.0    1.5  min ; p  < 0.0001).table  2duration of cardiac arrest in included studiesauthor , year [ reference]duration of cardiac arrest , min 
 adrie , 2008 32.0    6.6bernard , 2002 25.7    8.1dragancea , 2013 20    26.4elmer , 2016 23.3    0.15lemiale , 2013 24.1    0.6mentzelopoulos , 2013 16.1    8.0mulder , 2014 23    1.4nielsen , 2013 27.4    8.0rundgren , 2010 21.3    1.2 sivaraju , 2015 14.7    8.1stammet , 2009 25 [ 390 ] 
 c - cpr 

 24.0    1.7 
 avalli , 2012 69.1    3.9fagnoul , 2013 57.7    0.8lamhaut , 2013 79.0    5.7massetti , 2005 105.0    7.0megarbane , 2007 129.7    11.7megarbane , 2011 151.7    5.6pozzi , 2016 85.4    2.6rousse , 2015 115.5    3.5 
 e - cpr 

 94.7    2.9 * 

 overall 

 42.4    1.5 
 pooled data are reported as mean    se *  p  <  0.0001 vs. c - cpr 
 mean    standard deviation , median ( interquartile range ) , or median [ range ] 
  duration of cardiac arrest in included studies pooled data are reported as mean    se *  p  <  0.0001 vs. c - cpr 
 mean    standard deviation , median ( interquartile range ) , or median [ range ] in 15/26 studies all patients were treated using ttm . in seven studies ttm was used in part of the patient population ( range 19.570.8  % ) . in the remaining four studies temperature management was not reported . use of ttm was significantly more common in e - cpr vs. c - cpr studies ( 300/307 [ 97.7  % ] vs. 4601/7966 [ 57.8  % ] patients ; p  <  0.001 ) brain death was diagnosed at mean time of 3.2    0.4  days after recovery of circulation ( 11/26 studies ; table  3 ) . the rates of brain death ranged from 0 to 16.3  % of total population in studies conducted on patients resuscitated with c - cpr ( table  4 ) and from 5.9 to 42.9  % in studies conducted in patients resuscitated with e - cpr ( table  4 ) . among patients who died , this corresponded to 8.9 [ 7.011.0 ]  % of patients resuscitated from cardiac arrest . the prevalence of brain death was significantly higher in patients resuscitated with e - cpr than in patients resuscitated with c - cpr , both as a percentage of total deaths ( 27.9 [ 19.736.6 ] vs. 8.3 [ 6.510.4 ]  % ) and as a percentage of total patients ( 21.9 [ 16.627.5 ] vs. 5.4 [ 3.97.1 ]  % ; p  <  0.0001 for both).table  3timing of brain deathauthor , year [ reference]days after arrest 
 adrie , 2008 2.5 ( 2.04.2)avalli , 2012 3 ( 34)bernard , 2002 3 [ 24]calderon , 2014 3.8    1.7dragancea , 2013 5.0    1.3fagnoul , 2013 0.1 [ 0.12]lemiale , 2013 5 [ 36]nielsen , 2013 3.1    1.2pozzi , 2016 1.3    2.1rundgren , 2010 5.3    1.5stammet , 2009 2 ( 13 ) 
 overall ( mean    se ) 

 3.2    0.4 

 se standard error 
 mean    standard deviation , median ( interquartile range ) , or median [ range ] 
 table  4rates of mortality , brain death and organ donation in the included studiesauthor , year [ reference]no . of patientsmortality , n ( % ) brain death rateorgan donation rate 
 n 
 % of total patients% of deaths 
 n 
 % of brain deaths% of deaths 
 c - cpr 
 adrie , 2008 246210 ( 85)4016.319.01947.59.1bernard , 2002 7745 ( 58)22.64.4calderon , 2014 7246 ( 64)811.117.4dragancea , 2013 15984 ( 53)42.54.841004.8elmer , 2016 42652775 ( 65)3057.211.0geocadin , 2006 5848 ( 83)11.72.1greer , 2013 200180 ( 90)2010.011.1grossestreuer , 2013 194109 ( 56)42.13.7lemiale , 2013 1152768 ( 67)948.212.2mentzelopoulos , 2013 268149 ( 56)000mulder , 2014 15478 ( 51)85.210.3nielsen , 2013 939411 ( 44)181.94.4peberdy , 2003 14,72012,217 ( 83)11778.09.615913.51.3rundgren , 2010 9543 ( 45)33.27.031003.2sivaraju , 2015 10071 ( 71)77.09.9stammet , 2009 4522 ( 49)36.713.6 
 total c - cpr 

