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Aminophylline for bradyasystolic cardiac arrest in adults

  1. Katrina F Hurley1,*,
  2. Kirk Magee2,
  3. Robert Green3

Editorial Group: Cochrane Heart Group

Published Online: 15 AUG 2013

Assessed as up-to-date: 27 MAR 2012

DOI: 10.1002/14651858.CD006781.pub2


How to Cite

Hurley KF, Magee K, Green R. Aminophylline for bradyasystolic cardiac arrest in adults. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006781. DOI: 10.1002/14651858.CD006781.pub2.

Author Information

  1. 1

    IWK Health Centre, Department of Emergency Medicine, Halifax, Nova Scotia, Canada

  2. 2

    Dalhousie University, Department of Emergency Medicine, Halifax, Nova Scotia, Canada

  3. 3

    Dalhousie Univeristy, Co-appointments in Emergency Medicine and Critical Care, Halifax, Canada

*Katrina F Hurley, Department of Emergency Medicine, IWK Health Centre, 5850/5980 University Ave, PO Box 9700, Halifax, Nova Scotia, B3K 6R8, Canada. kfhurley@dal.ca.

Publication History

  1. Publication Status: New
  2. Published Online: 15 AUG 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 
Summary of findings for the main comparison. Aminophylline compared to placebo for bradyasystolic cardiac arrest in adults

Aminophylline compared to placebo for bradyasystolic cardiac arrest in adults

Patient or population: participants with bradyasystolic cardiac arrest in adults
Settings:
Intervention: aminophylline
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboAminophylline

Survival to hospital dischargeStudy populationOR 0.58
(0.12 to 2.74)
1254
(5 studies)
⊕⊕⊕⊝
moderate1,2

6 per 10004 per 1000
(1 to 17)

Moderate

0 per 10000 per 1000
(0 to 0)

Return of spontaneous circulationStudy populationOR 1.15
(0.89 to 1.49)
1254
(5 studies)
⊕⊕⊕⊕
high1

234 per 1000260 per 1000
(214 to 313)

Moderate

200 per 1000223 per 1000
(182 to 271)

Survival to admissionStudy populationOR 0.92
(0.61 to 1.39)
1232
(4 studies)
⊕⊕⊕⊝
moderate2

87 per 100080 per 1000
(55 to 116)

Moderate

100 per 100093 per 1000
(63 to 134)

Early administration of aminophylline: survival to hospital dischargeSee commentSee commentNot estimable37
(2 studies)
⊕⊕⊝⊝
low3

Early administration of aminophylline: survival to hospital admissionStudy populationOR 0.22
(0.02 to 2.36)
37
(2 studies)
⊕⊕⊝⊝
low3

150 per 100037 per 1000
(4 to 294)

Moderate

226 per 100060 per 1000
(6 to 408)

Early administration of aminophylline: return of spontaneous circulationStudy populationOR 1.61
(0.38 to 6.77)
37
(2 studies)
⊕⊕⊝⊝
low3

250 per 1000349 per 1000
(112 to 693)

Moderate

284 per 1000390 per 1000
(131 to 729)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1Dirks 1999 has unclear risk of bias because of limited information about the methodology on which to base the assessment. However, this represents a small number of participants.
2Because of the nature of the event (survival to hospital discharge from cardiac arrest), the "event" is relatively rare (i.e. fewer than 300 events).
3The nature of the outcome required data on the time at which the drug was administered. The subgroup was small and data were available from only 2 of the 5 included studies.

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of the condition

Out-of-hospital cardiac arrest is estimated to occur in 58.9 to 78.8 per 100,000 person-years (Hasegawa 2013). People suffering a cardiac arrest may have complete loss of cardiac electrical activity and heart rhythm (asystole), a slow heart rhythm but no cardiac output or a disorganised rhythm (ventricular fibrillation). Bradyasystole, defined as the absence of cardiac electrical activity confirmed in more than one lead or pulseless electrical activity at a rate of less than 60 beats per minute, is the most commonly recorded initial rhythm in cardiac arrest (Herlitz 1994; Sedgwick 1994; Steill 2004; Vaillancourt 2004). Fewer than 10% of patients suffering cardiac arrest (all rhythms) survive to discharge from hospital (Kette 1998; Hasegawa 2013). Overall survival from "non-shockable" rhythms is estimated to be less than 3% (Thomas 2013). The outlook for asystole, in particular, is more dismal, with fewer than 1% surviving (Steill 2004; Vaillancourt 2004). Interventions to improve outcomes in this group may have a significant impact in terms of lives saved.

Clinical trials on interventions in cardiac arrest have been hindered by variability in data definitions and outcome measures. This has been addressed in part by the Utstein style reporting template for out-of-hospital cardiac arrest from the International Liaison Committee on Resuscitation (ILCOR) (Cummins 1991; Cummins 1997; Jacobs 2004). These guidelines represent an international consensus on the definitions and core data needed to report and study resuscitation for both research purposes and clinical benchmarking. It is interesting to note that ILCOR could not reach a consensus on the definition of asystole or bradyasystole (Jacobs 2004).

