Antidotes for acute cardenolide (cardiac glycoside) poisoning
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the efficacy of antidotes for the treatment of acute cardenolide poisoning, in particular atropine, isoprenaline (isoproterenol), multiple‐dose activated charcoal, frustose‐1,6‐diphosphate, sodium bicarbonate, magnesium, phenytoin and anti‐digoxin Fab antitoxin.
Background
Cardenolides, sometimes referred to as cardiac glycosides or cardioactive steroids, are naturally occurring plant toxins which act primarily on the heart (Hoffman 2002). The most well known are the digitalis cardenolides (digoxin and digitoxin) which are used therapeutically for the treatment of cardiac failure. Poisoning with digitalis cardenolides are reported worldwide and require admission to a coronary care unit (if available) to monitor for significant cardiotoxicity, and administration of antidotes such as anti‐digoxin Fab antitoxin as needed. Case fatality ratios up to 20% have been reported, and severe toxicity may not occur until 24 hours post‐admission for digoxin, or up to five days for digitoxin poisonings (Taboulet 1993).
Cardiotoxicity is also reported from other cardenolides, in particular yellow oleander (Thevetia peruviana) and pink or white oleander (Nerium oleander), as well as the sea mango tree (Cerbera manghas). The oleander plants are found commonly through much of the tropics and subtropics around houses and gardens (Langford 1996). These cardenolides are structurally similar to digitalis, and treatments for digitalis poisoning such as the antidigoxin Fab antitoxin are effective in the management of acute poisoning with these cardenolides (Eddleston 2000). In parts of India and Sri Lanka, yellow oleander has become a popular means of self harm with tens of thousands of cases in South Asia each year, and probably thousands of deaths given the case fatality ratio of 5‐10%. Further, significant dysrhythmias may be delayed for up to 72 hours post ingestion, requiring prolonged hospital admissions (Roberts 2005). Unfortunately, because the Fab antitoxin is expensive it is not readily available worldwide, particularly in developing countries where poisonings with these cardenolides are common (Eddleston 2003). As such, the management of patients with severe cardenolide poisoning is generally difficult and costly in countries with limited resources.
A number of specific treatments for cardenolide poisoning have been either used or recommended, including atropine, isoprenaline (isoproterenol), multiple‐dose activated charcoal, frustose‐1,6‐diphosphate, sodium bicarbonate, magnesium, phenytoin and anti‐digoxin Fab antitoxins. The purpose of this systematic review is to evaluate the efficacy of all these treatments. The benefit of these treatments in the context of cost is also of high interest as most poisonings occur in developing countries where resources are very limited (Roberts 2005).
Objectives
To determine the efficacy of antidotes for the treatment of acute cardenolide poisoning, in particular atropine, isoprenaline (isoproterenol), multiple‐dose activated charcoal, frustose‐1,6‐diphosphate, sodium bicarbonate, magnesium, phenytoin and anti‐digoxin Fab antitoxin.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials.
Types of participants
Patients with acute symptomatic cardenolide poisoning, in particular digitalis or oleander who present within 24‐48 hours of poisoning.
Types of interventions
Interventions where antidotes are administered, in particular atropine, isoprenaline (isoproterenol), multiple‐dose activated charcoal, frustose‐1,6‐diphosphate, sodium bicarbonate, magnesium, phenytoin and anti‐digoxin Fab anti‐toxin. Randomised controlled trials comparing these results to patients who do not receive the antidote will be included. It is likely that all patients will continue to receive standard treatment in addition to the intervention.
Types of outcome measures
Primary
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mortality.
Secondary
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occurrence of serious cardiac dysrhythmias (second or third degree heart block or cardiac arrest)
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time to reversal of dysrhythmias
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occurrence of hyperkalaemia (serum K over 5.0mmol/L)
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time to reversal of hyperkalaemia
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requirement for pacemaker insertion
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adverse effects of the treatment.
