Aminophylline for bradyasystolic cardiac arrest in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this systematic review is to determine the effects of aminophylline for the treatment of patients in bradyasystolic cardiac arrest.
Background
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 disorganized 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). Less than 10% of patients suffering cardiac arrest (all rhythms) survive to discharge from hospital (Kette 1998). The outlook is more dismal for patients in asystole with fewer than 3% surviving, although this group accounts for at least 17% of cardiac arrest survivors overall (Pepe 1993). Interventions to improve outcomes in this group may have a significant impact in terms of lives saved.
Adenosine is an endogenous nucleotide which plays a role in the regulation of myocardial oxygen supply and demand (Mader 2000). In periods of cellular hypoxia, production of adenosine increases leading to accumulation in ischemic cardiac muscle. In what is ordinarily believed to be a cardio‐protective mechanism, adenosine acts to increase oxygen supply through coronary vasodilation and diminish oxygen demand by reducing pacemaker activity, blocking conduction at the AV node, and attenuating the response to catecholamines (Belardinelli 1995; Dobson 1983; Mader 2000; Malcolm 1993; Schrader 1977; Wesley 1989). These actions in the setting of cardiac ischemia 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 antagonist of adenosine (Mader 1997). Based on the pathophysiology, from an early case series and several case reports aminophylline appears to be a promising therapy for atropine resistant bradyasystolic arrest (Lee 2000; Mader 2000; Perouansky 1998; Viskin 1993).
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. Interestingly, ILCOR could not reach a consensus on the definition of asystole or bradyasystole (Jacobs 2004).
We propose to perform a systematic review and a meta‐analysis of trials of aminophylline for the treatment of bradyasystolic cardiac arrest.
Objectives
The objective of this systematic review is to determine the effects of aminophylline for the treatment of patients in bradyasystolic cardiac arrest.
Methods
Criteria for considering studies for this review
Types of studies
To be considered, clinical studies must be randomized controlled trials.
Types of participants
Only studies which include adult patients (16 years of age or older) with non‐traumatic, normothermic bradyasystolic cardiac arrest. Bradyasystole must be present at the time of administration of aminophylline.
Types of interventions
All patients must be randomized to receive treatment with either intravenous aminophylline or placebo during the resuscitation, in addition to standard advanced cardiac life support (ACLS). Depending on the preceding cardiac rhythms, standard care might include atropine, epinephrine and/or vasopressin. We will not be analysing the combinations of drugs with which aminophylline is combined. However, an a priori subgroup is planned to assess whether aminophylline was administered along with standard care (early in the resuscitation) or after standard care (late in the resuscitation).
Types of outcome measures
The primary outcome will be survival to hospital discharge. Secondary outcomes will include return of spontaneous circulation, survival to hospital admission (survived event), and neurologic outcome. These outcomes are defined according to the Utstein‐style guidelines and templates (Jacobs 2004).
Search methods for identification of studies
A comprehensive search on the Cochrane Central Register of Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, CINAHL and LILACS will be completed to identify relevant trials irrespective of language or publication status.
Below is the proposed search strategy for use on CENTRAL on The Cochrane Library, and this will be adapted appropriately for other databases.
#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)
We will use similar terms to search the grey literature through Google Scholar, the CISTI Catalogue and the British Library Public Catalogue. Reference lists of all available primary studies and review articles will be reviewed to identify potentially relevant citations. We will also contact authors of primary studies to inquire about other published or unpublished trials known to them. Scientific advisors for the various pharmaceutical companies that manufacture aminophylline will be contacted for any unpublished or interim results on the use of aminophylline in asystolic arrest. Finally, personal contact with colleagues, collaborators and other researchers working in the field of cardiac arrest and resuscitation will be made to identify potentially relevant studies.
Data collection and analysis
All trials that appear relevant on the basis of title, abstract and MeSH headings will be selected for full review by two reviewers (KH, RG). From the potentially relevant articles identified, these two reviewers will independently review their full text versions to select trials for inclusion in this review. Agreement will be measured using simple agreement and kappa statistics. Disagreement will be resolved by consensus or third party adjudication (KM).
Methodological quality
The methodological quality assessment will be performed by two reviewers (KH, RG) using the criteria recommended by the Cochrane Handbook (Higgins 2005) (A adequate; B: uncertain; C: clearly inadequate):
1. Selection: was the assignment truly randomized? Was the allocation sequence concealed?
2. Blinding: were investigators, patients and caregivers unaware of the treatment assignment?
3. Losses to follow‐up: were all study participants accounted for and analyses carried out in an intention to treat fashion?
The abstractors will not be blinded to the authors or the results of the study. Inter‐rater reliability will be measured by using kappa weighted statistics.
Data extraction
Data for the trials will be extracted independently by two reviewers (KH, KM) and entered into Review Manager software (RevMan 4.2). Data extraction will include the following items:
1. Population: age, sex, etiology of arrest, inclusion and exclusion criteria;
2. Intervention: dose and time to administration of aminophylline;
3. Control: definition of asystolic arrest, duration of resuscitation after administration of aminophylline, definition of neurologic outcome;
4. Outcome: return of spontaneous circulation, survival to admission, survival to discharge, neurologic outcome;
5. Design: method of randomization.
Statistical considerations
We intend to carry out the statistical analyses in an intention‐to‐treat fashion to deal with the "missing data" from individual trials. The data will be evaluated for publication bias using graphical and statistical methods. We will check for publication bias using a funnel plot. If publication bias is present, we will adjust the analysis accordingly. We also plan to assess the effects of the methodological quality of the included studies by using quality weighting based on three criteria: method of assignment; blinding; and losses to follow‐up.
Data will be combined in Review Manager. For dichotomous variables, individual and pooled statistics will be calculated as relative risk (RR) with 95% confidence intervals (95% CI); a random‐effects model will be used when more than five trials are pooled. When fewer trials or no statistically significant heterogeneity is identified, a fixed‐effect model will be employed. Heterogeneity will be assessed using the chi square and the I2 statistic (Higgins 2003). For continuous outcomes, individual and pooled statistics will be calculated as weighted mean differences (WMD) or standardized mean differences (SMD) and 5% CIs using a random‐effects model.
Subgroup analyses
Two subgroup analyses are planned a priori: comparison of results based on whether aminophylline was administered early in the course of the arrest or late and comparison of results based on whether the study followed Utstein‐style reporting guidelines (Cummins 1991; Cummins 1997; Jacobs 2004). We will assess the timing of administration of aminophylline using 5 minutes as the cut point between early and late. We will also assess whether aminophylline was administered in conjunction with standard ACLS care or after failure of ACLS. With respect to use of Utstein‐style reporting, we will consider explicit mention of Utstein‐style reporting in the study or in correspondence with study authors.
Sensitivity analyses
If significant heterogeneity (P < 0.1) exists, the groups will be divided in the following order:
1. Methodological quality: higher versus lower quality assessed
2. Population: duration of arrest
3. Intervention: dosage of aminophylline 250 mg or less versus more than 250 mg; and timing of aminophylline dose (before or after standard ACLS care)
Time frame
The first 3 months will be used to complete the search strategy and obtain manuscripts. In the next month, two reviewers will complete study selection and assess the methodological quality of those meeting inclusion criteria. In the final two months, we will enter the abstracted data into RevMan, conduct the statistical analysis and generate a draft of the report.