 

Description of the intervention

Aminophylline is a complex of theophylline and ethylenediamine. Aminophylline's active metabolite is theophylline, and pharmacokinetic data quoted in product monographs reference the active metabolite rather than the parent compound. These methylxanthines are metabolised by the liver with about 10% excreted (unchanged) by the kidneys (DrugDex). The average plasma half-life is 7 to 9 hours in healthy non-smoking adults and 4 to 5 hours in adult smokers (Rudusky 2005). The median half-life in septic patients is prolonged (18.8 hours). The specific pharmacokinetics of aminophylline administered in the setting of cardiac arrest is not known.

Methylxanthines are known to have numerous drug interactions. Prolonged clearance of theophylline has been particularly reported with cimetidine, macrolide antibiotics and ciprofloxacin. Adverse effects in the setting of cardiac arrest have not been reported.

 

How the intervention might work

Adenosine is an endogenous nucleotide that plays a role in the regulation of myocardial oxygen supply and demand (Mader 2000). In periods of cellular hypoxia, production of adenosine is increased, leading to accumulation in ischaemic cardiac muscle. In what is believed to be a cardioprotective mechanism, adenosine acts to increase oxygen supply through coronary vasodilation and to diminish oxygen demand by reducing intrinsic pacemaker activity, blocking conduction at the atrioventricular (AV) node and attenuating the response to catecholamines (Schrader 1977; Dobson 1983; Wesley 1989; Malcolm 1993; Belardinelli 1995; Mader 2000). These actions in the setting of cardiac ischaemia may lead to bradycardia or bradyasystole resistant to atropine, as it is independent of parasympathetic tone. Furthermore, adenosine diminishes the effectiveness of exogenous catecholamines (Belardinelli 1989; Visentin 1990).

Aminophylline is a competitive nonspecific antagonist of adenosine that potentiates cardiac response to beta-agonists and stimulates endogenous catecholamine release (Rudusky 2005). The pathophysiology of bradyasystolic arrest suggests that intravenous aminophylline may be a promising therapy for patients in whom atropine is ineffective (Mader 2000).

 

Why it is important to do this review

Although reported cases of successful resuscitation with aminophylline generated enthusiasm for this therapy, little has changed with respect to its use in standard care in the last 20 years (Viskin 1993; Perouansky 1998; Lee 2000). To date, a meta-analysis of randomised controlled trials on the use of aminophylline in bradyasystolic arrest has not been done. We propose a systematic review of randomised controlled trials comparing intravenous aminophylline with placebo in participants with bradyasystolic cardiac arrest to determine whether evidence is available to justify adopting aminophylline as a standard therapy in these patients.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

To determine the effects of aminophylline in the treatment of patients in bradyasystolic cardiac arrest, primarily survival to hospital discharge. We also considered survival to admission, return of spontaneous circulation, neurological outcomes and adverse events.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All randomised controlled trials comparing intravenous aminophylline with the administration of placebo.

 

Types of participants

Adult participants (16 years of age or older) with non-traumatic, normothermic bradyasystolic cardiac arrest. Bradyasystole must have been present at the time of administration of aminophylline.

 

Types of interventions

Bradyasystole was defined as the absence of cardiac electrical activity as confirmed in more than one lead or pulseless electrical activity at a rate of fewer than 60 beats per minute. All interventions that compare intravenous aminophylline with placebo during resuscitation from bradyasystolic cardiac arrest were studied, in addition to standard advanced cardiac life support (ACLS). Depending on the preceding cardiac rhythms, standard care may include atropine, epinephrine and/or vasopressin. We did not analyse the combinations of drugs administered along with aminophylline. However, we planned an a priori subgroup to assess whether aminophylline was administered early or late during resuscitation.

 

Types of outcome measures

Primary outcome.

  • Survival to hospital discharge.

Secondary outcomes.

  • Return of spontaneous circulation.
  • Survival to hospital admission (survived event).
  • Neurological outcome.
  • Adverse events.

Survival to hospital discharge, survival to hospital admission and return of spontaneous circulation were defined according to the Utstein style guidelines and templates (Jacobs 2004).

 

Search methods for identification of studies

A comprehensive search was completed to identify relevant trials, irrespective of language and publication status.

We initially searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4, 2009), MEDLINE, EMBASE, CINAHL and LILACS on 26 November 2009 (Appendix 1). These searches were updated in March 2012 (Appendix 2), except for LILACS, which was updated in June 2013 (Appendix 3). We also searched ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP; http://apps.who.int/trialsearch/), using the terms "cardiac arrest" or "asystole" or "bradyasystole" as the condition and "aminophylline" or "adenosine antagonist" as the intervention.

We used similar terms to search the grey literature through Google Scholar, the Canada Institute for Scientific and Technical Information (CISTI) Catalogue and the British Library Public Catalogue. We reviewed reference lists of all available primary studies and review articles to identify potentially relevant citations. We also contacted authors of primary studies to inquire about other published or unpublished trials known to them. Scientific advisors for the pharmaceutical companies that manufacture aminophylline (Omega Laboratories and Hospira Healthcare Corporation) were contacted for any unpublished results on the use of aminophylline in asystolic arrest. Finally, we reviewed reference lists of relevant trials and review articles as well as conference proceedings from the Canadian Association of Emergency Physicians, the American College of Emergency Physicians, the Society for Academic Emergency Medicine and the American Heart Association (1997-2012) and from the European Society of Cardiology (2005-2012).

