Glucocorticoid with cyclophosphamide for paraquat‐induced lung fibrosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effect of corticosteroid with cyclophosphamide on mortality in patients with paraquat toxication.
Background
Paraquat is a very effective herbicide, but is also a fatal toxin to humans. Since 1961 it has been commercially produced and sold in about 130 countries around the word (Tomlin 1994). Accidental or voluntary ingestion of paraquat costs many lives each year, and the majority of people who die live in developing countries.
Most (93%) fatalities from paraquat poisoning are cases of suicide. In developing countries, paraquat is a "major suicide agent" (Dinham 1996). Paraquat is readily available and highly potent, which makes preventing suicide difficult.
An epidemiology study of poisoning done in a geographically defined area in rural Sri Lanka, a developing agricultural country, indicate that the incidence of poisoning was 75 per 100 000 population and the death rate was as high as 22 per 100 000 population. Paraquat was the commonest poisoning agent, which also has a high fatality rate of 68% (Hettiarachchi 1989). The incidence and death rates from poisoning were highest in the 15‐34 age group and there were significant ethnic differences in the incidence of poisoning.
Victims in China are usually women and children in impoverished rural areas, who are not well‐educated and often unfairly treated. In many cases, the decision to drink paraquat is impulsive and follows intense interpersonal conflict (Wang 2008).
The care of a paraquat poisoned person involves reducing the quantity of paraquat ingested, and removing paraquat from the bloodstream. Vomiting should be induced as soon as possible to prevent further absorption of the toxin. Upon arrival at the emergency room, further interventions may include gastric aspiration, gastric lavage, repeated absorbents of activated charcoal or fuller's earth combined with purgatives such as mannitol or sorbitol (World Health Organization 2009). Hemodialysis, hemofiltration, and hemoperfusion may be instituted in the hope of reducing the load of poison in the blood, but these interventions have no proven effects for improving survival (Suzuki K 1993; Koo 2002), mainly because paraquat accumulates in the lung.
Paraquat molecules selectively accumulate in the lungs, which leads to irreversible pulmonary fibrosis which is also known as 'paraquat lung' (Smith 1975; Fukuda 1985). This accumulation process takes place immediately after absorption of paraquat and lasts from 2 to 4 weeks; a great proportion of patients appear asymptomatic until signs of breathing difficulty emerge. It is difficult to predict the outcome of a patient who appears normal but is actually suffering lung fibrosis (Eddleston 2003).
While numerous methods are applied to reduce paraquat concentration in the blood stream, the progression of lung injury activated by the deposited paraquat remains a major threat to patient's life. The strategy of using corticosteroid combined with cyclophosphamide as a way to suppress the immunoreactions which cause lung damage has been tested since the 1970s (Eddleston 2003), but the effectiveness of this treatment is unknown.
Description of the condition
The prognosis is associated with the amount of toxin which has been ingested:
In low dose poisoning (<20 mg paraquat ion per Kg body weight), patients are often asymptomatic or may develop vomiting or diarrhoea but have a good chance of recovery.
In moderate dose poisoning patients (20 to 40 mg paraquat ion per Kg body weight), initial renal and hepatic dysfunction is common. Mucosal damage may become apparent with sloughing of the mucous membranes in the mouth. Difficulty in breathing may develop after a few days in the more severe cases. After about 10 days, though renal function often returns to normal, radiological signs of lung damage usually develop. Lung damage is mostly followed by irreversible massive pulmonary fibrosis manifested by the progressive loss of the lung's function of breathing, which keeps deteriorating until death of the victim between 2‐4 weeks after ingestion.
In high dose poisoning patients (> 40 mg paraquat ion per kg body weight), toxicity is much more severe and death occurs early (24‐48 hrs) from multiple organ failure. The initial gastrointestinal symptoms are similar but very severe with considerable fluid loss. Renal failure, cardiac arrhythmias, coma, convulsions, esophageal perforation and death soon follow (WHO 2003).
Description of the intervention
In practice, this therapy comprises intravenous infusion of glucocorticoids and cyclophosphamide in combination. The timing and duration of intervention as well as the dosage of these drugs can be varied, due to the time and location of different studies.
How the intervention might work
After being actively accumulated by lung cells, paraquat catalyses the formation of certain chemicals, namely superoxide, singlet oxygen, hydroxyl, and peroxide radicals. These chemicals are also used by the immune system as 'weapons' to destroy items recognized as foreign to the human body (Smith 1998). Thus, it is believed that immunosuppressive methods will prevent the immune system from producing such chemicals thereby reducing damage. At the same time, the immunosuppressive agents are intended to halt the progress of fibrosis, which is a part of immune reaction (Jaeschke 1997).
Why it is important to do this review
Though many have inferred from experiment (Sang‐Sook Lee 1984) and clinical experience (Agarwal 2006) that immunosuppressive therapy might work, there has been no conclusion on the effectiveness of this treatment. Considering the hazards associated with immunosuppressive drugs (Winsett 2004), it is timely to have a systematic review on this topic to support decision‐making or suggest further research.
Objectives
To assess the effect of corticosteroid with cyclophosphamide on mortality in patients with paraquat toxication.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials will be included.
Types of participants
Any person with paraquat poisoning.
Types of interventions
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Glucocorticoids and cyclophosphamide in combination versus no glucocorticoids and cyclophosphamide, or placebo, or any other therapy for paraquat poisoning.
Studies that focus on any one single immunosuppressant or other combinations of therapies will be excluded.
