Urinary alkalinisation for acute chlorophenoxy herbicide poisoning
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the efficacy of methods used to induce urinary alkalinisation, in particular sodium bicarbonate, for the treatment of chlorophenoxy herbicide poisoning.
Background
Chlorophenoxy compounds are selective herbicides with agricultural and domestic uses. A number of compounds are included in this group, most notably 2,4‐dichlorophenoxyacetic acid (2,4‐D), 4‐chloro‐2‐methylphenoxyacetic acid (MCPA), 2,4,5‐trichlorophenoxyacetic acid (2,4,5‐T) and mecoprop (MCPP).
Severe toxicity (including coma, rhabdomyolysis and renal toxicity) and death from acute chlorophenoxy herbicide poisoning has been reported worldwide (Bradberry 2004; Roberts 2005). The incidence of severe toxicity and case‐fatality ratio for acute chlorophenoxy herbicide self‐poisoning is not well studied. A mortality of up to 33% has been noted from case reports and small case series of predominantly 2,4‐D poisonings (69 patients in total) (Bradberry 2004). A recent series of 181 consecutive patients with acute MCPA poisoning reported a lower, yet still significant, mortality of 4.4% (Roberts 2005). Whether outcomes differ between individual chlorophenoxy compounds has not been defined.
In the absence of a specific antidote for chlorophenoxy herbicides, the management of acute poisoning consists largely of appropriate decontamination, supportive measures and symptomatic care (Bradberry 2004; Roberts 2005). Intravenous fluids to rehydrate the patient and ensure an adequate urine output would be part of supportive care in most patients (Roberts 2005).
Animal studies support the application of urinary alkalinisation to enhance the elimination of chlorophenoxy herbicides (Braunlich 1989; Hook 1976). Some case reports suggest benefits from urinary alkalinisation in acute chlorophenoxy herbicide poisoning (Flanagan 1990; Friesen 1990; Prescott 1979; Schmoldt 1997). Standard clinical toxicology textbooks, expert reviews and a recent consensus statement (Proudfoot 2004) also recommend urinary alkalinisation for patients with severe poisoning. Despite this, it appears that urinary alkalinisation is not widely used in countries where acute poisonings with chlorophenoxy herbicides occur more commonly, such as Sri Lanka and India (Roberts 2005; Singh 2003).
Sodium bicarbonate is the most commonly recommended agent for inducing urinary alkalinisation, perhaps because it is cheap, widely available and stable in climatic extremes.
Objectives
To determine the efficacy of methods used to induce urinary alkalinisation, in particular sodium bicarbonate, for the treatment of chlorophenoxy herbicide poisoning.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials.
Types of participants
Patients ingesting a chlorophenoxy herbicide who present within 24‐48 hours of poisoning.
Types of interventions
Interventions which attempt to induce urinary alkalinisation (generally sodium bicarbonate, but others such as salts of acetate, citrate and citrotartrate) will be identified. Randomised controlled trials comparing these results to patients who do not receive alkalinisation will be included. It is likely that all patients will continue to receive standard treatment in addition to alkalinisation.
Types of outcome measures
Primary
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mortality
Secondary
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urinary chlorophenoxy herbicide clearance (pharmacokinetics)
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requirement for intubation and ventilation
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changes in creatine kinase (CK) and renal dysfunction (creatinine)
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incidence of adverse effects from the urinary alkalinisation regimen
Where information on cost of the intervention is available, the cost‐benefit will be determined.
Search methods for identification of studies
The following searches will be conducted on the complete database (neither date nor language limited).
MEDLINE search criteria
#1 explode "Hydrogen‐Ion‐Concentration" / all SUBHEADINGS in MIME,MJME
#2 explode "Carbonates‐" / all SUBHEADINGS in MIME,MJME
#3 explode "Acetates‐" / all SUBHEADINGS in MIME,MJME
#4 explode "Citrates‐" / all SUBHEADINGS in MIME,MJME
#5 ( (hydrogen?ion?concentration* or bicarbonate* or carbonate* or acetate* or citrate* or sodium?bicarbonate* or citrotartrate* or carbonic?acid* or hydrogen?carbonate* or acetic?acid?ester* or baking soda*) in TI ) or ( (hydrogen?ion?concentraion* or bicarbonate* or carbonate* or acetate* or citrate* or sodium?bicarbonate* or citrotartrate* or carbonic?acid* or hydrogen?carbonate* or acetic?acid?ester* or baking soda*) in AB )
#6 #1 or #2 or #3 or #4 or #5
#7 explode "Glycolates‐" / all SUBHEADINGS in MIME,MJME
#8 explode "Herbicides‐" / all SUBHEADINGS in MIME,MJME
#9 ( (glycolate* or herbicide*or defoliant*) in TI )or( (glycolate* or herbicide*or defoliant*) in AB )
#10 ( (halofenate* or meclofenoxate* or phenoxyacetate* ) in TI )or( (halofenate* or meclofenoxate* or phenoxyacetate*) in AB )
#11 ( (Dichlorophenoxyacetic Acid* or trichlorophenoxyacetic acid* or 2?methyl?4?chlorophenoxyacetic acid*) in TI ) or ( (Dichlorophenoxyacetic Acid* or trichlorophenoxyacetic acid* or 2?methyl?4?chlorophenoxyacetic acid*) in AB )
#12 ( (MCPA or 2?4?5?T or 2?4?D or mecoprop or MCPP) in TI )or( (MCPA or 2?4?5?T or 2?4?D or mecoprop or MCPP) in AB )
#13 ( (trichlorophenoxyacetic or dichlorophenoxyacetic or chlorophenoxy or methylphenoxyacetic) in TI ) or ( (trichlorophenoxyacetic or dichlorophenoxyacetic or chlorophenoxy or methylphenoxyacetic) in AB )
#14 #7 or #8 or #9 or #10 or #11 or #12 or #13
#15 #6 and #14
#16 #15 and the 'MEDLINE highly sensitive search strategy' outlined in the Cochrane Reviewers' Handbook
EMBASE search criteria