 

Data collection and analysis

 

Selection of studies

The full list of titles and abstracts retrieved from the searches were screened by two review authors (KFH, RG). All trials that appeared relevant on the basis of title, abstract and MeSH headings were selected for full review (KFH, RG). These two review authors independently reviewed the full-text articles identified as potentially relevant to select trials for inclusion in this review. Disagreement was resolved by consensus or by third party adjudication (KM).

 

Data extraction and management

Data were extracted independently from the trials by two review authors (KFH, KM) and were entered into Review Manager 5 software. Data extraction included the following items.

  • Population: age, sex, etiology of arrest, inclusion and exclusion criteria.
  • Intervention: dose and time to administration of aminophylline.
  • Control: definition of asystolic arrest, duration of resuscitation after administration of aminophylline, definition of neurological outcome.
  • Outcome: return of spontaneous circulation, survival to admission, survival to discharge, neurological outcome, adverse outcomes.
  • Design: method of randomisation.

 

Assessment of risk of bias in included studies

The assessment of risk of bias was performed by two review authors (KFH, RG), using the criteria recommended by theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (low risk, high risk, unclear).

  • Selection: Was the assignment truly randomised? Was the allocation sequence concealed? (selection bias)
  • Blinding: Were investigators, participants and caregivers unaware of the treatment assignment? (detection bias and performance bias)
  • Losses to follow-up: Were all study participants accounted for and analyses carried out in an intention-to-treat fashion? (attrition bias)
  • Reporting: Were all outcomes reported? (reporting bias)

We were not blinded to the identity of study authors or study results.

 

Measures of treatment effect

Data were combined in Review Manager 5. For dichotomous variables, individual and pooled statistics were calculated as risk ratios (RRs) with 95% confidence intervals (95% CIs). We used a fixed-effect model for data synthesis. Heterogeneity was assessed using the Chi2 test and the I2 statistic (Higgins 2003). For continuous outcomes, individual and pooled statistics were calculated as weighted mean differences (WMDs) or standardised mean differences (SMDs) and 5% CIs using a random-effects model.

 

Assessment of reporting biases

We planned to carry out the statistical analyses in an intention-to-treat fashion to deal with the "missing data" from individual trials. The data were evaluated for publication bias using graphical and statistical methods. We checked for publication bias using a funnel plot. We assessed the effects of risk of bias in the included studies by using three criteria: method of assignment, blinding and losses to follow-up.

 

Subgroup analysis and investigation of heterogeneity

Two subgroup analyses were planned a priori: comparison of results based on early administration of aminophylline using five minutes as the cut point between early and late administration. With respect to use of Utstein style reporting, we considered explicit mention of Utstein style reporting in the study or in correspondence with study authors.

 

Sensitivity analysis

Where significant heterogeneity (P < 0.1) existed, the groups were divided by higher versus lower risk of bias assessed.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

 

Results of the search

Structured database searches yielded 285 records. Further online searches through Google and GoogleScholar yielded an additional 21 records. After identifying and removing duplicates, we screened 264 records. Twenty-two articles were retrieved for detailed review. Two authors excluded 14 articles (Characteristics of excluded studies): Nine were Chinese papers that were reported to be randomised trials yet on further inquiry were found not to be prospectively designed (Meng 2001; Ma 2003; Dong 2006; Fu 2006; Jin 2006; Ma 2006; Xiao 2006; Shi 2007; Guo 2008); five articles reported mixed comparisons of aminophylline and epinephrine (Luo 2002; Wu 2002; Luo 2003; Shi 2008; Sun 2009). Two articles were conference abstracts reporting data that were also reported in full text (Mader 2003; Abu-Laban 2006).

Of the remaining studies, five met inclusion criteria for this review (Mader 1997; Dirks 1999; Mader 1999; Mader 2003; Abu-Laban 2006). One study is awaiting further classification (Snell 2000). Despite repeated attempts to make contact with the authors of this study (Snell 2000), which was published in abstract form only, we were unable to garner enough additional methodological information to include any of its data in this review.

See Figure 1 for the study flow diagram.

 FigureFigure 1. Study flow diagram.

 

Included studies

Data from five studies were included in this meta-analysis, and each study's particular features are summarised in Characteristics of included studies.

 

Setting

Each of the five trials included only out-of-hospital arrests and was conducted in an urban, prehospital setting. Trials were conducted in Canada (n = 971, one study), the United States (n = 215, three studies) and Germany (n = 68, one study). Two studies did not report the specific time frame in which they were conducted (Mader 1997; Dirks 1999). The remaining studies were conducted from 1996 to 2003.

 

Participants

The studies focused on adult participants. Abu-Laban 2006 excluded patients younger than 16 years, and each of Mader's studies excluded patients younger than 21 years (Mader 1997; Mader 1999; Mader 2003). Dirks 1999 did not specify the exclusion criteria in his published abstract, although communications with the author confirm that patients younger than 16 years were excluded. All trials excluded patients with suspected traumatic or hypothermic cardiac arrests. Most studies also excluded patients who were pregnant, using theophylline, known to have hypersensitivity to methylxanthines or known to have liver disease. Abu-Laban 2006 further excluded patients who had evidence of haemorrhage or were on renal dialysis.

