a b s t r a c t

Objectives: The post-Cardiac arrest survival rate has remained low since the 2010 cardiopulmonary resuscitation (CPR) guidelines were published. The present study aimed to review the 2010 vs 2005 CPR guideline outcomes in adults with in-hospital cardiac arrest.

Methods: The Pub Med, EMBASE, and Cochrane Library databases were searched for articles published between January 2006 and July 2015. We extracted the following from observational studies and intervention studies: first author’s name, Publication year, study duration, age of study population, and sample size. The primary outcome variables were return of spontaneous circulation (ROSC) and survival to discharge. The data were divided into 2005 (data collected before December 2010) and 2010 (data collected in December 2010 or later) CPR guidelines groups.

Results: Twenty-four original articles (77,605 patients) were included. Statistically significant heterogeneity (ROSC: P b .01, I² = 97.9%; survival to discharge: P b .01, I² = 98.3%) was seen, and a random-effects model was used to pool the outcomes. The pooled ROSC rate for the 2010 group (n = 5; mean, 48%; 95% confidence in- terval [CI], 0.38-0.58) was only slightly higher than that of the 2005 group (n = 19; mean, 47%; 95% CI, 0.38-0.57). The opposite result was noted in the pooled survival to discharge rates (2010: n = 5, mean, 14%; 95% CI, 0.08-0.20 vs 2005: n = 19; mean, 15%; 95% CI, 0.10-0.20). There was actually no significant difference in ROSC or survival to discharge outcomes between the 2 groups.

Conclusions: The 2010 CPR guidelines emphasized that high-quality chest compressions can increase the ROSC rate but did not show to improve long-term results.

(C) 2016

Introduction

The 2010 cardiopulmonary resuscitation (CPR) guidelines published by the American Heart Association especially emphasized the use of high-quality chest compressions during CPR. The most significant adult basic life support (BLS) change in this document is its recommen- dation of a compressions, airway, breathing sequence instead of the air- way, breathing, compressions sequence of the 2005 guidelines to minimize delays to the initiation of compressions and resuscitation [1]. However, the effect of high-quality CPR on survival has rarely been prospectively assessed in a randomized trial. One study reported that the CPR protocol of the 2010 guidelines was associated with a higher proportion of patients achieving return of spontaneous circulation (ROSC), but this did not translate to statistically significant

? Competing interest: The authors declare that they have no conflict of interest. The study was not supported by any fund.

* Corresponding author. Tel.: +86 731 82650264; fax: +86 731 82650262.

E-mail address: [email protected] (J. Zhang).

improvements in survival to discharge or Neurologically intact survival in adults with in-hospital cardiac arrest receiving CPR by an emergency team [2]. However, in children, the CPR intervention research according to the 2010 CPR guidelines was associated with a trend toward improved survival to hospital discharge and favorable neurological out- come but not ROSC [3]. Improved trends in survival to hospital dis- charge and neurological outcomes occurred in cases of both shockable and nonshockable arrest rhythms from out-of-hospital cardiac arrest between October 2005 and December 2012 [4]. With the increasing rate of dispatcher-assisted bystander CPR, significantly improved sur- vival and neurological outcomes also occurred in cases of metropolitan out-of-hospital cardiac arrest with the bystanders trained according to 2010 CPR guidelines [5].

survival outcomes after resuscitation were associated with age, elec- trocardiography rhythm, the timing of cardiac arrest, where CPR was performed, and the duration of CPR [6]. Adults had more frequent ROSC, 24-hour survival, and survival to discharge than children from In-hospital CPR in emergency department during 2000 to 2010 [7].

