Interventions for the symptoms and signs resulting from jellyfish stings
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The purpose of this systematic review is to determine the beneficial and harmful effects associated with the use of any intervention, in both adults and children, for the treatment of jellyfish stings as assessed in randomised controlled trials (RCTs).
Background
Description of the condition
Jellyfish are free‐swimming marine invertebrates. All jellyfish possess specialised stinging cells called nematocysts (Lotan 1996). Nematocysts are triggered by physical or chemical stimuli (or both), after which a barb is fired and venom is injected into the victim (see Figure 1). Due to the number of nematocysts which may discharge during a 'jellyfish sting' and the potential toxicity of the venom, a jellyfish sting may produce a range of signs and symptoms, of varying severity.
Nematocyst discharge from: http://commons.wikimedia.org/wiki/File:Nematocyst_discharge.png
Humans typically only come into contact with surface dwelling jellyfish species found in temperate coastal regions. As most jellyfish stings go unreported, it is difficult to obtain accurate incidence statistics. Between 2010 and 2011, there were 40,000 cases of marine sting emergency care around Australia, as reported by Surf Life Saving Australia (SLSA 2011). This represented a 30% rise in the number of cases from the previous year (SLSA 2011). Cubozoan or box jellyfish, in particular the family Chirodropid which includes the Indo‐Pacific box jellyfish (Chironex fleckeri), are considered the most dangerous of jellyfish. Chironex fleckeri (the major box jellyfish) has caused over 70 deaths in the past century, the majority being young children in remote areas (Tintinalli 2010). Deaths are also rarely caused by Physalia physalis, known as the Portuguese man‐o'‐war or bluebottle (Stein 1989).
Envenomation usually results in immediate stinging pain and a range of skin reactions including erythema (redness), urticaria (itching), wheals (raised itchy areas), vesicular formation (small skin bubbles), hypo/hyperpigmentation (patches of skin colour changes) and/or superficial necrosis (skin cell death) at the site of contact (Tintinalli 2010; Winter 2007). The pain of a jellyfish sting may be severe and may last for several weeks. Delayed hypersensitivity skin reactions may also occur (O'Reilly 2001), as well as more permanent skin markings including scarring and colour changes (Tintinalli 2010). Cubozoan or box jellyfish, in particular Carukia barnesi, may cause Irukandji syndrome, which is characterised by pain and redness at the site of the sting, followed by generalised severe abdominal, back or chest pain as well as autonomic features including tachycardia (increased heart rate), hypertension (increased blood pressure), sweating, piloerection (raised short hairs), agitation and, uncommonly, heart complications (myocardial depression with or without pulmonary oedema) (Currie 2005; Huynh 2003). Severe anaphylactic reactions to jellyfish stings may occur, but are extremely rare (Williamson 1996). Anaphylaxis (severe allergic reaction) is characterised by swelling of the airways (resulting in difficulty breathing), swelling and itching of the skin, nausea, vomiting, diarrhoea, reduced blood pressure leading to shock and potentially cardiac arrest (Tintinalli 2010). Anaphylaxis may be fatal (Tintinalli 2010).
Description of the intervention
Therapy ideally consists of: deactivation of attached nematocysts, neutralisation of venom effects, provision of symptomatic relief (including pain relief) and provision of supportive care. The mechanism of action for most 'jellyfish sting' interventions is poorly defined and some interventions may potentially perform more than one function, for example deactivation of attached nematocysts as well as provision of symptomatic relief. Some possible mechanisms of action include:
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inactivation of nematocysts, potentially achieved by fresh water, salt water and vinegar;
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neutralisation of venom effects through the use of antivenoms;
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symptomatic relief only, for example through the use of traditional analgesics (oral and parenteral), antihistamines and steroids;
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symptomatic relief and possible deactivation of nematocysts or neutralisation of venom, which may potentially be achieved by hot water or ice (Nomura 2002).
Supportive care may include dressings, oxygen supplementation, positive pressure ventilation (air pushed into the lungs to encourage breathing), antihypertensives (lowers blood pressure), inotropes (alters the force of heartbeats), parenteral magnesium and cardiopulmonary resuscitation (CPR) (Corkeron 2004).
Why it is important to do this review
Jellyfish stings range from the mild to the severe. Current treatment options are not clearly defined or evidence‐based. Currently, no systematic review concerning the treatment of jellyfish stings exists. Therefore, it is important that effective treatments are identified.
Objectives
The purpose of this systematic review is to determine the beneficial and harmful effects associated with the use of any intervention, in both adults and children, for the treatment of jellyfish stings as assessed in randomised controlled trials (RCTs).
Methods
Criteria for considering studies for this review
Types of studies
We will only include RCTs, as these give the best quality evidence for assessing the effectiveness of an intervention. There will be no language, publication date or publication status restrictions applied. We will exclude quasi‐randomised studies, for example where participants are randomised by date of birth or admission date. We will consider both studies comparing interventions to non‐active controls and interventions to other active interventions.