 22,744 

 17,256 ( 75.9 ) 

 1694 

 5.4 [ 3.97.1 ] 

 8.3 [ 6.510.4 ] 

 185 

 59.2 [ 18.095.7 ] 
 4.8 [ 0.411.5 ] 

 e - cpr 
 avalli , 2012 4231 ( 73.8)1228.638.7541.716.1fagnoul , 2013 2418 ( 75.0)520.827.81205.6lamhaut , 2013 76 ( 85.7)342.950266.733.3 le guen , 2011 5149 ( 96.1)1019.620.4massetti , 2005 4032 ( 80)1537.546.9megarbane , 2007 1714 ( 82.4)15.97.1megarbane , 2011 6665 ( 98.5)69.19.23504.6pozzi , 2016 6862 ( 91.2)1420.622.6000rousse , 2015 3230 ( 93.8)928.130thiagarajan , 2009 297216 ( 72.7)6120.528.2 
 total e - cpr 

 644 

 523 ( 81.2 ) 

 136 

 21.9 [ 16.627.5 ] * 

 27.9 [ 19.736.6 ] * 

 11 

 29.4 [ 4.360.8 ] 

 7.6 [ 0.517.8 ] 

 overall 

 23,388 

 17,779 ( 76.0 ) 

 1830 

 8.9 [ 7.011.0 ] 

 12.6 [ 10.215.2 ] 

 196 

 41.8 [ 20.251.0 ] 