It is unknown whether the recent improvements are due to the new 2010 guidelines or to an increased number of trained bystanders or other reasons. Recent meta-analyses of cardiac arrest research have

http://dx.doi.org/10.1016/j.ajem.2016.03.008

0735-6757/(C) 2016

Fig. 1. Literature search data.

focused on the use of new therapies including mechanical chest com- pression [8], extracorporeal CPR [9] and defibrillation [10], new medica- tions such as adrenaline [11] and antiarrhythmics [12], or resuscitation training [13]. However, no group has conducted a systematic review to precisely assess the outcomes of the 2010 CPR guidelines. Usually, out- of-hospital CPR is performed by a bystander and subject to availability of first aid equipment, whereas in-hospital arrests receive CPR by trained health care workers with minimal delay and immediately available equipment. We decided to focus on in-hospital rather than out-of- hospital arrests because the environment is more similar between stud- ies so results would more likely relate to the 2010 vs 2005 guidelines. Therefore, the goal of this study was to summarize and perform a meta-analysis of the 2010 vs 2005 CPR guidelines in a population of adults with in-hospital cardiac arrest.

Methods

Search strategy

A systematic review of the literature was based on the meta-analysis of observational studies in epidemiology statement. Relevant studies were identified from Pub Med, EMBASE, and Cochrane Library searches using the following terms: (outcome of in-hospital cardiopulmonary resuscitation [MeSH Terms]) OR (outcome after in-hospital cardiopul- monary arrest [MeSH Terms]) AND adult. Limits: Only studies of humans within the defined time frame (January 1, 2006, to July 31, 2015) were included.

First, the first author selected studies based on the titles and abstracts, and then, the 2 authors respectively screened the full texts of the remaining articles more thoroughly. Disagreements were settled by consensus or adjudication of the 2 authors.

The following eligibility criteria were required for inclusion: (1) ob- servational or intervention study, (2) publication after 2006 with data sources 2006 or newer, (3) in-hospital arrest, (4) adult population (de- fined as N 14 years), (5) survival data available, and (6) publication in English. We excluded studies of (1) CPR performed or started in the out-of-hospital setting; (2) CPR performed in the operating room;

(3) data combining arrests in both children and adults; and (4) CPR per- formed in a special population, including pregnant women, patients re- quiring extracorporeal CPR or mechanical resuscitation, or arrest of a patient who is already intubated.

Data extraction

In addition to study design, patient characteristics, and sample size, we extracted information including actual numbers of survivors and corresponding cohort sizes and event rates. ROSC and survival to dis- charge were the primary outcome variables, but we also obtained data on survival at 24 hours and favorable neurological outcomes. If survival to discharge data were not available, we considered 30-day survival as survival to discharge.

The data were divided into the 2005 and 2010 CPR guidelines groups. The data collected before December 2010 were entered into the 2005 group; those thereafter were included in the 2010 group.

