Extracorporeal blood purification for organophosphorus pesticide poisoning
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effect of extracorporeal blood purification techniques in the treatment of acute organophosphorus pesticide poisoning.
Background
Acute organophosphorus pesticide (OP) poisonings are reported world wide, but are a particularly serious problem in developing countries. Every year pesticides are associated with about three million poisonings and 200,000 deaths worldwide, while in China alone it is estimated that there are more than 100,000 deaths per year from acute OP poisoning (Eddleston 2000; Eddleston 2004b; He 1998; Jeyaratnam 1990).
The clinical effects of acute OP poisoning are well described (Eddleston 2004a; Karalliedde 2001). Standard treatment consists of resuscitation, antidotes (usually atropine and oxime), decontamination, and supportive care (Eddleston 2004a). Despite these treatments, mortality remains high, varying between 4% and 30% (Yamashita 1997). Further, the clinical effects of acute OP poisoning are generally prolonged. Most patients who survive the acute cholinergic phase remain in hospital for many days or weeks, during which time other complications may develop (Costa 2006; Karalliedde 2001). These problems have led clinicians to consider additional treatments for the management of acute OP poisoning.
Direct removal of organophosphorus pesticide from the blood of patients with acute poisoning has the potential to reduce total pesticide load and improve clinical outcomes. In particular, because oximes appear to be minimally effective when the concentration of OP is very high (Eyer 2003), blood purification may have a lifesaving role in these patients.
Extracorporeal blood purification, including hemoperfusion (HP) and hemodialysis, has been trialled for acute OP poisoning previously (Altintop 2005; Garella 1988; Koppel 1986; Luzhnikov 1977; Martinez‐Chuecos 1992; Nagler 1981). Despite these studies, its role in the management of these patients remains poorly defined (Borkan 2002; Garella 1988; Martinez‐Chuecos 1992). But on the basis of clinical experience and a recent retrospective uncontrolled study, some clinicians routinely use HP in the treatment of patients with severe OP poisoning (Altintop 2005). While complications were not noted from HP in the latter study, adverse effects (including death) secondary to extracorporeal blood purification have been reported previously (Borkan 2002; Pond 1991; Rennick 1976; Vale 1975). Another potential complication from extracorporeal blood purification in patients is increased clearance of the antidotes (for example, oximes), particularly when they are administered as intermittent boluses.
The objective of this systematic review is to determine the efficacy and adverse effects of extracorporeal blood purification for the treatment of acute organophosphorus pesticide poisoning.
Objectives
To determine the effect of extracorporeal blood purification techniques in the treatment of acute organophosphorus pesticide poisoning.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
RCTs are the best trial design for providing empiric evidence for the effect of this intervention on clinical outcomes. However, it is necessary to also have causal evidence of the effect ‐ in this case, pharmacokinetic studies that indicate that extracorporeal methods increase the elimination of particular OP (Peck 2003). This is essential data to justify further RCTs and to interpret the clinical outcomes from RCTs. We will therefore also review pharmacokinetic studies, presenting the results in the 'Additional tables' and consider their findings in the 'Discussion' of the completed review. Data obtained from pharmacokinetic studies will only be used for measuring the effect of extracorporeal elimination on the first and fourth secondary outcome measures (pharmacokinetics and complications), not clinical outcomes such as death.
Types of participants
Patients ingesting an organophosphorus pesticide who present within 24 to 48 hours of poisoning.
Types of interventions
Interventions where extracorporeal methods of blood purification (including hemoperfusion, hemodialysis, hemofiltration and plasmapheresis) are used for the treatment of acute OP poisoning will be identified.
Types of outcome measures
Primary outcomes
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Mortality.
Secondary outcomes
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Pharmacokinetics of the individual organophosphorus and oxime compounds, using techniques described by Lee et al (Lee 1980);
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Clinical manifestations of poisoning (for example, duration and severity of coma, incidence and duration of respiratory failure);
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Biochemical data ‐ cholinesterase activity, including: mixed cholinesterase tests, acetylcholine esterase (AChE) reactivatibility and/or time to recovery of butyrylcholine esterase (BuChE);
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Complications or adverse effects of the intervention.
Search methods for identification of studies
During the searching of the resources listed below, we will record the following:
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title of database searched;
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name of the host;
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date search was run (month, day, year);
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years covered by the search;
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complete search strategy used, including all search terms (preferably cut and pasted);
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one or two sentence summary of the search strategy indicating which lines of the search strategy were used to identify records related to the health condition and intervention, and which lines were used to identify studies of the appropriate design;
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the absence of any language restrictions.