 5.8 [ 2.110.9 ] 
 pooled rates are reported in italics as point estimate ( 95  % cis ) 
 c - cpr conventional cardiopulmonary resuscitation , e - cpr extracorporeal cardiopulmonary resuscitation 
 p  <  0.0001 vs. c - cpr 
  timing of brain death 
 mean    standard deviation , median ( interquartile range ) , or median [ range ] rates of mortality , brain death and organ donation in the included studies pooled rates are reported in italics as point estimate ( 95  % cis ) c - cpr conventional cardiopulmonary resuscitation , e - cpr extracorporeal cardiopulmonary resuscitation 
 p  <  0.0001 vs. c - cpr rates of organ donation were reported in 9/26 studies . donation rates ranged from 0 to 100  % of brain deaths and from 0 to 33.3  % of total deaths . the estimated pooled rates were 41.8 [ 20.251.0 ] and 5.8 [ 2.110.9 ]  % , respectively ( 9/26 studies , 1264 patients ; table  4 ) . there was no significant difference in the rate of organ donation between studies on patients resuscitated with e - cpr and those on patients resuscitated with c - cpr ( p  =  0.544 and 0.471 , respectively ) . the heterogeneity within and across subgroups was significant for both brain death rate and organ donation rate ( esm figs .  1 , 2 ) . one study   reported the outcome of organs ( kidneys and livers ) retrieved from patients with brain death after cardiac arrest and compared it with that of organs retrieved from patients with brain death due to a primary brain injury ( head injury or stroke ) . this study found no significant difference in 5-year survival rates of transplanted organs between these two groups . only one study   specifically investigated early predictors of brain death . in that study , none of the clinical or laboratory findings distinguished the patients with brain death from those who died without a diagnosis of brain death . the initial search on pubmed , isi web of science and the cochrane database of systematic reviews yielded 862 records , and 177 additional records were identified through forward search ( fig .  1 ) . after duplicate removal and abstract screening , 274 articles were considered for full - text analysis . among them , 248 were excluded because they did not fulfil inclusion criteria . the remaining 26 studies ( total 23,388 patients ) were included in our review . the overall quality of evidence was very low ( esm table  2).fig . sixteen out of 26 studies included patients resuscitated using c - cpr [ 46 , 8 , 14 , 2636 ] while ten studies included patients resuscitated using e - cpr [ 3746 ] . the characteristics of these two patient subgroups are described in table  1.table  1patients characteristics in the included studiesauthor , year [ reference]ihca or ohcano . of patientsmales , n ( % ) age , year 
 vf / pvt , n ( % ) witnessed , n ( % ) ttm , n ( % ) 
 c - cpr 
 adrie , 2008 ohca246174 ( 70.7)55.2    17.662 ( 25.2)198 ( 80.5)71 ( 28.9)bernard , 2002 ohca7752 ( 67.5)66.5    9.777 ( 100)73 ( 94.8)48 ( 55.8)calderon , 2014 mixed7242 ( 58.3)59.0    1631 ( 43.1)n / a72 ( 100)dragancea , 2013 mixed159109 ( 68.6)67    13.797 ( 60.5)n / a159 ( 100)elmer , 2016 ohca42652740 ( 64.2)65 ( 5377)1835 ( 43)2809 ( 65.9)1858 ( 43.8)geocadin , 2006 mixed5841 ( 70.7)57.2    15n / an / an / agreer , 2013 mixed200124 ( 62)59.9    16.568 ( 34)n / a39 ( 19.5)grossestreuer , 2013 ohca194114 ( 58.8)57.0    1676 ( 40)n / a194 ( 100)lemiale , 2013 ohca1152842 ( 73.1)58.4    15.4654 ( 56.8)1054 ( 87.7)764 ( 66.3)mentzelopoulos , 2013 ihca268183 ( 68.3)63    18.245 ( 16.8)247 ( 92.2)68 ( 25.4)mulder , 2014 ohca154104 ( 67.5)59.0    1683 ( 53.9)154 ( 100)154 ( 100)nielsen , 2013 ohca939761 ( 81)64    12.6752 ( 80.1)839 ( 89.4)939 ( 100)peberdy , 2003 ihca14,7208390 ( 57)67.0    153680 ( 25)12,659 ( 86)n / arundgren , 2010 mixed9568 ( 71.6)65 ( 5074)57 ( 60)n / a95 ( 100)sivaraju , 2015 n / a10059 ( 59)62.3    16.233 ( 33)n / a100 ( 100)stammet , 2009 mixed4530 ( 66.7)56    1722 ( 48.9)n / a45 ( 100 ) 
 total c - cpr 

 22,744 

 13,833 ( 60.8 ) 

 60.9    0.86 

 7572 ( 33.3 ) 

 18,033 ( 82.6 ) 

 4601 ( 57.8 ) 

 e - cpr 
 avalli , 2012 mixed4233 ( 78.6)64.8    11.728 ( 66.7)42 ( 100)42 ( 100)fagnoul , 2013 mixed2414 ( 58.3)48 ( 3855)10 ( 41.7)22 ( 91.7)17 ( 70.8)lamhaut , 2013 ohca76 ( 85.7)42    165 ( 71.4)7 ( 100)7 ( 100)le guen , 2011 ohca5146 ( 90.2)42    1532 ( 62.7)51 ( 100)51 ( 100)massetti , 2005 mixed4023 ( 57.5)42    15n / an / an / amegarbane , 2007 mixed175 ( 29.4)47 ( 2757)017 ( 100)17 ( 100)megarbane , 2011 mixed6651 ( 77.3)46 ( 3955)30 ( 45.5)66 ( 100)66 ( 100)pozzi , 2016 ohca6850 ( 73.5)43.7    11.432 ( 47.1)68 ( 100)68 ( 100)rousse , 2015 ohca3223 ( 71.9)43.2    14.319 ( 59.4)32 ( 100)32 ( 100)thiagarajan , 2009 n / a297195 ( 65.7)52 ( 3564)n / an / an / a 
 total e - cpr 

 644 

 466 ( 72.4 ) 

 47.6    1.44 
 * 
 156 ( 50.8 ) * 

 305 ( 99.3 ) * 

 300 ( 97.7 ) * 

 overall 

 23,388 

 14,299 ( 61.1 ) 

