Xuebijing para la intoxicación por paraquat
Resumen
Antecedentes
Actualmente, existe una falta de tratamientos efectivos para la intoxicación por paraquat. La inyección de Xuebijing es una prescripción china tradicional compleja que consta de Flos Carthami, Radix Paeoniae Rubra, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae y Radix Angelicae Sinensis. Aunque la experiencia clínica indica que la inyección de Xuebijing podría tener potencial para el tratamiento de la intoxicación por paraquat, no existe ninguna conclusión sobre la efectividad de este tratamiento.
Objetivos
Evaluar los efectos de la inyección de Xuebijing en pacientes con intoxicación por paraquat.
Métodos de búsqueda
Se hicieron búsquedas en el registro especializado del Grupo Cochrane de Lesiones (Cochrane Injuries Group), en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL, The Cochrane Library), MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EBSCO), ISI Web of Science: Science Citation Index Expanded, ISI Web of Science: Conference Proceedings Citation Index‐Science, Chinese bio‐medical literature and retrieval system (CBM), China National Knowledge Infrastructure Database (CNKI), y en la Traditional Chinese Medicine Database. La búsqueda se realizó el 29 de mayo 2013.
Criterios de selección
Se incluyeron todos los ensayos controlados aleatorios (ECA) que compararon la inyección de Xuebijing combinada con atención convencional versus atención convencional sola.
Obtención y análisis de los datos
Dos o tres autores, de forma independiente, seleccionaron los estudios, evaluaron la calidad de los mismos y extrajeron los datos. Se calculó el cociente de riesgos (CR) de la mortalidad y el intervalo de confianza (IC) del 95%. Los datos sobre la mortalidad por todas las causas al final del seguimiento se resumieron en un metanálisis.
Resultados principales
Se identificaron dos ensayos que incluyeron a 84 personas. Aunque hubo menos muertes en los pacientes tratados con inyección de Xuebijing, el metanálisis mostró que no proporcionó un beneficio estadísticamente significativo en cuanto a la reducción de la mortalidad por todas las causas en pacientes con intoxicación por paraquat comparado con el grupo de control (CR 0,71; IC del 95%: 0,48 a 1,04; P = 0,08).
Conclusiones de los autores
Sobre la base de los hallazgos de dos ECA pequeños, la inyección de Xuebijing no presentó un beneficio estadísticamente significativo en cuanto a la reducción de la mortalidad por todas las causas en pacientes con intoxicación por paraquat. Sin embargo, ambos estudios incluidos tuvieron números pequeños de participantes y se consideraron de calidad metodológica deficiente. Los resultados son imprecisos y fácilmente compatibles con la intervención del azar. La inyección de Xuebijing puede ser efectiva para los pacientes con intoxicación por paraquat; sin embargo, esta afirmación necesita ser demostrada con pruebas de alta calidad adicionales.
Resumen en términos sencillos
Xuebijing para la intoxicación por paraquat
El paraquat es un herbicida no selectivo y se usa frecuentemente a nivel mundial. Actualmente, existe una falta de fármacos efectivos para los pacientes con intoxicación por paraquat. La inyección de Xuebijing es una preparación china tradicional compleja compuesta de Flos Carthami, Radix Paeoniae Rubra, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae y Radix Angelicae Sinensis. Esta revisión procuró evaluar los efectos de la inyección de Xuebijing en pacientes con intoxicación por paraquat. Se identificaron dos ensayos que implicaron a 84 personas. Aunque hubo menos muertes en los pacientes tratados con inyección de Xuebijing, el metanálisis mostró que no hubo un beneficio estadísticamente significativo en la reducción de la mortalidad por todas las causas en pacientes con intoxicación por paraquat. Ambos estudios incluidos implicaron un número reducido de participantes y se consideraron de calidad metodológica deficiente. La inyección de Xuebijing puede ser efectiva para los pacientes con intoxicación por paraquat, aunque los efectos deben demostrarse con más pruebas de alta calidad.
Authors' conclusions
Background
Paraquat is a non‐selective herbicide and is commonly used in developing countries. In spite of numerous fatal intoxications, paraquat is registered for use in over 120 developed and developing countries (Dinis‐Oliveira 2008). In a number of countries, use of paraquat has been forbidden or is stringently restricted for use by certified people only (Wesseling 2001). However, in many developing countries including China where there are less stringent regulations on the sale and use of paraquat, prevention of paraquat poisoning is difficult. Most cases of paraquat poisoning are caused by suicidal attempts rather than by accidental exposure (Stephens 1997).
Recently, the Chinese government officially announced that the sale or use of paraquat in China will be banned in 2016 (Ministry of Agriculture 2012). Although it will be banned, suicides may still occur for a number of years because old paraquat is still available in storage. It has also not been banned for sale in other countries in Asia, therefore poisoning could still occur.