Types of participants
For the purpose of this review, anyone who reports being stung by a jellyfish will be eligible for inclusion. We will consider all age groups. We have decided to take a pragmatic approach to trial conduct and so visual identification of the offending jellyfish by an independent observer will not be required. We will consider trial participants presenting with any jellyfish symptoms, not just those who present with pain. There will be no baseline threshold of pain or any other symptoms for inclusion in the review.
Types of interventions
There is no clear consensus on which interventions should be used in the treatment of jellyfish stings. Therefore, we will consider any intervention, given at any dose, duration or intensity. When more than one intervention is combined, the control group must have received a similar intervention to be included in the review for consistency across trial groups (for example, if a trial compared warm water treatment to cold water treatment but the warm water group also received vinegar treatment, then the cold water group must also have received vinegar treatment). Trials that use two or more interventions or two controls will have those interventions analysed as one entity (for example, we will analyse warm water and analgesia together). We will place interventions into the following categories: interventions for deactivation of attached nematocysts, reversal of venom effects, provision of symptomatic relief (including pain relief) and supportive care. Treatments may be considered across more than one category.
Types of outcome measures
Primary outcomes
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Number of participants obtaining 50% maximum possible pain relief within six hours, using a validated pain scale such as Numeric Rating Scale, Visual Analogue Scale or Faces Rating Scale.
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Adverse events due to treatment: number of adverse event withdrawals, number of participants with any serious adverse event (defined as death, being life‐threatening, requiring inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, being a congenital anomaly/birth defect or requiring intervention to prevent permanent impairment or damage) and number of participants with any minor adverse event (defined as an adverse event that does not qualify as serious) at one day and one week.
Secondary outcomes
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Number of participants obtaining 50% maximum pain relief at zero to one hour, one to six hours, six hours to one day, and one day to one week using a validated pain scale.
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Median time to re‐medication with the same intervention.
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Percentage re‐medicating with the same intervention at zero to one hour, one to six hours, six hours to one day, and one day to one week.
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Percentage requiring supportive care, for example dressings, oxygen supplementation or positive pressure ventilation at one day.
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Percentage requiring hospital treatment, either as inpatient or outpatient, including emergency department visits at one day.
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Percentage with dermatological signs, for example scarring, hyperpigmentation or delayed hypersensitivity at one week.
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All‐cause mortality: number of participants dead irrespective of cause at one month.
Search methods for identification of studies
Electronic searches
We will search the following electronic databases: the Cochrane Pain, Palliative and Supportive Care Group Register (current issue), the Cochrane Central Register of Controlled Trials (CENTRAL): The Cochrane Library (current issue), MEDLINE (via Ovid SP) (1948 to present), EMBASE (via Ovid SP) (1980 to present) and the Web of Science (1980 to present). We will search for both published and unpublished data.
Our search strategy for MEDLINE via OvidSP is provided in Appendix 1. For the MEDLINE search, we will run the subject search with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity‐maximising version (2008 revision) as referenced in Chapter 6 and detailed in box 6.4.a‐d (c for Ovid) of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 (updated March 2011) (Cochrane 2011). We will adapt this search for the remaining databases.
Searching other resources
We will search the reference lists of all eligible studies and key references for additional studies. We will seek further studies through contacting content experts, Surf Life Saving Australia and searching of the WHO International Clinical Trials Registry Platform (ICTRP).
Data collection and analysis
Selection of studies
Two review authors will conduct study selection including title and abstract screening independently. The review authors will read the abstracts as well as the full text if the abstract has insufficient information to determine the study eligibility. If the full text is still insufficient to make a decision, we will make an attempt to contact the original authors of the study for clarification. We will resolve disagreements by discussion and consensus agreement, involving a third review author if required. We will only include studies agreed upon by both review authors in the analysis. We will not include studies that do not use validated pain scales in the quantitative analysis but they will still contribute to the qualitative analysis. The review authors will not be blinded during this process. We will not include studies that do not meet the inclusion criteria in this review. The search will attempt to identify all relevant studies irrespective of language. We will assess non‐English papers and, if necessary, translate them with the assistance of a translator.
Data extraction and management
Two review authors will extract data from each study independently using a standardised data extraction form. We will resolve disagreements by discussion and consensus agreement, involving a third review author if required. The review authors will not be blinded for this procedure.
We will extract the following data.
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General information: study author(s), title, source, contact address, year of study, country of study, language of publication, year of publication, any author conflicts of interest, study setting (e.g. hospital emergency department, general practice, at the beach).
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Study characteristics and eligibility for review: trial design, randomisation method, recruiting method, duration of trial, trial location, length of follow‐up, any obvious concerns of bias.
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Participants: inclusion and exclusion criteria, age, gender, co‐morbidities, total number of participants, country of origin, number of dropouts or withdrawals and the reasons if recorded.