Types of outcome measures
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Mortality at 30 days following the ingestion of paraquat.
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All‐cause mortality at the end of the follow‐up period.
Search methods for identification of studies
The search will not be restricted by date, language or publication status.
Electronic searches
Electronic searches will be carried out in both English and Chinese databases, using English and Chinese search terms.
We will search the following databases;
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Cochrane Injuries Group Specialised Register (to latest version),
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CENTRAL (The Cochrane Library, latest issue),
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MEDLINE (Ovid SP) (1950 to most recent date available),
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EMBASE (Ovid SP) (1980 to most recent date available),
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Clinicaltrials.gov,
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Controlled‐trials.com,
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Chinese bio‐medical literature & retrieval system (CBM),
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Chinese medical current contents (CMCC),
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Chinese medical academic conference (CMAC),
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ISI Web of Science: Science Citation Index Expanded (SCI‐EXPANDED) (1970 to most recent date available),
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ISI Web of Science: Conference Proceedings Citation Index‐Science (CPCI‐S) (1990 to most recent date available).
Electronic searches will be based on the following MEDLINE search strategy and will be adapted, where appropriate, for each database;
Ovid MEDLINE(R) 1950 to July Week 1 2009
1.exp Herbicides/
2.exp Paraquat/
3.(Paraquat or (methyl adj3 viologen) or gramoxone or paragreen or Herbicide* or Pyridinium Compound*).mp.
4.1 or 2 or 3
5.exp Lung Diseases/
6.exp Pulmonary Fibrosis/
7.((Pulmonary or lung) adj3 (fibrosis or fibroses)).ab,ti.
8.((Alveolitis or alveolitides) adj3 fibrosing).ab,ti.
9.5 or 6 or 7 or 8
10.exp Glucocorticoids/
11.glucocorticoid*.ab,ti.
12.exp Cyclophosphamide/
13.(Cyclophosphamide* or cytophosphan or cyclophosphane or procytox or sendoxan or b‐518 or neosar or cytoxan or endoxan or nsc‐26271).ti,ab.
14.10 or 11 or 12 or 13
15.randomi?ed.ab,ti.
16.randomized controlled trial.pt.
17.controlled clinical trial.pt.
18.placebo.ab.
19.clinical trials as topic.sh.
20.randomly.ab.
21.trial.ti.
22.15 or 16 or 17 or 18 or 19 or 20 or 21
23.(animals not (humans and animals)).sh.
24.22 not 23
25.4 and 9 and 14 and 24
Due to the paucity of trials in this area, we will not restrict our search by using a filter for RCTs but will seek to identify all types of trials in the hope that this will lead us to identify trials we may have otherwise missed.
Searching other resources
We will search the Internet for information relevant to our review using search engines such as Google.com or Baidu.com. We will also search conference abstracts. We will seek further potentially relevant, published or unpublished studies by checking reference lists of trial reports and literature reviews. We will communicate with authors of relevant papers to help identify further published and unpublished studies.
Data collection and analysis
Selection of studies
The search results will be screened independently by LL and BC. Duplication of reports will be identified and handled during the selection. The full content of the selected study reports will be obtained and assessed according to the inclusion criteria. Different reports of the same or connected studies will be linked together, and where necessary, confirmation will be obtained from the study authors. Any disagreements will be resolved by consensus; if further questions remain, YC will give his opinion.
Data extraction and management
Data will be extracted on the total number of participants in the intervention and control groups, and how many in each group survived on an intention to treat basis. Loss to follow‐up in each study will also be analysed. Information about the design of each trial, such as the strategy for generation of the randomisation sequence, allocation concealment as well as technique for blinding will be extracted. The data will be managed in Review Manager software provided by the Cochrane Collaboration.
Assessment of risk of bias in included studies
Evaluation of each trial will be managed by two independent authors (LL and BC), with arbitration from YC in the event of disagreement. All trials will be assessed on the following potential sources of bias: sequence generation, allocation concealment, blinding, incomplete reporting, selective outcome reporting or any other sources of bias. The trial authors will be contacted for further information if the trial report does not fully address these issues. For each trial, each source of bias will be evaluated and described in the risk of bias table. Each domain will contain one of the following answers: 'Yes' means low risk of bias, 'Unclear' means not enough information was provided, and 'No' means there is potential for high risk of bias as defined by (Higgins 2008). The judgments made to those domains will be summarized and explicitly presented in the form of two special figures provided by this tool.
Measures of treatment effect
Risk ratio and its 95% confident interval will be calculated for each study using Review Manager version 5.
Dealing with missing data
Loss of follow‐up will be retrieved and the impact of it on the result will be weighed for each included study.
Assessment of heterogeneity
If suspicion of clinical heterogeneity arises, the differences in study design among trials will be inspected. Where possible and appropriate, the statistical heterogeneity will be examined using the Chi2 test. A p‐value below 0.10 indicates heterogeneity, but this should be interpreted with caution and will be properly discussed in the results section of the review. An I² statistic will be calculated to assess the attribution of heterogeneity to the diversity of results from different studies.
Assessment of reporting biases
If the number of included studies is sufficient, funnel plots will be employed to detect reporting bias. However funnel plots are not the gold standard, thus an asymmetrical funnel plot is nothing more than a suggestion of reporting bias (Higgins 2008).
Data synthesis
If there are sufficient studies, a meta‐analysis will be undertaken to make a summary risk ratio and 95% confidence interval using a fixed‐effect model.