Patients in extremis have no realistic hope of recovery with current treatments (Gawarammana 2011). Initial treatment for paraquat poisoning involves preventing further absorption and reducing the load of paraquat in the blood by haemoperfusion or haemodialysis. However, the effectiveness of conventional treatments is extremely limited. Xuebijing injection is a complex traditional Chinese preparation. Clinical trials have found that Xuebijing injection can protect organs from paraquat injury and reduce mortality due to paraquat poisoning (Li 2008; Liang 2009).
Description of the condition
Since the first case of death that resulted from oral paraquat poisoning was reported in 1966 (Bullivant 1966), many studies and clinical efforts have been dedicated to increasing the survival of people with paraquat poisoning. However, little improvement has occurred and average mortality remains as high as 50% to 80% (Sullivan 2001; Sabzghabaee 2010).
The clinical effects and prognosis in paraquat poisoning is associated with the amount of toxin ingested (Vale 1987):
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low dose (< 20 mg paraquat ion per kilogram body weight = 10 mL of a 20% to 24% concentrate). These patients are often asymptomatic, or may develop gastrointestinal symptoms, but usually recover completely;
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moderate dose (20 to 40 mg paraquat ion per kilogram body weight = 10 to 20 mL of 20% to 24% concentrate). Mucosal damage may become apparent with severe caustic lesions in the gastrointestinal tract. Renal dysfunction is common, but may recover spontaneously. Dyspnoea may develop after a few days in the more severe cases. Massive pulmonary fibrosis manifested by progressive dyspnoea may cause death between two and three weeks after ingestion;
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high dose (> 40 mg paraquat ion per kilogram body weight = 20 mL of 20% to 24% concentrate). Toxicity is much more severe and death occurs within hours from multiple organ failure (cardiac, respiratory, hepatic, renal, neurological).
Description of the intervention
Initial treatment for paraquat poisoning involves preventing further absorption and reducing the load of paraquat in the blood. Conventional treatment for paraquat poisoning includes gastrointestinal decontamination and haemodialysis/haemoperfusion. Gastrointestinal decontamination, including gastric lavage and a single dose of activated charcoal or Fuller's earth, is recommended for people who present within one hour of ingestion of paraquat (Vale 2004). However, Gawarammana 2011 did not recommend gastric lavage as its use is contraindicated in caustic injury and it is likely to add little to the amount removed by spontaneous vomiting and adsorbents. Haemodialysis and haemoperfusion could be instituted in order to remove paraquat, but these interventions have no confirmed effects for improving survival (Suzuki 1993; Koo 2002). Li 2012 included three randomised controlled trials (RCTs) and showed that glucocorticoid with cyclophosphamide could reduce all‐cause mortality in people with moderate to severely paraquat poisoning. However, this result needs to be proven by more high quality evidence due to limitations with the existing studies.
Xuebijing injection is a complex traditional Chinese preparation consisting of Flos Carthami, Radix Paeoniae Rubra, Rhizoma Chuanxiong, Radix Salviae Miltiorrhizae and Radix Angelicae Sinensis (Huang 2011). Xuebijing injection combined with dexamethasone for the treatment of paraquat ingestion can protect pulmonary structure and ameliorate pulmonary fibrosis and consolidation by inhibiting transforming growth factor beta1 (TGF‐β1), reducing fibroblast migration, and activating and suppressing production of collagenous protein (Wang 2008c). Moreover, several clinical trials have found that Xuebijing injection can protect organs from paraquat injury and reduce mortality due to paraquat poisoning (Li 2008; Liang 2009).
How the intervention might work
Oxidative stress is an important mediator of multi‐organ (particularly pulmonary) damage in severe paraquat poisoning (Suntres 2002; Gawarammana 2011). Xuebijing injection is based on the "bacteria, endotoxin, inflammatory mediator treated simultaneously" theory (Lu 2010). A total of 21 different compounds, including amino acids, phenolic acids, flavonoid glycoside, terpene glycoside and phthalide, have been identified in the Xuebijing preparation (Huang 2011). The main determinants of product quality are saffron yellow A, ligustrazine, danshensu, ferulic acid and paeoniflorin, most of which possess antioxidant properties (Lee 2002; Lee 2005). Furthermore, ferulic acid and ligustrazine have a role in removing oxygen free radicals, and preventing and treating lung fibrosis and lung injury (Qin 2011).
Why it is important to do this review
Although clinical experience suggests that Xuebijing injection might have potential in the management of paraquat poisoning (Li 2008; Sun 2009a; Sun 2009b), there is no conclusion on the effectiveness of this treatment. Given the high prevalence and poor prognosis of paraquat poisoning, it is timely to provide clinicians and patients with the best available evidence of the efficacy of Xuebijing injection for paraquat poisoning.
