To assess the efficacy and safety between the Standard dose of epinephrine (neonates and children: 0.01 mg per kilogram per time; adults:1mg per time) and the high-dose epinephrine (neonates and children :>0.1 mg per kilogram per time; adults:>1mg per time) in a cardiopulmonary resuscitation.
To assess the efficacy and safety of the accumulated maximum dosage of epinephrine in a cardiopulmonary resuscitation.
Searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (accessed 1 September 2012), MEDLINE (1966 to September week 1, 2012) and EMBASE (1974 to September2012).
To increase the yield of relevant studies, references of all identified studies were searched. We looked for any ongoing trials registered with the World Health Organization (WHO) International Clinical Trials Register. There were no language or publication restrictions.
Types of study to be included
Randomized controlled trials or controlled clinical trials, parallel design
Condition or domain being studied
Cardiac arrest, (also known as cardiopulmonary arrest or circulatory arrest) is the cessation of normal circulation of the blood due to failure of the heart to contract effectively (Jameson 2005). It remains a serious health concern in the world, and in North America there was an estimated 300,000 cases annually (zhong 2005). Despite the rigorous algorithms for cardiopulmonary resuscitation (CPR) and advance cardiac life support (ACLS), the reported survival rates following cardiac arrest remain low, ranging from 2 to 24% (Stiell 2004; Becker 1991; Horsted 2004; Rudiger 2004). Epinephrine has been the first-line pharmacologic agent in the treatment of cardiac arrest refractory for approximately 100 years (Gottlieb 1897), although it increases myocardial oxygen consumption during CPR and increases the likelihood of cardiac failure after restoration of spontaneous circulation (Paradis 2002).
As the main drug for CPR, the dose of epinephrine has been controversial. In 1992, the American Heart Association recommended that the first epinephrine IV dose is 0.01 mg per kilogram(standard dose), the second and subsequent doses “should be 0.1 mg per kilogram (high-dose)” in children, while in adult ,the first IV dose is 1mg (standard dose), and then should be 3mg, 5mg (high-dose) (Guidelines 1992). However, the latest American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science(2010) recommended IV dose is 0.01 to 0.03 mg/kg per dose (standard dose) in children and 1mg per dose (standard dose) in adult every 3 to 5 minutes during cardiac arrest (Guidelines 2010).
Participants/ population
Participants who were implemented of CPR will be eligible for entry into the study. CPR is an emergency procedure which is performed in an effort to manually preserve intact brain function until further measures are taken to restore spontaneous blood circulation and breathing in a person in cardiac arrest. It is also indicated in those who are unresponsive with no breathing or abnormal breathing, for example agonal respirations. CPR involves chest compressions and artificial respirations.
Intervention(s), exposure(s)
1) Standard dose of epinephrine (neonates and children: 0.01 mg per kilogram per dose; adults:1mg per dose) + routine treatments
Comparison: high-dose epinephrine (neonates and children :>0.1 mg per kilogram per dose; adults:>1mg per dose) + routine treatments
2) Comparison between the different total doses of epinephrine.
Comparator(s)/ control
Standard dose of epinephrine (neonates and children: 0.01 mg per 1) Standard dose of epinephrine (neonates and children: 0.01 mg per kilogram per dose; adults:1mg per dose) + routine treatments
Comparison: high-dose epinephrine (neonates and children :>0.1 mg per kilogram per dose; adults:>1mg per dose) + routine treatments
2) Comparison between the different total doses of epinephrine
Outcome(s)
Primary outcomes
1.the rate of return of spontaneous circulation?
2.the rate of survival at 24 hours
3.the rate of Survival to hospital discharge
Secondary outcomes
1.the incidence of arrhythmia
2.the rate of disability
Risk of bias (quality) assessment
Dealing with missing data: We performed sensitivity analyses to assess how sensitive results are to reasonable changes in the assumptions that are made. For all outcomes we carried out analyses, as far as possible, on an intention-to-treat basis.
Assessment of heterogeneity: We used a Chi-squared test of heterogeneity and the I-squared statistic measure of inconsistency to quantify the level of statistical heterogeneity for each outcome. The Chi-squared test assesses whether observed differences in results are compatible with chance alone. A low P value (or a large Chi-squared statistic relative to its degree of freedom) provides evidence of heterogeneity of intervention effects (variation in effect estimates beyond chance). A useful statistic for quantifying inconsistency is the I-squared (measure of inconsistency). A rough guide to interpretation of the I-squared statistic is as follows: 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity (Higgins 2011).We performed a fixed-effect meta-analysis where no heterogeneity was present. We considered possible explanations where substantial heterogeneity ( I-squared statistic above 50%) was detected and where applicable, we used a random-effects model to test the robustness of the findings, or considered not combining the results and presenting a descriptive analysis instead.We also investigated heterogeneity through subgroup and sensitivity analyses.
Assessment of reporting biases: We searched comprehensively for studies that met the eligibility criteria for this review to avoid reporting bias. We excluded the study reports that may selectively present results, reference lists may selectively cite sources and duplicate publication of results can be difficult to spot. Furthermore, in order to reduce reporting biases caused by time-lag bias, we included unpublished studies and trial registries. Prospective trial registration has the potential to substantially reduce the effects of publication bias.Small study effects are one of the possible causes of publication bias. When there was evidence of small study effects we attempted a funnel plot to understand the source of the small study effects and considered their implications in sensitivity analyses.
Strategy for data synthesis
We estimated risk ratios (RR) and 95% confidence intervals (CI) for dichotomous data. We used fixed-effect inverse variance meta-analysis for combining data where trials are examining the same intervention, and the trials' populations and methods are judged sufficiently similar. Where we suspect clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials, we used random-effects meta-analysis. If substantial heterogeneity is identified in a fixed-effect meta-analysis, we noted this and repeat the analysis using a random-effects method.
Analysis of subgroups or subsets
In order to assess the impact of these possible sources of heterogeneity, We performed subgroup analyses for the following groups:
Neonates(0-28d)/Children(29d-18y)/Adult(>18y).
Dissemination plans
Although some randomised studies and guidelines have suggested that there is no benefit of high-dose epinephrine rescue therapy for cardiacarrest after failure of an initial standard dose of epinephrine, we have been unable to identify meta-analyses or systematic reviews on epinephrine for cardiopulmonary resuscitation.
Contact details for further information
Shan Gao
Department of Paediatrics, West China Second University Hospital, Sichuan University.
No. 17 Section Three, Ren Min Nan Lu Avenue Chengdu China 610041
huaxigaoshan@163.com
Organisational affiliation of the review
West China Second University Hospital, Sichuan University.
http://www.motherchildren.com/
Review team
Dr Shan Gao, Pediatrician Dr Chaomin Wan, Professor, Director of paediatric department Dr Rong Luo, Professor, Director of paediatric department
Formal screening of search results against eligibility criteria
Data extraction
Risk of bias (quality) assessment
Data analysis
Prospective meta-analysis
PROSPERO This information has been provided by the named contact for this review. CRD has accepted this information in good faith and registered the review in PROSPERO. CRD bears no responsibility or liability for the content of this registration record, any associated files or external websites.