Mean age of included participants ranged from 65 to 76.8 years. Females represented a minority (377/1186), although this varied from 28.5% (Abu-Laban 2006) to 45% (Mader 2003). Dirks 1999 did not report these data.

Four studies reported data about the presumed cause of the cardiac arrest (Dirks 1999; Mader 1999; Mader 2003; Abu-Laban 2006). Three studies reported that suspected ischaemic cardiac events were the most common cause of the arrest, ranging from 64% to 82% (Dirks 1999; Mader 1999; Abu-Laban 2006). Mader 2003 reported that 20.7% of participants were suspected to have suffered a primary non-ischaemic cardiac event, but that most causes remained "uncertain."

 

Interventions

All trials compared the administration of IV aminophylline with placebo as an adjunct to standard ACLS resuscitation in bradyasystolic cardiac arrest. Four studies used 250 mg doses of aminophylline, and one study used 240 mg doses (Dirks 1999). Four studies required failure of standard ACLS interventions for one to two minutes before the study medication was administered. One study administered aminophylline along with initial doses of epinephrine and atropine (Mader 1999). Mean time to arrival of the paramedic crew ranged from 5.3 to 9.3 minutes. Because of differences in reporting, it is difficult to comment on the time from the event to administration of aminophylline, although the time from arrival of paramedics to administration of aminophylline ranged from 11 to 16.6 minutes (Mader 1997; Dirks 1999; Abu-Laban 2006).

 

Risk of bias in included studies

The assessed risk of bias for each study is detailed in the Characteristics of included studies table. In general, the included studies were well-designed randomised, placebo-controlled trials. Random sequence generation was aided by computer (Abu-Laban 2006) or by an investigational drug service (Mader 1997; Mader 1999; Mader 2003). Use of matched syringes, provided by a third party, assisted with both blinding and allocation concealment (Mader 1997; Mader 1999; Mader 2003; Abu-Laban 2006). Risks of performance bias, detection bias and attrition bias were low for four studies (Mader 1997; Mader 1999; Mader 2003; Abu-Laban 2006). The degree of risk associated with randomisation, allocation, blinding and incomplete outcomes data for Dirks 1999 remains "unclear" because the details about study methodology that were available in the published abstract and in the poster provided by the study's lead author were minimal. Further details about methodology could not be obtained from the study's lead author despite repeated attempts to make contact by email. The risk of selective reporting bias was deemed to be low in all studies (Mader 1997; Dirks 1999; Mader 1999; Mader 2003; Abu-Laban 2006) because each study reported the outcomes expected from a cardiac arrest study, namely, return of spontaneous circulation, survival to admission, survival to discharge and neurological outcomes. See Figure 2 and Figure 3 for a summary of risk of bias.

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Effects of interventions

See:  Summary of findings for the main comparison Aminophylline compared to placebo for bradyasystolic cardiac arrest in adults

Few disagreements arose between review authors (KFH, RG) in assessing studies for inclusion, assessing risk of bias or extracting data. Disagreements were readily resolved by discussion to reach consensus. With only five studies included in this systematic review, it is difficult to draw conclusions regarding the funnel plot. For example, only two studies included participants who experienced the primary outcome (survival to hospital discharge). The funnel plot for "return of spontaneous circulation" was asymmetrical, possibly suggesting a publication bias (Figure 4). It is unlikely that smaller studies whose results favoured placebo would have significantly affected the pooled results of this analysis. All results discussed below are given as pooled risk ratio (RR) and its 95% confidence interval (CI) for aminophylline versus placebo.

 FigureFigure 4. Funnel plot of comparison: 1 Aminophylline versus placebo, outcome: 1.2 Return of spontaneous circulation.

 

Survival to discharge

All studies (including 1254 participants) reported survival to hospital discharge-the primary outcome. These findings were homogeneous (Chi2 = 0.08, degrees of freedom (df) = 1, P = 0.77). This event was rare, with only six survivors in total. We are reporting the analyses using a fixed-effect model. As seen in  Analysis 1.1, aminophylline was found to have no effect (RR 0.58, 95% CI 0.12 to 2.74). No change in the results was noted when a random-effects model was used. Dirks 1999 reported that their lone survivor was still alive at six months post event. Four survivors in Abu-Laban 2006 were still alive at one year, and one refused follow-up after discharge from the hospital.

 

Survival to admission

Data on the secondary outcome-survival to hospital admission-were found to be homogeneous (Chi2 = 2.73, df = 3, P = 0.43). Aminophylline was found to have no effect on this secondary survival outcome ( Analysis 1.3: RR 0.92, 95% CI 0.61 to 1.39).

 

Return of spontaneous circulation

Data on return of spontaneous circulation were also found to be homogeneous (Chi2 = 2.41, df = 4, P = 0.66). Aminophylline was found to have no effect on return of spontaneous circulation ( Analysis 1.2: RR 1.15, 95% CI 0.89 to 1.49).

 

Neurologic outcome

Data about neurological outcomes were limited. Abu-Laban 2006 reported that all five survivors had "excellent neurological and functional outcomes", and Dirks 1999 did not comment about the neurological status of the lone survivor in their study.