Table 1

The characteristics of the studies included in this meta-analysis

Reference (first author)	Country	Sample source	Inclusion period	Intervention	n (% MALE)	Age range	Mean age	ROSC (%)	Survival to discharge(%)
Study in 2005 CPR guidelines Muller MP, 2014 [16]	Germany	Single hospital	2008-2010	CPR team	58 (72.4)	Adult	67-68	28 (48)	11 (19)
Mentzelopoulos SD, 2013 [17]	Greece	Multiple hospitals	2008.9-2010.10	Drug intervention	268 (68.3)	? 18	63	200 (75)	25 (9)
Khasawneh FA, 2013 [31]	USA	ICU of single hospital	2008.1-2009.6	NI	104 (62.5)	Adult	49.7 +- 15.3	36 (35)	6 (6)
Lee HK, 2013 [24]	Korea	ICU of single hospital	2009.1-2010.6	NI	131 (64.9)	? 18	61.0 +- 16.5	96 (73)
Chon GR, 2013 [25]	Korea	Single hospital	2008.3-2010.2	CPR team	238 (59.7)	? 18	61.3 +- 15.2	151 (63)	46 (19)
Chan JC, 2013 [26]	China	2 hospitals	2008.1-2008.12	NI	431 (61.7)	24-97	73.6	139 (32)	23 (5)
Toledo FO, 2013 [37]	Brazil	Single hospital	2007.1-2009.12	NI	81 (61.7)	? 18	55 +- 22	46 (57)	13 (16)
Chan PS, 2013 [32]	USA	GWTG	2007-2010	NI	48,841 (58.3)	N 18	65.6 +- 16.1		10,290 (21)
Akhtar N, 2012 [18]	England	Multiple hospitals	2009.12-2010.4	CPR team	191 (/)	Adult	/	73 (38)	39 (20)
Ong ME, 2012 [30]	Singapore	Multiple hospitals	2006.3-2009.1	Drug intervention	727 (69.4)	N 16	64.6-64.9	225 (31)	19 (3)
Bhalala US, 2012 [33]	USA	2 hospitals	2008-2010	NI	98 (63.3)	? 18	73		39 (40)
Chakravarthy M, 2012 [27]	India	Single hospital	2007.3-2009.3	NI	78 (60.3)	Adult	/	50 (64)	24 (31)
Tarmey NT, 2011 [19]	UK	Single hospital	2009.12-2010.6	Hospital’s	52 (100)	18-36	24.5	14 (27)	4 (8)
Sodhi K, 2011 [28]	India	Single hospital	2009.1-2010.6	trauma team CPR team	627 (55.8)	N 14	57	149 (24)	79 (13)
Yokoyama H, 2011 [35]	Japan	J-RCPR	2008.1-2009.12	NI	491 (63.3)	? 18	71.0 +- 14.9	318 (65)	136 (28)
Einav S, 2011 [29]	Israel	Single hospital	2008-2010	CPR team	30 (50.0)	16-92	74	17 (57)	6 (20)
Lutchmedial S, 2010 [15]	USA	Single hospital	2008.7-2009.4	NI	264 (70.0)	Adult		36 (14)	29 (11)
Olasveengen TM, 2009 [20]	Norway	Single hospital	2006.1-2007.12	CPR team	482 (66.6)	Adult	64 +- 18	147 (30)	63 (13)
Mentzelopoulos SD, 2009 [21]	Greece	Single hospital	2006.6-2007.3	Drug intervention	100 (59.0)	? 18	65-69	66 (66)	11 (11)
Edelson DP, 2008 [34]	USA	Single hospital	2006.2-2007.3	CPR team	123 (48.0)	? 18	60.7 +- 16	73 (59)	9 (7)
Nolan J.P, 2014[22]	UK	NCAA	2011.4-2013.3	NI	23,554 (55.0)	? 16	73.9	10,607 (45)	4153 (18)
Amer M.S., 2014 [36]	Egypt	Single hospital	2011.1-2012.6	NI	380 (36.8)	? 60	67.98 +- 7.9	124 (33)	32 (8)
Michael P. Muller, 2014 [16]	Germany	Single hospital	2011-2012	CPR team	61 (63.9)	Adult	67-72	44 (72)	21 (34)
Ahmed M, 2014 [23]	UK	NCEPOD	2011.1-2012.9	NI	69 (/)	Adult	/		7 (10)
Taha H.S, 2015 [14]	Egyptian	Multiple hospitals	2012.3-2012.12	NI	126 (63.5)	? 18	56.4 +- 14.8	60 (48)	9 (7)

NCEPOD, National Confidential Enquiry into Patient Outcome and Death; GWTG: Get With The Guidelines–Resuscitation; NCAA, United Kingdom National Cardiac Arrest Audit database; J-RCPR, registry of in-hospital CPA and resuscitation in Japan; NI, no intervention; n: number of patients in the study.

If the detailed data contained outcomes from both before and after 2011, then it was entered into the 2005 or 2010 group, respectively. Study data that lacked specific date were excluded.

Statistical analysis

All included studies were either observational or clinical trials. We put the extracted clinical data into an Excel database and analyzed it using Stata version 12.0 (Stata Corp, College Station, TX). Estimates were segregated into the 2005 and 2010 CPR guidelines groups. Survival outcomes were ROSC and survival to hospital discharge.

Because of the study heterogeneity, a random-effects model was used to combine the studies. To assess study heterogeneity, the Cochrane Q test and the I² index were used. P values b .05 were consid- ered significant in the heterogeneity test. We also explored potential sources of heterogeneity by applying a multivariate Meta-regression analysis examining guidelines version, continent, time, sample source, intervention, and sample size. Effect sizes were reported as mean differ- ences. Standard errors were calculated using group standard deviation or 95% confidence interval (CI) measures.