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Interventions: number of participants for each intervention, a detailed description of the interventions and comparison interventions including, where relevant, the type, dose, concentration and duration of application.
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Outcomes: specific outcomes reported, assessment instruments used, scoring range where appropriate.
We will perform data collection using the Review Manager (RevMan) 5.1 software (RevMan 2011).
If any of this required information is unclear or missing, we will make an attempt to contact the authors of the original report.
Assessment of risk of bias in included studies
We will assess risk of bias using the suggested domains and guidance provided in the 'Cochrane Collaboration's tool for assessing risk of bias' as detailed in section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane 2011). We will assess the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias (in particular funding source). For domains initially judged as 'unclear risk', we will try to clarify the risk of bias by contacting the study authors. We will initially include all studies irrespective of the risk of bias. We will also perform a sensitivity analysis. If the sensitivity analysis shows substantial difference, we will exclude studies with high risk of bias from the review.
Measures of treatment effect
We will conduct data analysis according to the guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane 2011).
Dichotomous data
We will present results as a summary risk ratio (RR), with 95% confidence intervals (CI) and, where relevant, risk difference (RD), numbers needed to treat to benefit (NNT) and numbers needed to treat to prevent an event (NNTp).
Continuous data
We will present results as mean difference (MD) if outcomes are measured in the same way between studies. We will use the standardised mean difference (SMD) to combine studies that measure the same outcome but have used different methods.
Unit of analysis issues
We will analyse any cluster‐randomised trials after taking into account the effect of clustering to prevent unit of analysis errors as detailed in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane 2011).
Dealing with missing data
We will analyse data for all participants in the group to which they are allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants are not analysed in the group to which they were randomised and there is sufficient information in the study, we will make an attempt to restore them to the correct group, i.e. we will conduct intention‐to‐treat (ITT) analysis where it is possible to do so. Where missing data are suspected, we will attempt to seek clarification, obtain the data from the study authors, or both. If ITT analysis is not possible, then we will use per‐protocol analysis. We may perform a sensitivity analysis to determine the significance of any missing data.
Assessment of heterogeneity
We will assess heterogeneity among studies, if appropriate, using the I² statistic and Cochran Q statistics. If substantial heterogeneity is detected (statistical heterogeneity of I² more than 50% or Chi² P value less than 0.10, or clinical heterogeneity of different interventions or patient characteristics), we will explore it by prespecified subgroup analysis.
Assessment of reporting biases
Where more than 10 studies are included in an analysis, we will use a funnel plot to check for publication bias. If reporting bias is suspected due to missing data, we will make an attempt to contact study authors to request provision of the data. Where this is not possible and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis. This will be achieved by omitting the incomplete studies and observing any substantive difference in the final result. If there is no substantive difference, then we will leave those incomplete studies in the final analysis. Examples of potential reporting bias include only reporting significant results.
Data synthesis
We will conduct data analysis using the Review Manager software (version 5.1). We will use random‐effects meta‐analysis to analyse studies that are judged sufficiently similar. We will judge trials that compare similar interventions, populations and outcomes as sufficiently similar. We will consider and stratify all jellyfish species into bluebottles (Physalia species), box jellyfish that do not cause Irukandji syndrome (such as the major box jellyfish Chironex fleckeri), jellyfish causing the Irukandji syndrome, and other jellyfish. We will consider a P value of 0.05 or less statistically significant. If any factorial trials exist, we may investigate them separately only if reports from the study show no important interaction between the interventions studied (as suggested in chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions) (Cochrane 2011).
Subgroup analysis and investigation of heterogeneity
It is expected a priori that the following areas would cause a difference in outcomes, and so we plan to carry out the following subgroup analyses.
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Studies with low risk of bias compared with studies with high risk of bias. For this subgroup analysis, we will identify high risk of bias as one or more domains on the risk of bias tool judged as 'high risk'. This is the advice in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane 2011). We will categorise all remaining trials as low risk of bias for this analysis.
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The severity of a sting: mild/moderate (not requiring hospitalisation) versus severe (requiring hospitalisation).
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Co‐interventions used (for example, one study may assess the efficacy of warm water with analgesics as a co‐intervention, while another may assess the efficacy of warm water with psychosocial support as a co‐intervention).
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Participants' age group: children (aged 18 years or younger) compared to adults (aged 18 to 55 years) and the more aged population (aged 65 and over).
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Type of jellyfish.
We will assess differences among subgroups by testing for interaction.
Sensitivity analysis
We will carry out sensitivity analysis if unpublished studies, studies with data missing and studies published only as abstracts are included in a meta‐analysis. Regardless of the outcome of sensitivity analysis, we will place all results into the review, even if they are not included in the final analysis.
Nematocyst discharge from: http://commons.wikimedia.org/wiki/File:Nematocyst_discharge.png