 

Adverse events

No adverse events were reported (Mader 1997; Dirks 1999; Mader 1999; Mader 2003; Abu-Laban 2006). However, "adverse events" were not specifically mentioned in any data reporting schema that we reviewed.

 

Subgroup analysis

A subgroup analysis was performed on the basis of whether aminophylline was administered early in the resuscitation, using five minutes as the cut point. Data from two studies were used in this analysis. Abu-Laban 2006 provided raw study data and relevant published data were pulled from Mader 1997 for a cumulated total of 37 participants. In this small sample of participants, no one survived to hospital discharge ( Analysis 1.4). Three participants survived to admission ( Analysis 1.5), and 11 had return of spontaneous circulation ( Analysis 1.6). We did not find benefit derived from the use of aminophylline in this subgroup analysis. Subgroup data from the other studies were not available.

 

Sensitivity analysis

The results were unchanged ( Analysis 1.7;  Analysis 1.8;  Analysis 1.9) when data taken only from studies with low risk of bias were selectively pooled (Mader 1997; Mader 1999; Mader 2003; Abu-Laban 2006).

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Summary of main results

This systematic review did not find a survival benefit for the administration of IV aminophylline during adult, out-of-hospital bradyasystolic arrest. We did not find statistically significant heterogeneity between studies. Overall, the studies were well designed and the assessed risk of bias was low. Only one (Abu-Laban 2006) of the five included studies was adequately powered to detect a significant difference in event rates for the primary outcome (return of spontaneous circulation). Because return of spontaneous circulation is a precursor to other survival outcomes and our analysis demonstrated no significant benefit of aminophylline for this outcome, it is reasonable to conclude that a larger study is unlikely to demonstrate significant survival benefit. Nonetheless, no study was powered to detect a significant difference in our primary outcome-survival to hospital discharge. Given the relative rarity of survival to hospital admission ( Analysis 1.3) and survival to hospital discharge ( Analysis 1.1), drawing conclusions about neurological status and adverse events is problematic as well.

Because the studies included in this review were performed in the prehospital setting, the duration of arrest before administration of aminophylline was significant, with mean times from paramedic arrival to administration of study drug as long as 16 minutes (Mader 1997; Abu-Laban 2006). The subgroup analysis considered the effects of early administration of aminophylline but included only 37 participants with no survivors to hospital discharge (primary outcome). Mader 1999 looked specifically at early administration, with mean times (from diagnosis of asystole to administration of study drug) less than five minutes. However, the mean time from dispatch to arrival to the scene in this population, where 49% of arrests were witnessed, was 6.5 minutes, suggesting that the duration of arrest before aminophylline exceeded ten minutes for most participants. This study accumulated 82 participants, none of whom survived. Hence, the effect of early administration of aminophylline remains unknown.

The unadjusted survival for adult out-of-hospital cardiac arrest in a large population-based registry was 4.9% (Hasegawa 2013). Patients presenting in "unshockable" rhythms such as asystole and pulseless electrical activity typically have a poorer prognosis (Thomas 2013). The survival rate in this meta-analysis, which is derived primarily from a large Canadian study (Abu-Laban 2006), is in keeping with other published Canadian data (Steill 2004; Vaillancourt 2004). Survival from in-hospital adult asystolic arrest appears to be in the range of 10%, with good neurological outcomes reported in 61% of survivors (Morrison 2013). The improved survival in this population may be attributable, in part, to the rapid onset of resuscitative efforts when a patient suffering a cardiac arrest is both monitored and witnessed (Brady 2011). Although 73% of in-hospital arrests are both monitored and witnessed, out-of-hospital arrests are witnessed by a health care provider in fewer than 9% of cases (Brady 2011; Hasegawa 2013). Use of aminophylline has not been studied in the "in-hospital" cardiac arrest population.

As part of the search strategy, a number of Chinese language studies were recovered, most of which were found through extensive searching in Google and Google Scholar. Some studies have noted the poor quality of reporting of randomised controlled trials in leading medical journals and conference proceedings in China (Xu 2008; Duan 2009; Chen 2010). One study found that only 6.8% of apparent randomised controlled trials in China were authentic randomised controlled trials (Wu 2009). We asked the lead author of that study to assess whether the "apparent" randomised controlled trials that we identified were "authentic" and found that nine of them were not prospectively designed (Meng 2001; Ma 2003; Dong 2006; Fu 2006; Jin 2006; Ma 2006; Xiao 2006; Shi 2007; Guo 2008). None of the trials based in China met the criteria to be included in this review.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

Although the mechanistic investigations and early case reports were promising, available data from well-designed randomised controlled trials do not warrant the addition of intravenous aminophylline to standard advanced cardiac life support algorithms for out-of-hospital bradyasystolic arrest at this time.