Results

In this manner, the search resulted in 3204 articles (Fig. 1). A total of 2718 articles were obtained from Pub Med, 469 from EMBASE, and 15 from the Cochrane Library. Of them, 112 articles about systematic re- view were excluded and 2941 articles which did not meet our eligibility criteria were excluded after reviewing of the title and abstract, leaving 151 studies for review of full papers. Of these, 127 articles were exclud- ed because of lack of ROSC data or survival to hospital discharge data, data including children and adults or including patients with out-of- hospital cardiac arrest, or data including pre-2005. Two additional arti- cles were identified in a manual search [14,15]. Finally, a total of 24 studies were included in the meta-analysis. The data from 1 study [16] were split into both the 2005 and the 2010 group because it contained data from both before 2010 and after 2011.

Study characteristics

Table 1 displays the study characteristics and variables used in the meta-analysis. Eight studies were performed in Europe [16-23], 7 in Asia [24-30], 6 in the United States [15,31-35], 2 in Egypt [14,36], and 1 in Brazil [37]. The number of patients in each study ranged from 30 to 48,841, with a total of 77,605 patients in all 24 studies (median, 3104 patients). The mean patient age ranged from 24.5 years in trauma patients to 73.9 years in general patients. Fifteen articles were from a single hospital, 6 were from multiple hospitals, and 4 were from the Na- tional Registry of CPR. Three articles were studies of drug interventions, 8 were of CPR teams, and 13 were general research. Of all studies, 20 were of the 2005 CPR guidelines and 6 were of the 2010 CPR guidelines.

Return of spontaneous circulation

A total of 22 articles recorded integrated ROSC data. A random- effects model was applied because of high heterogeneity (P b .01, I² = 97.9%). Fig. 2 shows a forest plot of the ROSC outcomes of each study, weighting of each study based on sample size, and the meta- analysis results of all studies from 2005 and 2010 CPR guidelines. The ROSC rate after in-hospital CPR was 14%-73%, whereas the overall pooled ROSC rate was 48% (95% CI, 0.41-0.54). The mean ROSC rate for studies of patients treated according to the 2005 CPR guidelines (n = 19, mean = 47%; 95% CI, 0.38-0.57) did not differ significantly from the mean ROSC rate for studies with patients treated according to the 2010 CPR guidelines (n = 5, mean = 48%; 95% CI, 0.38-0.58).

Fig. 3 displays the ROSC rates by study start year. Examined by simple linear regression, there was no absolute increase in ROSC rate between 2006 and 2012 (? = -0.0039; t = -0.17, P = .866).

Survival to discharge

Twenty-four articles recorded integrated survival to discharge data. The heterogeneity of survival to discharge was P b .01, I² = 98.3%. Fig. 4 shows a forest plot of the rate of survival to discharge of each

Fig. 2. Forest plot of studies reporting ROSC after CPR.

study, weighting of each study based on sample size, and the meta- analysis results of all studies. The rate of survival to discharge following in-hospital CPR was 3%-40% with an overall pooled rate of 15% (95% CI, 0.12-0.18). The mean survival to discharge rate of studies with patients treated according to the 2005 CPR guidelines (n = 19, mean = 15%; 95% CI, 0.10-0.20) did not differ significantly from the mean survival to dis- charge rate of studies with patients treated according to the 2010 CPR guidelines (n = 5, mean = 14%; 95% CI, 0.08-0.20).

Fig. 5 displays the survival to discharge rates by study start year. Examined by simple linear regression, there was no absolute increase in survival to discharge rate between 2006 and 2012 (? = 0.0024, t =

-0.21, P = .838).

Fig. 3. Percentage ROSC by starting year of study.

Survival at 24 hours

Only 3 articles [24,35,36] recorded survival at 24 hours. The 3 studies found 350 survivals at 24 hours in the total number of 1002 cases and respectively ranged from 48 of 380 (13%) [36], 57 of 131 (44%) [24] to

245 of 491 (50%) [35]. The overall pooled survival at 24 hours rate was 36% (95% CI, 0.08-0.63) with meta-analysis.

