Adrenaline for the treatment of anaphylaxis with and without shock
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the benefits and harms of adrenaline (epinephrine) in the treatment of anaphylaxis.
Background
Anaphylaxis is a potentially life‐threatening acute systemic allergic reaction with many possible trigger factors, including foods, insect venoms, medications, anaesthetics, latex and exercise (Brown 2001; Brown 2004a; Kemp 2002; Lieberman 2003; Sampson 2005; Simons 2002). Historically, it has been defined mechanistically as an immediate hypersensitivity reaction involving the release of mediators from mast cells and basophils following allergen interaction with cell bound immunoglobulin E (IgE), and therefore exclusive of non‐IgE‐mediated (anaphylactoid) reactions. This distinction is however now seldom used as the clinical picture and treatment of anaphylaxis are similar regardless of pathophysiologic mechanism (Kemp 2002; Lieberman 2003; Sampson 2006).
Anaphylaxis is not a reportable disease, and the true incidence is unknown (Bohlke 2004; Hebling 2004; Klein 1995; Lieberman 2006; Neugut 2001; Peng 2004; Sheikh 2001). Estimated incidence in the general population is influenced by definitions, coding issues, and misclassification errors. A population‐based study using data collected in the mid‐1980s calculated an annual incidence of 30 per 100,000 person years and raised the concern that anaphylaxis is frequently not recognized (Yocum 1999). Other studies suggest the true incidence may be up to 590 per 100,000 person years. Anaphylaxis from the four most common triggers (foods, insect venoms, medications, and latex rubber) may affect more than 1% of the general population (Neugut 2001), with considerable variations in age‐specific aetiology (Alves 2001).
Cutaneous symptoms and signs, including generalized urticaria, angioedema, flushing, and itching are the most common manifestations of anaphylaxis (90% of those affected), followed by respiratory symptoms (70%) and gastrointestinal symptoms (40%). Hypotension occurs in 10‐30% (Brown 2001; Brown 2004b; Kemp 2002; Lieberman 2003; Simons 2002). Symptoms often occur within 5 to 30 minutes of exposure to the trigger factor, although occasionally they do not develop for several hours. Anaphylaxis may be fatal within minutes (Pumphrey 2000). The diagnosis of anaphylaxis is based largely on history and physical findings. Laboratory tests have proved to be disappointing in clinical practice. Serum histamine may be elevated but is only reliable when measured within one hour of onset and is not stable during routine handling, so is seldom used (Lin 2000). Serum tryptase level (greater than 15ng/mL) within 12 hours (preferably within 3 hours) of the onset of an episode is more widely used as a confirmatory test. True mortality rates in anaphylaxis are unknown because of under‐recognition and diagnosis of the disease (Pumphrey 2000).
Adrenaline (epinephrine) is generally advocated as the initial treatment of choice for anaphylaxis (McLean‐Tooke 2003; Simons 2004a; Simons 2004b), although the strength of the evidence‐base underpinning this recommendation is unclear.
This initial emergency management may or may not be supervised by a physician or other healthcare professional. When anaphylaxis occurs in the community in a non‐medical setting, the standard of first‐aid treatment is the administration of self‐injectable adrenaline into the lateral thigh using an EpiPen, EpiPen Jr, Anapen, AnaHelp, Twinject, or other adrenaline formulation (Sicherer 2005; Simons 2004a; Simons 2004c). In healthcare settings, the intramuscular &/or intravenous routes are preferred (Brown 2006).
Adrenaline is an alpha‐ and beta‐adrenergic agonist with bidirectional cyclic adenosine monophosphate‐mediated pharmacologic effects on target organs, and a narrow therapeutic index. Adrenaline results in vasoconstriction, increased peripheral vascular resistance, decreased mucosal edema, inotropic and chronotropic effects, bronchodilation, and decreased mediator release from mast cells and basophils. The plasma and tissue concentrations of adrenaline needed for recovery from anaphylaxis have not been defined in humans. Furthermore, there have been no prospective human studies performed to evaluate the bioavailability and optimal dose of adrenaline given intramuscularly (i.m.) during anaphylaxis or to assess the incidence of adverse effects during the management of anaphylaxis. Case reports and large mortality reviews indicate that side effects can be serious, usually in the setting of inappropriate dosing by medical staff (Pumphrey 2000).
Only the intravenous (i.v.) route was used in the two studies that indicate a beneficial treatment effect were for reactions characterized by cardiovascular collapse (Fisher 1978, Brown 2004b). Work in a canine model of severe anaphylactic shock found that the i.m. route is ineffective with a dose of 0.01 mg/kg, that an i.v. bolus of 0.01 mg/kg results in transient improvement, and that i.v. infusion at 0.19‐0.45 mcg/kg/min was the only method to produce a sustained improvement (Bautista 2002; Mink 2004). The therapeutic effect in this model was from positive inotropy, with no increases in either systemic vascular resistance or pulmonary arterial wedge pressure. Thus, for severe reactions at the generally recommended doses, adrenaline on its own might not adequately counteract the effects of vasodilation and distributive‐hypovolaemic shock, even when given as an intravenous infusion.
In summary, the use of adrenaline is based largely on extrapolation and assumption. It is possible that the usually recommended dose and route is useful only for mild‐moderate reactions that would otherwise improve without treatment. Therefore, inappropriate dosing of adrenaline may cause harm more often than lives are saved.
Objectives
To assess the benefits and harms of adrenaline (epinephrine) in the treatment of anaphylaxis.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials comparing adrenaline with no intervention, placebo and other adrenergic agonists. We will also include randomized controlled trials comparing different approaches to the administration of adrenaline.