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 "Antidotes‐" / all SUBHEADINGS in MIME,MJME
#2 explode "Antitoxins‐" / all SUBHEADINGS in MIME,MJME
#3 explode "Antibody‐Affinity" / all SUBHEADINGS in MIME,MJME
#4 explode "Immunoglobulins‐" / all SUBHEADINGS in MIME,MJME
#5 explode "Charcoal‐" / all SUBHEADINGS in MIME,MJME
#6 explode "Atropine‐" / all SUBHEADINGS in MIME,MJME
#7 explode "Phenytoin‐" / all SUBHEADINGS in MIME,MJME
#8 explode "Magnesium‐" / all SUBHEADINGS in MIME,MJME
#9 explode "Fructosediphosphates‐" / all SUBHEADINGS in MIME,MJME
#10 explode "Isoproterenol‐" / all SUBHEADINGS in MIME,MJME
#11 explode "Sodium‐Bicarbonate" / all SUBHEADINGS in MIME,MJME
#12 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
#13 ( (antidote* or antitoxin* or antibod* or immunoglobulin* or charcoal* or atropine* or phenytoin* or magnesium* or fructosediphosphate* or isoproterenol* or sodium?bicarbonate*) in TI )or( (antidote* or antitoxin* or antibod* or immunoglobulin* or charcoal* or atropine* or phenytoin* or magnesium* or fructosediphosphate* or isoproterenol* or sodium?bicarbonate*) in AB )
#14 #12 or #13
#15 explode "Cardenolides‐" / all SUBHEADINGS in MIME,MJME
#16 explode "Apocynaceae‐" / all SUBHEADINGS in MIME,MJME
#17 explode "Cardiac‐Glycosides" / all SUBHEADINGS in MIME,MJME
#18 explode "Thevetia‐" / all SUBHEADINGS in MIME,MJME
#19 explode "Nerium‐" / all SUBHEADINGS in MIME,MJME
#20 explode "Digoxin‐" / all SUBHEADINGS in MIME,MJME
#21 explode "Digitoxin‐" / all SUBHEADINGS in MIME,MJME
#22 #15 or #16 or #17 or #18 or #19 or #20 or #21
#23 ( (cardenolide* or cardiac?glycoside* or apocynacae* or thevetia* or nerium* or digoxin* or digitoxin*) in TI )or( (cardenolide* or cardiac?glycoside* or apocynacae* or thevetia* or nerium* or digoxin* or digitoxin*) in AB )
#24 #22 or #23
#25 #14 and #24
#26 #25 and the 'MEDLINE highly sensitive search strategy' outlined in the Cochrane Reviewers' Handbook
EMBASE search criteria
((explode 'isoprenaline‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'fructose‐bisphosphatase' / all subheadings in DEM,DER,DRM,DRR) or (explode 'immunoglobulin‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'drug‐antibody' / all subheadings in DEM,DER,DRM,DRR) or (explode 'bicarbonate‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'antitoxin‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'antidote‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'atropine‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'activated‐carbon' / all subheadings in DEM,DER,DRM,DRR) or (explode 'charcoal‐' / all subheadings in DEM,DER,DRM,DRR) or (charcoal) or (atropine) or (phenytoin) or (magnesium) or (FDP) or (fructose) or (isoprenaline) or (isoproterenol) or (sodium‐bicarbonate) or (Fab)) AND (explode 'Apocynaceae‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'digitoxigenin‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'peruvoside‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'Nerium‐oleander‐extract' / all subheadings in DEM,DER,DRM,DRR) or (explode 'digitoxin‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'acetyldigoxin‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'alpha‐acetyldigoxin' / all subheadings in DEM,DER,DRM,DRR) or (explode 'metildigoxin‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'digoxin‐' / all subheadings in DEM,DER,DRM,DRR) or (explode 'cardenolide‐derivative' / all subheadings in DEM,DER,DRM,DRR) or (explode 'cardenolide‐' / all subheadings in DEM,DER,DRM,DRR) or (nerium) or (thevetia) or (digoxin) or (cardenolide) or (oleander) or (cardiac‐glycoside) or (apocynacae) or (digitoxin))
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 database will be searched using the following terms: cardenolides, cardiac glycoside, apocynacae, oleander, thevetia, nerium, digoxin and digitoxin.
The Cochrane Central Register of Controlled Trials.
Search on http://www.google.com: (cardenolide OR digitalis OR digoxin OR digitoxin OR oleander OR cardiac‐glycoside OR thevetia OR nerium) AND (antidote OR antitoxin OR Fab OR antibody OR immunoglobulin OR charcoal OR atropine OR isoprenaline OR isoproterenol OR phenytoin OR fructose OR bicarbonate OR magnesium). The first 500 entries will be reviewed.
Cochrane.us/cochranemainpage.asp to review the master list of journals being hand searched
'Info Trac' ‐ The Journal of Toxicology ‐ Clinical Toxicology and a number of cardiology journals are accessed by this search engine. The Journal of Toxicology ‐ Clinical Toxicology publishes abstracts from the two major international clinical toxicology conferences. This database will be searched using the following terms: cardenolides, cardiac glycoside, apocynacae, oleander, thevetia, nerium, digoxin and digitoxin.
Reference lists of relevant studies identified by the above search will be searched.
Consultation with experts in the field, including authors of textbook chapters and review articles on cardenolide 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 a reference to acute cardenolide poisoning and treatment with a potential antidote. 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 author(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 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. Authors will perform this process independently, and compare the results. The data to be extracted will consist of:
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study characteristics: number of participants, method of allocation, type of study, participant selection, treatment regimen of the antidote, 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 serious dysrhythmias, 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. multi‐dose activated charcoal or Fab antitoxin) 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.