Neurological outcome

Five articles [17,19,24,35,37] recorded neurological outcomes, but their evaluation criteria of the neurological outcome were not exactly the same. A total of 164 survivors achieved a good neurological recovery in these 5 studies of 1023 cases. The 5 studies found favorable neurolog- ical outcome to be 16 of 268 (6%, achieved 1-Year survival with a cere- bral performance category [CPC] score of 1 or 2) [17], 27 of 131 (21%,

survival at 3 month) [24], 4 of 52 (8%) [19], 12 of 81 (15%) [37] (dis-

charge with a CPC score of 1 or 2), and 105 of 491 (21%, 30-day CPC score of 1 or 2) [35]. The overall pooled neurological outcome rate was 14% (95% CI, 0.06-0.22) with meta-analysis.

Source of heterogeneity

Meta regression analyses were used to explore source of heteroge- neity (Table 2). The multivariate meta-regression analyzed rate of ROSC against guidelines version, continent, time, sample source, and in- tervention and showed no statistically significant relationship with the exception of sample size (P = .030). The rate of survival to discharge showed no statistically significant relationship with these variables.

Discussion

This systematic review reports on the outcomes of more than 77,000 episodes of in-hospital adult cardiac arrest treated according to the

Fig. 4. Forest plot of studies reporting survival to hospital discharge after CPR.

2005 and 2010 CPR guidelines from published data in 24 data sets. Most of the studies reported only Short-term outcomes such as ROSC and hos- pital discharge, and fewer studies examined neurological outcomes. The most striking finding is that there was no significant difference in ROSC or survival to discharge between the 2005 and 2010 CPR guidelines. However, the ROSC of the latter was slightly increased compared with that of the former, which is in line with the goal of the 2010 CPR guide- lines; but the hospital discharge findings were contrary.

According to the 2010 CPR guidelines, the most important evidence-

based recommendations for the performance of BLS are that rescuers should begin CPR with chest compressions rather than rescue breathing, with a strong emphasis on pushing hard to a depth of at least 2 in (5 cm)

Fig. 5. Percentage survival to discharge by starting year of study.

at a rate of at least 100 compressions per minute. To provide effective chest compressions, push hard and push fast [1]; such high-quality chest compressions can indeed increase the ROSC rate. Research shows that the ROSC rates peaked at a compression rate of ~ 125/min and then declined, but a higher survival to hospital discharge rate was not seen [38]. Following BLS curriculum revision after publication of the 2010 guidelines, cardiac arrest was associated with a higher propor- tion of patients achieving ROSC but not survival to discharge [16]. Some research showed that after adjustment for chest compression fraction and depth, compression rates between 100 and 120 per minute were associated with greatest survival to hospital discharge [39]. These data suggest an optimum target of between 100 and 120 compressions per minute. Consistent rates greater than or less than that range appear to reduce survival to discharge [40].

When exceeding a certain range, the faster the compression rate is, the shorter the diastolic time of the heart is, which will lead to a de- crease in blood volume of the heart and reduce the effectiveness of com- pressions. On the other hand, there was an inverse association between depth and compression rate [41], which may imply that the excessive increase of compression speed is difficult to guarantee the depth of compression. For survival to discharge, the study of Stiell et al [42] re- vealed that the maximum survival is at a depth of 45.6 mm (15-mm in- terval with highest survival between 40.3 and 55.3 mm) with no differences between men and women, suggesting that the 2010 American Heart Association cardiopulmonary resuscitation guideline target may be too high. Vadeboncoeur et al [43] assessed that each 5- mm increase in mean chest compressions depth significantly increased the odds of survival and survival with favorable functional outcome: odds ratio = 1.29 (95% CI, 1.00-1.65) and odds ratio = 1.30 (95% CI, 1.00-1.70), respectively.

chest compression depth and rate were associated with ROSC and survival outcomes. Our goal after CPR is to have higher ROSC rates and better neurological function, but this meta-analysis was unable to find