Electronic searches
We will search the following electronic databases (details of the search strategies are described in Appendix 1):
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CENTRAL
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MEDLINE
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EMBASE
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Current Awareness in Clinical Toxicology
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www.google.com
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Info Trac
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China Biomedical Literature Database on disc (based on Table 1, with terms translated into Chinese)
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Science Citation Index
Searching other resources
We will also search the reference lists of relevant studies.
We will contact experts, including authors of textbook chapters and review articles on OP pesticides or extracorporeal elimination in clinical toxicology, and other experts in the field of clinical toxicology. We will make contact by email and encourage each expert to forward the message on to other experts knowledgeable in the area.
Data collection and analysis
Selection of studies
Two authors (Peng and Roberts) will review the results of searches and identify any article that may be eligible, given reference to acute OP poisoning and treatment with any form of extracorporeal blood purification. Each study will then be discussed between all authors to confirm eligibility for inclusion in the systematic review.
Data extraction and management
We will extract data from studies meeting inclusion criteria onto a computer spreadsheet. All authors will perform this process independently, and compare the results. The data extracted will consist of;
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number of participants,
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method of allocation,
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type of study,
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participant selection,
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method and regimen of extracorporeal blood purification,
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details of concurrent treatments,
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outcome measures listed above, including standard deviations if applicable.
Assessment of risk of bias in included studies
Since there is evidence that the quality of allocation concealment particularly affects the results of studies (Schulz 1995), we will score the quality of the RCTs on the scale used by Schulz as shown below, assigning C to poorest quality and A to best quality:
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A = trials deemed to have taken adequate measures to conceal allocation (for example, central randomization; serially numbered, opaque, sealed envelopes; or other description that contained elements convincing of concealment).
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B = trials in which the authors either did not report an allocation concealment approach at all or reported an approach that did not fall into one of the other categories.
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C = trials in which concealment was inadequate (such as alternation or reference to case record numbers or to dates of birth).
Where the method used to conceal allocation was not clearly reported, the study investigator(s) will be contacted for clarification, if possible. We will then compare the allocated scores and resolve any differences by discussion.
The overall quality of each trial will be independently assessed by each author according to the method of Jadad using the following criteria, where the maximum possible score for any study is 5/5 (Jadad 1996):
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Randomly assigned: A method to generate the sequence of randomisation will be regarded as appropriate if it allowed each study participant to have the same chance of receiving each intervention and the investigators could not predict which treatment was next. This criteria is scored when the method to generate the sequence of randomisation was described (one point) and it was appropriate (table of random numbers, computer generated, etc) (one point).
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Double blind: A study must be regarded as double blind if the word "double blind" is used. The method will be regarded as appropriate if it is stated that neither the person doing the assessments nor the study participant could identify the intervention being assessed, or if in the absence of such a statement the use of active placebos, identical placebos, or dummies is mentioned. This criteria is scored when the method of double blinding was described (one point) and it was appropriate (one point).
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Withdrawals and dropouts described: Participants who were included in the study but did not complete the observation period or who were not included in the analysis must be described (one point).
Data obtained from pharmacokinetic studies will only be considered if sufficient information is provided for an adequate assessment, as described by Lee et al (Lee 1980).
Data synthesis
We will calculate relative risk (RR) of death plus 95% confidence interval (CI), such that a relative risk of more than one indicates a higher risk of death (or respiratory failure, etc) in the first group named. We will use RR because it is more readily applied to the clinical situation. For continuous data the weighted mean difference (WMD) plus 95% CI will be used.
If the data are suited to meta‐analysis, a random‐effects model relevant to the data (dichotomous or continuous) will be used given that heterogeneity between studies is likely. The presence of heterogeneity of the observed treatment effects will be assessed using the I2 statistic, which describes the percentage of total variation across studies due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity. Where heterogeneity appears significant, pooled results will be interpreted with caution.
Subgroup analysis will be performed only where a number of studies using the same intervention (for example, hemoperfusion) are located, or if the same OP is ingested. We will consider:
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intervention type (that is, hemoperfusion versus hemodialysis versus hemofiltration versus plasmapheresis);
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OP type.
If the data are not suited to meta‐analysis, we will discuss them in a narrative review.