 57.5    0.74 

 7728 ( 33 ) 

 18,338 ( 82.9 ) 

 4901 ( 59.2 ) 
 total percentages are referred to studies with available data 
 c - cpr conventional cardiopulmonary resuscitation , e - cpr extracorporeal cardiopulmonary resuscitation , ihca in - hospital cardiac arrest , n / a not available , ohca out - of - hospital cardiac arrest , ttm targeted temperature management , vf / pvt ventricular fibrillation / pulseless ventricular tachycardia *  p  <  0.0001 vs. c - cpr 
 mean    standard deviation or median ( interquartile range ) 
 pooled estimate of the mean    se 
  patients characteristics in the included studies total percentages are referred to studies with available data 
 c - cpr conventional cardiopulmonary resuscitation , e - cpr extracorporeal cardiopulmonary resuscitation , ihca in - hospital cardiac arrest , n / a not available , ohca out - of - hospital cardiac arrest , ttm targeted temperature management , vf / pvt ventricular fibrillation / pulseless ventricular tachycardia *  p  <  0.0001 vs. c - cpr 
 mean    standard deviation or median ( interquartile range ) 
 pooled estimate of the mean    se eleven out of 26 studies ( 42.3  % ) included only patients resuscitated from ohca , two ( 7.7  % ) included only patients resuscitated from ihca , 11 studies ( 42.3  % ) included both ihca and ohca patients while in two studies ( 7.7  % ) the location of cardiac arrest was not specified . the cause of arrest was cardiac in three studies ( 11.5  % ) , cardiac or respiratory in 17 studies ( 65.4  % ) , while in six studies ( 23.1  % ) the cause of arrest was not specified . patients had a mean age of 57.5 ( 0.74 ) years and 14,299 ( 61.1  % ) were male . patients resuscitated with e - cpr were significantly younger than those resuscitated with c - cpr ( 47.6 vs. 60.9  years ; p  <  0.001 ) . the first recorded rhythm was shockable in 7728 ( 33.0  % ) patients ( 7572/22,686 [ 33.3  % ] c - cpr patients vs. 156/307 [ 50.8  % ] e - cpr patients ; p  <  0.001 ) . the overall duration of cardiac arrest was 42.4    1.5  min ( 19/26 studies ; table  2 ) . patients resuscitated with e - cpr had a significantly longer duration of arrest than those resuscitated with c - cpr ( 94.7    2.9 vs. 24.0    1.5  min ; p  <  0.0001).table  2duration of cardiac arrest in included studiesauthor , year [ reference]duration of cardiac arrest , min 
 adrie , 2008 32.0    6.6bernard , 2002 25.7    8.1dragancea , 2013 20    26.4elmer , 2016 23.3    0.15lemiale , 2013 24.1    0.6mentzelopoulos , 2013 16.1    8.0mulder , 2014 23    1.4nielsen , 2013 27.4    8.0rundgren , 2010 21.3    1.2 sivaraju , 2015 14.7    8.1stammet , 2009 25 [ 390 ] 
 c - cpr 

 24.0    1.7 
 avalli , 2012 69.1    3.9fagnoul , 2013 57.7    0.8lamhaut , 2013 79.0    5.7massetti , 2005 105.0    7.0megarbane , 2007 129.7    11.7megarbane , 2011 151.7    5.6pozzi , 2016 85.4    2.6rousse , 2015 115.5    3.5 
 e - cpr 