Table 2

Multivariate meta-regression for rate of ROSC and survival to hospital discharge

	Meta-regression coefficient (%)	95%CI	P
Return of spontaneous circulation
Guide version (2005 CPR vs 2010 CPR)	16.57	-0.21 to 0.54	.361
Continenta	-00.36	-0.10 to 0.10	.939
Sample sourceb	7.96	-.016 to 0.17	.097
Time to start collecting data	-2.28	-0.11 to 0.07	.597
Interventionc	10.46	-0.07 to 0.28	.214
Sample size (>= 500 vs b500)	-28.74	-0.54 to 0.03	.030
Survival to hospital discharge
Guide version (2005 CPR vs 2010 CPR)	-4.00	-0.25 to 0.17	.691
Continent	-2.75	-0.08 to 0.03	.298
Sample source	-0.40	-0.05 to 0.05	.869
Time to start collecting data	00.08	-0.05 to 0.05	.973
Intervention	-6.32	-0.16 to 0.03	.187
Sample size (>= 500 vs b500)	-0.51	-0.13 to 0.12	.935
a Continent: Europe, Asia, USA, others.

^b Sample source: intensive care unit of hospital, single hospital, multiple hospitals, the National Registry of CPR.

^c Intervention: no intervention, drug interventions, CPR teams or trauma team.

any of these statistical improvements after the change to the 2010 guidelines. On the contrary, in another meta document [44], chest com- pression depth was significantly associated with survival to hospital dis- charge (mean difference between survivors and nonsurvivors, 2.59 mm; 95% CI, 0.71-4.47); and with ROSC (mean difference, 0.99 mm; 95% CI, 0.04-1.93). Within the range of approximately 100- 120 compressions per minute, compression rate was significantly asso- ciated with survival to hospital discharge. Moreover, hospital discharge is related to the patient’s own disease, follow-up treatment, and hypox- ia time during CPR process [6].

This review showed that overall pooled rate of hospital discharge from in-hospital CPR does not appear to be different after 2010. But for out-of-hospital cardiac arrest, overall rates of survival improved dra- matically with accompanying lower rates of neurological disability, as well as increasing rates of bystander CPR and automated external defi- brillator use during the study period [4]. One reason that the 2010 guidelines might make a difference in out-of-hospital but not in- hospital is that bystanders who are not health care professionals and who do not have Personal protective equipment available are hesitant to provide mouth-to-mouth resuscitation to strangers, whereas in a health care setting, responders have gloves, masks, etc, and can treat the airway with bag valve masks or intubation while avoiding skin-to- skin contact. Another reason might be that often in-hospital arrests have large code response teams, so someone is able to provide continu- ous compressions while a second person is able to provide respirations simultaneously. How to get higher ROSC rates and better outcomes are areas which deserve more discussion.

This review is based on observational, real-world clinical data from 5 continents. In heterogeneity analysis, the rate of ROSC is not related to CPR guidelines version, continent, time, sample source, or intervention. In the future, studies on CPR from large databases are a way to reduce heterogeneity because sample size is one of the sources of heterogeneity.

Study limitations

However, these individual studies had potential limitations. First of all, only reports in English literature were included in our study, which led to the loss of raw data from reports in other languages. There were 2 studies in other languages that were excluded. We also ex- cluded 2 documents [45,46] because their data come from Get With The Guidelines–Resuscitation (2000-2010), which is the same as the study of Chan et al [32] (2007-2010). Only 5 studies examined the 2010 CPR guidelines. Another limitation is that we do not know when hospitals retrained their staff. Likely, there was a fair amount of lag between the announcement of the new guidelines in December 2010 and when hos- pital staff would have started using the new guidelines. Selection bias

and confounding seem inevitable because most of the research is from observational studies. Other potential sources of heterogeneity included race, discharge standards, and other specific sources such as hospital size, hospital quality, lag time between arrest and code response, and who responded to the code (nurse, physician, resident). Such heteroge- neity should be considered in any meta-analysis.

Conclusions

In conclusion, the 2010 CPR guidelines emphasize that high-quality chest compressions can increase the ROSC rate when initiated early without delaying for airway interventions; however, this change to the 2010 guidelines has not improved ROSC rates or survival-to- discharge for in-hospital cardiac arrest when compared with 2005 CPR guidelines. It is worth considering that appropriate compression rate and depth appear to have stronger evidence for improvement in outcomes of cardiopulmonary resuscitation.

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