((explode 'urine‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'urine‐pH' / all subheadings in DEM,DER,DRM,DRR) or (explode 'acetic‐acid' / all subheadings in DEM,DER,DRM,DRR) or (explode 'citric‐acid' / all subheadings in DEM,DER,DRM,DRR) or (explode 'bicarbonate‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'buffer‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'alkalosis‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'citrate‐sodium' / all subheadings in DEM,DER,DRM,DRR) or (explode 'metabolic‐alkalosis' / all subheadings in DEM,DER,DRM,DRR) or (explode 'citrate‐potassium‐sodium' / all subheadings in DEM,DER,DRM,DRR) or (explode 'citrate‐potassium' / all subheadings in DEM,DER,DRM,DRR) or (explode 'sodium‐carbonate' / all subheadings in DEM,DER,DRM,DRR)) AND ((explode 'herbicide' / all subheadings in DEM,DER,DRM,DRR) or (explode 'glycolic‐acid‐derivative' / all subheadings in DEM,DER,DRM,DRR) or (MCPA) or (2,4‐D) or (2,4,5‐T) or (mecoprop))
Current Awareness in Clinical Toxicology (CACT) gives a selected list of up‐to‐date references and abstracts relevant to clinical toxicology. It has been produced by the National Poisons Information Service (Birmingham Centre, UK) since 1997. It provides key coverage of topics in clinical, occupational, and environmental toxicology. This will be searched using the terms 'MCPA', '2,4‐D', '2,4,5‐T', 'mecoprop', 'MCPP', '4‐chloro‐2‐methylphenoxyacetic acid', '2‐methyl‐4‐chlorophenoxyacetic acid', '2,4‐dichlorophenoxyacetic acid' and '2,4,5‐trichlorophenoxyacetic acid'.
The Cochrane Central Register of Controlled Trials.
Search on http://www.google.com: (chlorophenoxy or MCPA or 2,4‐D or Mecoprop or 2,4,5‐T or herbicide) AND (urine or urinary) AND (alkalinisation or alkalinization or bicarbonate or citrate or citrotartrate or acetate or HCO3). The first 500 entries will be reviewed.
Science Citation Index, searching each animal and human study addressing alkalinisation in chlorophenoxy herbicide poisoning which is identified.
Cochrane.us/cochranemainpage.asp to review the master list of journals being hand searched.
'Info Trac' ‐ The Journal of Toxicology ‐ Clinical Toxicology is accessed by this search engine. This journal publishes abstracts from the two major international clinical toxicology conferences. This will be searched using the terms 'MCPA', '2,4‐D', '2,4,5‐T', 'mecoprop', 'MCPP', '4‐chloro‐2‐methylphenoxyacetic acid', '2‐methyl‐4‐chlorophenoxyacetic acid', '2,4‐dichlorophenoxyacetic acid' and '2,4,5‐trichlorophenoxyacetic acid'.
Reference lists of relevant studies identified will be searched.
Consultation with experts in the field, including authors of textbook chapters and review articles on chlorophenoxy herbicide poisoning, and other experts in the field of clinical toxicology. Contact will be made by e‐mail, and each expert will be encouraged to forward the e‐mail to other experts knowledgeable in the area.
Upon searching each of these resources, the following will be recorded:
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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.
Data collection and analysis
Trial identification and selection
One author (DMR) will review the results of all searches and identify any article that may be eligible, given reference to acute chlorophenoxy herbicide poisoning and treatment with any form of alkalinisation. Each study will then be discussed between authors to confirm eligibility for inclusion in the systematic review.
Quality assessment
Since there is evidence that the quality of allocation concealment particularly affects the results of studies (Schulz 1995), we will score this quality on the scale used by Schulz as shown below, assigning C to poorest quality and A to best quality:
A = trials deemed to have taken adequate measures to conceal allocation (i.e. central randomisation; serially numbered, opaque, sealed envelopes; or other description that contained elements convincing of concealment).
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.
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.
Both authors will independently assess the overall quality of each trial according to the method of Jadad 1996.
Data extraction
Data from studies meeting inclusion criteria will be entered into a computer spreadsheet. Both authors will perform this process independently, and compare the results. The data extracted will consist of:
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study characteristics: number of participants, method of allocation, type of study, participant selection, method and regimen of urinary alkalinisation, details of concurrent treatments;
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outcome measures listed above, including standard deviations if applicable.
Analysis
We will calculate relative risk (RR) of death plus 95% confidence interval (CI), such that a relative risk of more than 1 indicates a higher risk of death (or ventilation, etc) in the first group named. We will use relative risk 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 (e.g. sodium bicarbonate) are located. We will consider:
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time to presentation: the sooner that management is initiated following acute poisoning, the more likely it is to be effective;
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severity of toxicity (symptomatic patients versus those with severe toxicity as defined in Roberts 2005): there is a wide range of severity. Trivial poisonings where no effect is possible are relatively common. Conversely, many patients present in a moribund state where any intervention is unlikely to have time to be effective. Patients with severe poisoning who are not about to expire are those who are most likely to benefit from a treatment.
If the data are not suited to meta‐analysis, we will discuss them in a narrative review.