 94.7    2.9 * 

 overall 

 42.4    1.5 
 pooled data are reported as mean    se *  p  <  0.0001 vs. c - cpr 
 mean    standard deviation , median ( interquartile range ) , or median [ range ] 
  duration of cardiac arrest in included studies pooled data are reported as mean    se *  p  <  0.0001 vs. c - cpr 
 mean    standard deviation , median ( interquartile range ) , or median [ range ] in 15/26 studies all patients were treated using ttm . in seven studies ttm was used in part of the patient population ( range 19.570.8  % ) . in the remaining four studies temperature management was not reported . use of ttm was significantly more common in e - cpr vs. c - cpr studies ( 300/307 [ 97.7  % ] vs. 4601/7966 [ 57.8  % ] patients ; p  <  0.001 ) . brain death was diagnosed at mean time of 3.2    0.4  days after recovery of circulation ( 11/26 studies ; table  3 ) . the rates of brain death ranged from 0 to 16.3  % of total population in studies conducted on patients resuscitated with c - cpr ( table  4 ) and from 5.9 to 42.9  % in studies conducted in patients resuscitated with e - cpr ( table  4 ) . among patients who died , this corresponded to 8.9 [ 7.011.0 ]  % of patients resuscitated from cardiac arrest . the prevalence of brain death was significantly higher in patients resuscitated with e - cpr than in patients resuscitated with c - cpr , both as a percentage of total deaths ( 27.9 [ 19.736.6 ] vs. 8.3 [ 6.510.4 ]  % ) and as a percentage of total patients ( 21.9 [ 16.627.5 ] vs. 5.4 [ 3.97.1 ]  % ; p  <  0.0001 for both).table  3timing of brain deathauthor , year [ reference]days after arrest 
 adrie , 2008 2.5 ( 2.04.2)avalli , 2012 3 ( 34)bernard , 2002 3 [ 24]calderon , 2014 3.8    1.7dragancea , 2013 5.0    1.3fagnoul , 2013 0.1 [ 0.12]lemiale , 2013 5 [ 36]nielsen , 2013 3.1    1.2pozzi , 2016 1.3    2.1rundgren , 2010 5.3    1.5stammet , 2009 2 ( 13 ) 
 overall ( mean    se ) 

 3.2    0.4 

 se standard error 
 mean    standard deviation , median ( interquartile range ) , or median [ range ] 
 table  4rates of mortality , brain death and organ donation in the included studiesauthor , year [ reference]no . of patientsmortality , n ( % ) brain death rateorgan donation rate 
 n 
 % of total patients% of deaths 
 n 
 % of brain deaths% of deaths 
 c - cpr 
 adrie , 2008 246210 ( 85)4016.319.01947.59.1bernard , 2002 7745 ( 58)22.64.4calderon , 2014 7246 ( 64)811.117.4dragancea , 2013 15984 ( 53)42.54.841004.8elmer , 2016 42652775 ( 65)3057.211.0geocadin , 2006 5848 ( 83)11.72.1greer , 2013 200180 ( 90)2010.011.1grossestreuer , 2013 194109 ( 56)42.13.7lemiale , 2013 1152768 ( 67)948.212.2mentzelopoulos , 2013 268149 ( 56)000mulder , 2014 15478 ( 51)85.210.3nielsen , 2013 939411 ( 44)181.94.4peberdy , 2003 14,72012,217 ( 83)11778.09.615913.51.3rundgren , 2010 9543 ( 45)33.27.031003.2sivaraju , 2015 10071 ( 71)77.09.9stammet , 2009 4522 ( 49)36.713.6 
 total c - cpr 

 22,744 

 17,256 ( 75.9 ) 

 1694 

 5.4 [ 3.97.1 ] 

 8.3 [ 6.510.4 ] 

 185 

 59.2 [ 18.095.7 ] 
 4.8 [ 0.411.5 ] 

 e - cpr 
 avalli , 2012 4231 ( 73.8)1228.638.7541.716.1fagnoul , 2013 2418 ( 75.0)520.827.81205.6lamhaut , 2013 76 ( 85.7)342.950266.733.3 le guen , 2011 5149 ( 96.1)1019.620.4massetti , 2005 4032 ( 80)1537.546.9megarbane , 2007 1714 ( 82.4)15.97.1megarbane , 2011 6665 ( 98.5)69.19.23504.6pozzi , 2016 6862 ( 91.2)1420.622.6000rousse , 2015 3230 ( 93.8)928.130thiagarajan , 2009 297216 ( 72.7)6120.528.2 
 total e - cpr 

 644 

 523 ( 81.2 ) 

 136 

 21.9 [ 16.627.5 ] * 

 27.9 [ 19.736.6 ] * 

 11 

 29.4 [ 4.360.8 ] 