We will also include quasi‐randomized controlled trials: that is, trials where an attempt to approximate randomisation has been made (e.g. alternate allocation); controlled trials with little attempt to minimise bias during allocation will however not be eligible for inclusion.
Types of participants
We will include all patients (infants, children and adults; community or hospital based) experiencing anaphylaxis caused by food, insect venom, medication, vaccination, latex or any other trigger.
Types of interventions
We will include studies involving any systemic (intravenous, intramuscular, subcutaneous or inhaled from a metered‐dose inhaler or a nebulizer) administration of adrenaline by patient or lay caregiver (of a child) or medical professional. Adrenaline may be administered anywhere in the community, including a physician's office or an ambulance, or anywhere in the hospital, including emergency departments, clinics, wards, operating rooms. It may also be administered after another medication. The comparative treatments of interest are no intervention, placebo, other adrenergic agonists and different treatment approaches to the administration of adrenaline.
Types of outcome measures
Our outcome measures of interest will be:
Primary outcome
1. Death
Secondary outcomes
2. Requirement for second dose of adrenaline
3. Improvement in arterial blood pressure (greater than 50 mmHg systolic)
4. Resolution of symptomatic bronchospasm
5. Resolution of urticaria
6. Admission to hospital
7. Length of emergency department stay
8. Length of hospital stay
9. Re‐presentation for therapy within 24 hours
10. Adverse events due to therapy in either arm
Search methods for identification of studies
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE (1966 to present); EMBASE (1966 to present), CINAHL (1982 to present), BIOSIS (to present), ISI Web of Knowledge (to present) and LILACS (to present).
We will search MEDLINE using Ovid using the Cochrane randomized controlled trial filter (Higgins 2005) and the following key words: anaphyl* and adrenaline. Our full search strategy is detailed in Table 1. We will adapt our search terms for other databases.
| MEDLINE search terms |
| 1. randomized controlled trial.pt. |
We will not apply any language restriction.
In an attempt to uncover additional relevant published data, grey literature, unpublished data and research in progress we will:
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develop a database of first and last authors of potentially eligible studies and The Science Citation Index Expanded (SCI‐EXPANDED, 1945 to 2006) will be searched using these names for additional studies;
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search the bibliographies of identified studies;
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compile a database of international experts in anaphylaxis;
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contact relevant pharmaceutical companies;
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search the UK's National Research Register;
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search websites listing ongoing trials: http://clinicaltrials.gov/ and http://www.controlledtrials.com/ and http://www.actr.org.au/.
Data collection and analysis
Selection of studies
Two authors (YS and AS) will independently review titles and abstracts from literature searches for relevant trials for full review. The full text copies of all potentially eligible studies will be obtained and subjected to independent review using the inclusion criteria detailed above.
We will resolve any disagreements by discussion between both of the authors; in the case of consensus not being reached, a third author (ES) will be involved and, if necessary, will arbitrate.
Data extraction
Two authors (YS and AS) will independently extract data using a suitably adapted version of the data extraction form developed by the Cochrane Anaesthesia Review Group. We will resolve any disagreements by discussion between both of the authors; in the case of consensus not being reached, a third author (ES) will be involved and, if necessary, arbitrate.
Assessment of methodological quality of included studies
We will assess and document the methodological quality of included controlled trials following the Cochrane approach using the methods detailed in section six of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). We will concentrate on using the following five parameters to assess quality: allocation concealment, method of allocation to treatment, documentation of exclusions, completeness of follow‐up, methods of documentation of complications. We will grade each parameter of trial quality : A ‐ low risk of bias; B ‐ moderate risk of bias; C ‐ high risk of bias and an overall assessment for each controlled trial using the same three criteria will be made.
Two authors will independently assess study quality: reviewers will not be masked to study details. The agreement of authors on methodological quality assessment will be assessed; disagreements will be resolved by discussion and, if necessary, with the involvement of a third author (ES).
Data analysis
We will use Review Manager (RevMan 4.2) for data analysis and quantitative data synthesis. For dichotomous data, we will calculate individual and pooled statistics as relative risks (RR) with 95% confidence intervals (95% CI). For continuous data, we will calculate individual and pooled statistics as mean differences (MD) and/or standardized means differences with 95% CI. We will give consideration to the appropriateness of meta‐analysis in the presence of significant clinical or statistical heterogeneity. We will test for heterogeneity using the I2 statistic and significant heterogeneity will be assumed if I2 is greater than 40% (i.e. more than 40% of the variability in outcome between trials could not be explained by sampling variation) (Higgins 2002). We will use a fixed‐effects model in the absence of statistical heterogeneity and a random‐effects model if such heterogeneity is likely. Any statistical or clinical heterogeneity will be explored using sensitivity or subgroup analysis (see below). Quantitative analyses of outcomes will be, wherever possible, on an intention to treat basis. We will assess for evidence of publication bias graphically using Funnel plots and statistically using Begg and Egger tests (Begg 1994; Egger 1997).
Subgroup analysis
In the event of uncovering significant heterogeneity, we will investigate by undertaking sub‐group analyses. Our sub‐groups of interest are:
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presence or absence of shock;
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mild / more severe anaphylaxis (Brown 2004b);
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mode of administration of treatment (intramuscular versus intravenous; patient versus healthcare professional administered);
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time from onset of anaphylaxis to receiving treatment;
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age (infants, children and adults);
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trigger agents (iatrogenic versus community, antibiotic versus other drugs and muscle relaxants versus other agents).
Sensitivity analysis
We will undertake sensitivity analysis for the allocation of missing data by best and worst case analysis and will also undertake sensitivity analysis on the basis of only including randomized studies, which will allow an assessment of the impact on the review conclusions of excluding quasi‐randomized studies judged to be at increased risk of bias.
| MEDLINE search terms |
| 1. randomized controlled trial.pt. |