 
Implications for research

Further research on administration of aminophylline in prehospital bradyasystolic arrest may not be justified. The low event rate for important outcomes such as survival to discharge dictates the need for larger trials to detect a difference. The data on use of aminophylline early in resuscitative efforts are not adequate to show whether it is effective. Future research directed towards a more carefully selected population of participants, in whom witnessed arrest occurs during prehospital care or in another health care setting where aminophylline can be administered quickly, may more aptly demonstrate its potential.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

The review authors would like to thank Dr Taixiang Wu of the Chinese Cochrane Centre for assisting us in assessing the "apparent" randomised controlled trials that we found.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Aminophylline vs. placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Survival to hospital discharge51254Odds Ratio (M-H, Fixed, 95% CI)0.58 [0.12, 2.74]

 2 Return of spontaneous circulation51254Odds Ratio (M-H, Fixed, 95% CI)1.15 [0.89, 1.49]

 3 Survival to admission51254Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.61, 1.37]

 4 Early administration of aminophylline: Survival to hospital discharge237Odds Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Early administration of aminophylline: Survival to hospital admission237Odds Ratio (M-H, Fixed, 95% CI)0.22 [0.02, 2.36]

 6 Early administration of aminophylline: Return of spontaneous circulation237Odds Ratio (M-H, Fixed, 95% CI)1.61 [0.38, 6.77]

 7 Sensitivity analysis: survival to discharge41186Odds Ratio (M-H, Fixed, 95% CI)0.66 [0.11, 3.99]

 8 Sensitivity analysis: survival to admission41186Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.52, 1.25]

 9 Sensitivity analysis: return of spontaneous circulation41186Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.86, 1.48]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Search strategies 2009

 

CENTRAL

#1 MeSH descriptor heart arrest explode all trees
#2 heart next arrest*
#3 cardiac next arrest*
#4 cardiopulmonary next arrest*
#5 sudden next cardiac next death
#6 asystol*
#7 MeSH descriptor Cardiopulmonary Resuscitation explode all trees
#8 resuscitat*
#9 Bradyasystol*
#10 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9)
#11 MeSH descriptor aminophylline explode all trees
#12 aminophyllin*
#13 MeSH descriptor Adenosine explode all trees with qualifier: AI
#14 adenosine next antagonist*
#15 adenosine next inhibitor*
#16 (Adenosine near/6 Block* )
#17 (#11 or #12 or #13 or #14 or #15 or #16)
#18 (#10 and #17)

 

MEDLINE

#1 "Death, Sudden, Cardiac"[Mesh] OR "Cardiopulmonary Resuscitation"[Mesh] OR "Heart Arrest"[Mesh] (29885)

#2 "sudden cardiac death" or "cardiopulmonary resuscitation" or "heart arrest" or "cardiac arrest" or asystol* (43164)

#3 #1 OR #2 (47970)

#4 "Aminophylline"[Mesh] OR "Adenosine/antagonists and inhibitors"[Mesh] (4723)

#5 Aminophylline (4984)

#6 #4 OR #5 (5816)

#7 #3 AND #6 (57)

#8 #3 AND #6 Limits: Humans (41)

 

EMBASE

#1. 'sudden death'/exp OR 'resuscitation'/exp OR 'heart arrest'/exp (85,049)

#2. 'sudden cardiac death'/exp OR 'sudden cardiac death' OR 'cardiopulmonary resuscitation'/exp OR 'cardiopulmonary resuscitation' OR 'heart arrest'/exp OR 'heart arrest' OR 'cardiac arrest'/exp OR 'cardiac arrest' OR asystol* (94,133)

#3. #1 OR #2 (94,133)

#4. 'aminophylline'/exp OR 'adenosine receptor blocking agent'/exp (18,617)

#5. 'aminophylline'/exp OR aminophylline (12,594)

#6. #4 OR #5 (19,106)

#7. #3 AND #6 (268)

#8. #7 AND [humans]/lim (204)

 

CINAHL

S1 (MH "Death, Sudden, Cardiac") or (MH "Resuscitation, Cardiopulmonary+") or (MH "Heart Arrest) (7943)

S2 "sudden cardiac death" or "cardiopulmonary resuscitation" or "heart arrest" or "cardiac arrest" or asystol* (6080)

S3 S1 or S2 (9378)

S4 (MH "Aminophylline") or (MH "Adenosine/AI") (111)

S5 aminophylline (130)

S6 S4 or S5 (149)

S7 (S4 or S5) and (S3 and S6) (15)

 

LILACS

Search words included combinations of:

asystole (405) or bradyasystole (0) or cardiac arrest (399) or heart arrest (399)

AND

aminophylline (77) or (adenosine AND antagonist) (10)

Yeild: 1 citation

 

Appendix 2. Search strategies 2012

 

CENTRAL (search restricted to years 2009-2012)

#1           MeSH descriptor Heart Arrest explode all trees

#2           (heart next arrest*)

#3           (cardiac next arrest*)

#4           (cardiopulmonary next arrest*)

#5           "sudden cardiac death"

#6           (asystol*)

#7           MeSH descriptor Cardiopulmonary Resuscitation explode all trees

#8           (resuscitat*)

#9           (Bradyasystol*)

#10         (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9)

#11         MeSH descriptor Aminophylline explode all trees

#12         aminophyllin*

#13         MeSH descriptor Adenosine explode all trees

#14         (adenosine next antagonist*)

#15         (adenosine next inhibitor*)

#16         (Adenosine near/6 Block* )

#17         (#11 OR #12 OR #13 OR #14 OR #15 OR #16)

#18         (#10 AND #17)

 

MEDLINE (OVID)

Cochrane sensitive-maximising RCT filter applied (Handbook 2011)

 1     Heart Arrest/ (20420)

2     heart arrest*.tw. (572)