 7.6 [ 0.517.8 ] 

 overall 

 23,388 

 17,779 ( 76.0 ) 

 1830 

 8.9 [ 7.011.0 ] 

 12.6 [ 10.215.2 ] 

 196 

 41.8 [ 20.251.0 ] 

 5.8 [ 2.110.9 ] 
 pooled rates are reported in italics as point estimate ( 95  % cis ) 
 c - cpr conventional cardiopulmonary resuscitation , e - cpr extracorporeal cardiopulmonary resuscitation 
 p  <  0.0001 vs. c - cpr 
  timing of brain death 
 mean    standard deviation , median ( interquartile range ) , or median [ range ] rates of mortality , brain death and organ donation in the included studies pooled rates are reported in italics as point estimate ( 95  % cis ) 
 c - cpr conventional cardiopulmonary resuscitation , e - cpr extracorporeal cardiopulmonary resuscitation 
 p  <  0.0001 vs. c - cpr rates of organ donation were reported in 9/26 studies . donation rates ranged from 0 to 100  % of brain deaths and from 0 to 33.3  % of total deaths . the estimated pooled rates were 41.8 [ 20.251.0 ] and 5.8 [ 2.110.9 ]  % , respectively ( 9/26 studies , 1264 patients ; table  4 ) . there was no significant difference in the rate of organ donation between studies on patients resuscitated with e - cpr and those on patients resuscitated with c - cpr ( p  =  0.544 and 0.471 , respectively ) . the heterogeneity within and across subgroups was significant for both brain death rate and organ donation rate ( esm figs .  1 , 2 ) . one study   reported the outcome of organs ( kidneys and livers ) retrieved from patients with brain death after cardiac arrest and compared it with that of organs retrieved from patients with brain death due to a primary brain injury ( head injury or stroke ) . this study found no significant difference in 5-year survival rates of transplanted organs between these two groups . only one study   specifically investigated early predictors of brain death . in that study , none of the clinical or laboratory findings distinguished the patients with brain death from those who died without a diagnosis of brain death . in studies included in our review , 8.9  % of patients initially resuscitated from cardiac arrest developed brain death . they represented more than 12  % of total patients who died before hospital discharge . the prevalence of brain death in patients resuscitated with e - cpr was more than three times higher than in those resuscitated with c - cpr , despite similar mortality rates . e - cpr patients were significantly younger and had significantly higher rates of witnessed arrest or shockable rhythms compared to c - cpr patients , which reflects that e - cpr programs use restrictive indications to select patients with favourable characteristics who are most likely to benefit . however , in our review e - cpr patients had significantly longer arrest times than c - cpr patients , because e - cpr is used when c - cpr fails to restore spontaneous circulation and it requires longer to initiate . if the severity of hypoxic - ischaemic neuronal death is proportional to the duration of arrest , this may explain the higher prevalence of brain death in e - cpr patients . however , since the mechanism of brain death has not been described in studies included in our review , we could not exclude other possible explanations . for example , in some patients resuscitated using e - cpr , brain death could have been due to cerebral haemorrhage induced by anticoagulation needed to maintain extracorporeal circulation . since none of the indices currently used to report outcome after cardiac arrest , such as cerebral performance categories ( cpc ) , modified rankin scale ( mrs ) or glasgow outcome scale ( gos ) , distinguishes between death due to neurological causes ( as brain death or death after wlst because of severe brain damage ) and death from other causes , such as irreversible cardiovascular collapse or multiorgan failure , we suggest that those indices should be modified to include this information ( e.g. cpc 5b to indicate brain death ) . we also suggest that the authors should be encouraged to report the detailed mechanism of death in post - resuscitation studies . in studies included in our review the pooled rate of organ donation from brain dead patients after cardiac arrest was 41  % . according to recent studies [ 50 , 51 ] each year approximately 167,000 ohca patients are treated by the emergency medical services in the usa . of these , 41,750 ( 25  % ) on the basis of the results of our review , we estimate that 3716 [ 95  % ci 29234593 ] patients yearly will evolve to brain death , of whom 1553 could potentially donate organs . with this perspective , intensive life support of patients with severe post - resuscitation brain injury should be maintained for a sufficiently long time to detect not only the occurrence of cerebral recovery but also to determine progression to brain death . the diagnosis of brain death was made at a mean of 3  days and up to 6  days after rosc in studies included in our review , which is consistent with the fact that neuronal death occurring after global brain ischaemia is typically delayed [ 52 , 53 ] . delayed massive cerebral oedema leading to brain death and occurring at 4872  h after rosc has also been described . since both ttm and sedation / paralysis used to maintain ttm may interfere with clinical neurological examination [ 55 , 56 ] , it is reasonable to evaluate resuscitated patients for occurrence of brain death after rewarming and cessation of interference from sedation ( see suggested algorithm in fig .  