3     cardiac arrest*.tw. (16709)

4     cardiopulmonary arrest*.tw. (1314)

5     "sudden  cardiac death".tw. (7255)

6     asystol*.tw. (2762)

7     exp Cardiopulmonary Resuscitation/ (9801)

8     resuscitat*.tw. (36321)

9     Bradyasystol*.tw. (35)

10     or/1-9 (65110)

11     exp Aminophylline/ (3957)

12     aminophyllin*.tw. (3243)

13     Adenosine/ or Adenosine A1 Receptor Antagonists/ or Receptor, Adenosine A1/ (24221)

14     adenosine antagonist*.tw. (702)

15     adenosine inhibitor*.tw. (31)

16     or/11-15 (29166)

17     randomized controlled trial.pt. (321630)

18     controlled clinical trial.pt. (83679)

19     randomized.ab. (226659)

20     placebo.ab. (129223)

21     drug therapy.fs. (1511329)

22     randomly.ab. (163835)

23     trial.ab. (233719)

24     groups.ab. (1080338)

25     17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 (2803360)

26     exp animals/ not humans.sh. (3683920)

27     25 not 26 (2379403)

28     10 and 16 and 27 (80)

 

EMBASE (OVID)

Cochrane RCT filter (Handbook 2011)

1     Heart Arrest/ (34654)

2     heart arrest*.tw. (553)

3     cardiac arrest*.tw. (21853)

4     cardiopulmonary arrest*.tw. (1693)

5     "sudden  cardiac death".tw. (10360)

6     asystol*.tw. (3562)

7     exp Cardiopulmonary Resuscitation/ (51750)

8     resuscitat*.tw. (45607)

9     Bradyasystol*.tw. (42)

10     or/1-9 (103904)

11     exp Aminophylline/ (10575)

12     aminophyllin*.tw. (3639)

13     Adenosine/ or Adenosine A1 Receptor Antagonists/ or Receptor, Adenosine A1/ (31627)

14     adenosine antagonist*.tw. (829)

15     adenosine inhibitor*.tw. (37)

16     or/11-15 (42425)

17     random$.tw. (711168)

18     factorial$.tw. (18452)

19     crossover$.tw. (41977)

20     cross over$.tw. (18657)

21     cross-over$.tw. (18657)

22     placebo$.tw. (171422)

23     (doubl$ adj blind$).tw. (125724)

24     (singl$ adj blind$).tw. (11915)

25     assign$.tw. (199022)

26     allocat$.tw. (66529)

27     volunteer$.tw. (153413)

28     crossover procedure/ (33346)

29     double blind procedure/ (107813)

30     randomized controlled trial/ (318508)

31     single blind procedure/ (15595)

32     17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 (1177109)

33     (animal/ or nonhuman/) not human/ (4404105)

34     32 not 33 (1032782)

35     10 and 16 and 34 (44)

 

CINAHL (EBSCO)

S1           (MH "Heart Arrest+")

S2           "heart arrest*"

S3           "cardiac arrest*"

S4           "sudden cardiac death"

S5           asystol*

S6           (MH "Resuscitation, Cardiopulmonary+")

S7           resuscitat*

S8           Bradyasystol*

S9           S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8

S10         (MH "Aminophylline") 

S11         aminophyllin*

S12         (MH "Adenosine+")

S13         "adenosine antagonist*"

S14         "adenosine inhibitor*"

S15         Adenosine N6 Block*

S16         S10 or S11 or S12 or S13 or S14 or S15

S17         S9 and S16

S18         (singl* blind*)

S19         (doubl* blind*)

S20         (tripl* blind*)

S21         (trebl* blind*)

S22         (trebl* mask*) or (tripl* mask*) or (doubl* mask*) or (singl* mask*)

S23         (randomi?ed control* trial*)

S24         (MH "Random Assignment")

S25         (random* allocat*)

S26         (MH "Placebos")

S27         (MH "Quantitative Studies")

S28         (allocat* random*)

S29         S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28

S30         S17 and S29

 

Appendix 3. Search strategies 2013

 

LILACS

asystole (405) or bradyasystole (0) or cardiac arrest (399) or heart arrest (399)

AND

aminophylline (77) or (adenosine AND antagonist) (10)

Yeild: 1 citation

 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Protocol first published: Issue 4, 2007
Review first published: Issue 8, 2013


DateEventDescription

8 September 2008AmendedConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Served as guarantor of the review: Dr Hurley
Drafted the protocol: Drs Hurley and Magee
Searched for trials: Dr Hurley
Obtained copies of trials: Dr Hurley
Selected which trials to include: Drs Hurley, Green & Magee
Extracted data from trials: Drs Hurley, Green & Magee
Entered data into RevMan: Drs Hurley & Magee
Carried out the analysis: Drs Hurley & Magee
Interpreted the analysis: Drs Hurley, Magee & Green
Drafted the final review: Drs Hurley, Green & Magee
Updated the review: Dr Hurley

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • Dalhousie University, Canada.