2 ) . nevertheless , brain death can be suspected even during sedation or paralysis on the basis of clinical signs such as fixed , dilated pupils , diabetes insipidus , and acute cardiocirculatory changes that suggest cerebral herniation.fig . 2suggested algorithm for brain death screening after cardiac arrest . in a resuscitated patient who is unresponsive after rewarming from targeted temperature management ( ttm ) , and after having excluded confounders , brain death can be suspected earlier if a catastrophic brain injury is demonstrated on ct or if the patient shows signs like fixed , dilated pupils , diabetes insipidus , or cardiovascular changes suggesting herniation . brain death is confirmed by clinical observation and/or by confirmatory tests like apnoea , a flat eeg or absent cerebral blood flow , according to local legislation or protocols . organ donation is considered after ascertainment of brain death . in cases where circulatory death occurs , either spontaneously or as a consequence of withdrawal of life - sustaining treatment ( wlst ) , donation after circulatory death ( dcd ) can be considered . for the european resuscitation council and the european society of intensive care medicine ( erc  esicm ) recommended neuroprognostication protocol , see ref . 
  suggested algorithm for brain death screening after cardiac arrest . in a resuscitated patient who is unresponsive after rewarming from targeted temperature management ( ttm ) , and after having excluded confounders , brain death can be suspected earlier if a catastrophic brain injury is demonstrated on ct or if the patient shows signs like fixed , dilated pupils , diabetes insipidus , or cardiovascular changes suggesting herniation . brain death is confirmed by clinical observation and/or by confirmatory tests like apnoea , a flat eeg or absent cerebral blood flow , according to local legislation or protocols . organ donation is considered after ascertainment of brain death . in cases where circulatory death occurs , either spontaneously or as a consequence of withdrawal of life - sustaining treatment ( wlst ) , donation after circulatory death ( dcd ) can be considered . for the european resuscitation council and the european society of intensive care medicine ( erc  esicm ) recommended neuroprognostication protocol , see ref .   in some cases , this is common when cardiac arrest is due to neurological causes , most commonly a subarachnoid haemorrhage [ 58 , 59 ] . when a neurological rather than a cardiac cause of arrest is suspected , a brain computerized tomography ( ct ) immediately after rosc is recommended . if brain ct demonstrates a catastrophic brain injury , an early evaluation for brain death may be considered . clinical examination for ascertainment of brain death confirmatory tests such as electroencephalogram or evaluation of cerebral blood flow may be required when confounders can not be excluded or when requested by local legislation . whenever circulatory death occurs , either spontaneously or as a consequence of wlst , donation after circulatory death ( dcd ) may be considered , according to local legislation and practices . the potential for organ donation in patients resuscitated from cardiac arrest has important ethical implications . from one side cpr to save lives  is not limited to the life of the patient who is being resuscitated but it extends also to the potential recipients of organs retrieved from resuscitated patients who proceed to brain death . from the opposite side , however , if cpr was started with the only aim of organ procurement , the community - level beneficence represented by organ donation would potentially conflict with the general principle of individual non - maleficence (  first , do not harm  ) . firstly , its primary outcome measure , the prevalence of brain death , was reported in only 10  % of studies screened for inclusion , so we can not exclude a selection bias . in addition , some variables like the timing of brain death and the rate of organ donation were reported in less than 50  % of included studies . however , this shows that brain death after cardiac arrest is underreported in current literature , and confirms the utility of our review . secondly , our analysis used aggregated data , so our ability to investigate the factors associated with the occurrence of brain death after cardiac arrest was limited . our pooled analysis showed a significant heterogeneity , which likely reflects differences in terms of case mix , treatment and possibly criteria for the diagnosis of brain death . an individual patient data meta - analysis will be needed to adjust adequately for these confounders . in particular , we could not investigate the association between location of cardiac arrest ( ihca vs. ohca ) and the prevalence of brain death , because in 13/26 ( 50  % ) studies the location of cardiac arrest was either mixed or not specified . similarly , we could not investigate the association between use of ttm and occurrence of brain death . this is also because  in order to reflect current post - resuscitation practice  we restricted our analysis to studies published after 2002 , in whom most of the patients received ttm . future studies investigating different temperature management strategies after cpr might include the occurrence of brain death among their endpoints to specifically address this question . thirdly , our study did not include dcd , which in some countries   represents a major source of organ donation after cardiac arrest . this is because our study was focused only on the epidemiology of brain death after cardiac arrest , whose prevalence is underreported , and whose importance as a source of organ donation may consequently have been underrecognised [ 8 , 10 ] . despite being only rarely reported in current literature , brain death represented more than 10  % of deaths in the 23,388 adult cardiac arrest patients included in our review . this rate was significantly higher after extracorporeal than after conventional cpr , probably because of the higher severity of anoxic - ischaemic brain injury in that group of patients . more than 40  % of patients brain dead after cardiac arrest donated organs . given this potential for organ donation , patients who are unconscious after resuscitation from cardiac arrest , especially when resuscitated using e - cpr , should be carefully screened for brain death before deciding on withdrawal of life support . below is the link to the electronic supplementary material . 
 supplementary material 1 ( docx 19  kb ) 
 supplementary material 2 ( docx 18  kb ) 
 supplementary material 3(docx 46  kb ) supplementary material 4 ( doc 328  kb ) 
  supplementary material 1 ( docx 19  kb ) supplementary material 2 ( docx 18  kb ) supplementary material 3(docx 46  kb ) supplementary material 4 ( doc 328  kb ) on behalf of all authors , the corresponding author states that there is no conflict of interest .
backgroundthe occurrence of brain death in patients with hypoxic - ischaemic brain injury after resuscitation from cardiac arrest creates opportunities for organ donation . 
 however , its prevalence is currently unknown.methodssystematic review . 
 medline via pubmed , isi web of science and the cochrane database of systematic reviews were searched for eligible studies ( 20022016 ) . 
 the prevalence of brain death in adult patients resuscitated from cardiac arrest and the rate of organ donation among brain dead patients were summarised using a random effect model with double - arcsine transformation . 
 the quality of evidence ( qoe ) was evaluated according to the grade guidelines.results26 studies [ 16 on conventional cardiopulmonary resuscitation ( c - cpr ) , 10 on extracorporeal cpr ( e - cpr ) ] included a total of 23,388 patients , 1830 of whom developed brain death at a mean time of 3.2    0.4  days after recovery of circulation . 
 the overall prevalence of brain death among patients who died before hospital discharge was 12.6 [ 10.215.2 ]  % . 
 prevalence was significantly higher in e - cpr vs. c - cpr patients ( 27.9 [ 19.736.6 ] vs. 8.3 [ 6.510.4 ]  % ; p  <  0.0001 ) . 
 the overall rate of organ donation among brain dead patients was 41.8 [ 20.251.0 ]  % ( 9/26 studies , 1264 patients ; range 0100  % ) . 
 the qoe was very low for both outcomes.conclusionsin patients with hypoxic - ischaemic brain injury following cpr , more than 10  % of deaths were due to brain death . 
 more than 40  % of brain - dead patients could donate organs . 
 patients who are unconscious after resuscitation from cardiac arrest , especially when resuscitated using e - cpr , should be carefully screened for signs of brain death.electronic supplementary materialthe online version of this article ( doi:10.1007/s00134 - 016 - 4549 - 3 ) contains supplementary material , which is available to authorized users .