 

External sources

  • No sources of support supplied

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. Additional references
Abu-Laban 2006 {published and unpublished data}
  • Abu-Laban RB, McIntyre CM, Christenson JM, van Beek CA, Innes GD, O'Brien R, et al. Aminophylline in bradyasystolic cardiac arrest: a randomized placebo-controlled trial. Academic Emergency Medicine 2004;11(5):435.
  • Abu-Laban RB, McIntyre CM, Christenson JM, van Beek CA, Innes GD, O'Brien RK, et al. Aminophylline in bradyasystolic cardiac arrest: a randomised placebo-controlled trial. Lancet 2006;367(9522):1577-84. [PUBMED: 16698410]
Dirks 1999 {published and unpublished data}
  • Dirks B, Lindner K. Randomized comparison using aminophylline vs. placebo patients in out-of-hospital cardiac arrest with asystole or pulseless electrical activity. Circulation 1999;100(18 (Suppl I)):I-314.
Mader 1997 {published data only (unpublished sought but not used)}
Mader 1999 {published data only (unpublished sought but not used)}
Mader 2003 {published data only (unpublished sought but not used)}
  • Mader TJ, Durkin LJ, Smithline HA, Stevens M. Aminophylline in atropine-resistant asystolic out-of-hospital cardiac arrest. Academic Emergency Medicine 2002;9(5):357.
  • Mader TJ, Smithline HA, Durkin L, Scriver G. A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest. Acad Emerg Med 2003;10(3):192-7. [PUBMED: 12615581]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. Additional references
Dong 2006 {published data only}
  • Dong L, Jiang J. Clinical study of aminophylline on the treatment of cardiac arrest patient who are invalid with epinephrine. Practical Clinical Medicine 2006;7(10):33-5.
Fu 2006 {published data only}
  • Fu XH, Zhou GP, Zhu QY, Ma B, Chen C. A clinical survey for aminophylline and epinephrine for 30 patients with cardiac arrest. Jiangxi Medicine 2006;41(12):981-2.
Guo 2008 {published data only}
  • Guo XF. Effective observation on treatment of 30 cases with respiratory and cardiac arrest by aminophylline. J Henan Univ Sci Tech (Med Sci) 2008;26(1):32-3.
Jin 2006 {published data only}
  • Jin RH, Ma SZ, Li QL. Clinical research on joined application with aminophylline in early period of cardiac arrest. Lingnan Journal of Emergency Medicine 2006;11(3):161-2.
Luo 2002 {published data only}
  • Luo ZC, Ling ZX, Wang PF. Study on administration of epinephrine combined with vasopressin and aminophylline during cardiopulmonary resuscitation. Modern Medical and Health 2002;18(3):170-1.
Luo 2003 {published data only}
  • Luo JL, Wang CT, Pan J, An ZQ. Clinical application of ultra-routine dose epinephrine associated with aminophylline in the patients with cardiac arrest. Modern Medical and Health 2003;19(12):1529-30.
Ma 2003 {published data only}
  • Ma Y, Meng QY, Qian YY, Zhizhong W, Tong G, Jinming L. Clinical effect of aminophylline associating with epinephrine on the treatment of cardiac arrest. Chinese Journal of Critical Care Medicine 2003;23(4):232-3.
Ma 2006 {published data only}
  • Ma SZ, Jin RH, Zhang YM. Patients with cardiac arrest early in conjunction with aminophylline and epinephrine effect. Practical Clinical Medicine 2006;7(5):42-3.
Meng 2001 {published data only}
  • Meng QY, Lai H, Lai SH. Resuscitation using aminophylline in cardiac arrest refractory to epinephrine and atropine: results of a 32 patient study. Canadian Journal of Cardiology 2001;17(11 Suppl C):210C.
Shi 2007 {published data only}
  • Shi QB, Huang X, Zhang FX, Wang SY, Wang GE, Sun GL. The application value study of the aminophylline and epinephrine with uniform method at the same time and rapidly combination on cardiopulmonary resuscitation. China J Postgrad Med 2007;30(1):18-21.
Shi 2008 {published data only}
  • Shi QB, Zhang FX, Wang GE, Jiang FZ, Xu YS, Huang X. Study on the value of the formula of rapid synchronous stepwise increase in dosage of epinephrine combined with aminophylline (7 mg/kg) in cardiopulmonary resuscitation. Chinese Critical Care Medicine 2008;20(7):409. [PUBMED: 18611339]
Sun 2009 {published data only}
  • Sun Y. Clinical study on rapidly and synchronously using epinephrine in combination with aminophylline for patients undergoing cardiopulmonary resuscitation. Chinese Nurs Res 2009;23(2):322-5.
Wu 2002 {published data only}
  • Wu B, Wang J, Hou Z. Study on administration of epinephrine combined with vasopressin and aminophylline during cardiopulmonary resuscitation. Modern Medicine Health 2002;18(3):170-2.
Xiao 2006 {published data only}
  • Xiao Z, Liu JM, Zhuang JY. The curative effect of epinephrine and aminophylline on cardiopulmonary resuscitation in patients with cardiac arrest onset out of hospital. Medicine World 2006;8:148-50.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. Additional references
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Kette 1998
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Morrison 2013
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Perouansky 1998
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Schrader 1977
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Sedgwick 1994
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Steill 2004
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Thomas 2013
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Vaillancourt 2004
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Visentin 1990
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Viskin 1993
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Wesley 1989
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Wu 2009
Xu 2008