Objectives
To assess the effects of Xuebijing injection in people with paraquat poisoning.
Methods
Criteria for considering studies for this review
Types of studies
RCTs.
Types of participants
All patients with paraquat poisoning.
Types of interventions
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Intervention: conventional care plus Xuebijing injection.
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Control: conventional care plus placebo or conventional care alone.
Types of outcome measures
Primary outcomes
All‐cause mortality at the end of the follow‐up period.
Search methods for identification of studies
The search was not restricted by date, language or publication status.
Electronic searches
The Cochrane Injuries Group's Trials Search Co‐ordinator searched the following databases:
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Cochrane Injuries Group's Specialised Register (29 May 2013);
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Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, issue 4, 2013);
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MEDLINE (OvidSP) (1946 to September Week 3 2012);
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EMBASE (OvidSP) (1974 to 2012 Week 39);
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CINAHL Plus (EBSCO) (1937 to May 2013);
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ISI Web of Science: Science Citation Index Expanded (1970 to May 2013);
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ISI Web of Science: Conference Proceedings Citation Index‐Science (1990 to May 2013);
We searched the following Chinese databases:
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Chinese bio‐medical literature and retrieval system (CBM) (1978 to December 2012);
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China National Knowledge Infrastructure Database (CNKI) (1915 to December 2012);
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Traditional Chinese Medicine Database (1949 to December 2012).
Search strategies are listed in Appendix 1.
Searching other resources
We searched the reference lists of included studies and previously published reviews for additional materials. We also contacted authors and experts in the field to identify additional studies. We searched various web‐based sources such as Google Scholar and investigated the online trials registers. such as ClinicalTrials.gov (http://clinicaltrials.gov/), Current Controlled Trials (http://www.controlled‐trials.com/) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/).
Data collection and analysis
We worked with the Cochrane Injuries Group's Trials Search Coordinator to run the searches. The search results were collated using a bibliographic software and duplicates were removed before two review authors (JD, DH) independently carried out the screening process. The review was completed according to the methods described in the protocol for this review (Deng 2012).
Selection of studies
Two review authors (JD and DH) independently examined the titles or abstracts, or both, of studies identified by the searches, and excluded all studies that were clearly not relevant to the review. We obtained the full‐text of all articles that appeared to fulfil the pre‐determined inclusion criteria or were unclear. The same review authors (JD and DH) evaluated these studies independently to establish whether they met the inclusion criteria.
Data extraction and management
Two review authors (JD and LZ) independently extracted information on study design, general characteristics of patients, the intervention and control treatment, and outcome data from studies. Extracted data were entered into the Cochrane Collaboration's statistical software, Review Manager 2013, by one author (LZ). Data entry was checked by JD. Trial authors were contacted for missing data where appropriate.
Assessment of risk of bias in included studies
Each study was assessed for risk of bias by three review authors (JD, DH and LZ) independently. The Cochrane Collaboration's tool for assessing risk of bias comprises a description and a judgement for the following criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias. Each criteria was judged 'low risk of bias', 'high risk of bias', or 'unclear risk of bias', which meant either a lack of information or uncertainty over the potential for bias (Higgins 2011).
Measures of treatment effect
We calculated the mortality risk ratio (RR) and 95% confidence interval (CI), and summarised data on all‐cause mortality at the end of follow‐up in a meta‐analysis.
Unit of analysis issues
The patient was the unit of analysis.
Dealing with missing data
In cases of missing data, we contacted study authors directly in order to seek the required information.
Assessment of heterogeneity
We assessed clinical heterogeneity by considering the design of each study. If clinical heterogeneity was not evident, we assessed statistical heterogeneity using the Chi2 test (P < 0.1 indicating significance) and quantified using the I2 statistic (I2 value > 50% means significant heterogeneity) (Higgins 2011).
Assessment of reporting biases
We planned to examine reporting bias using a funnel plot if 10 or more studies were included. As we only included two studies, we did not use funnel plots to investigate reporting bias.
Data synthesis
As statistical heterogeneity was not present among the results of the included studies, we performed a fixed‐effect meta‐analysis and calculated the mortality risk ratio (RR) and 95% confidence interval (CI).
Subgroup analysis and investigation of heterogeneity
We planned to perform subgroup analyses on the oral dose of paraquat ion (low: < 20 mg; moderate: 20 to 40 mg; high: > 40 mg; doses are per kg of body weight). However, the included studies did not report in sufficient detail information of patients' oral dose of paraquat ion. We were unable to obtain this information even after contacting the study authors, and so no subgroup analyses were performed.
Sensitivity analysis
We planned to conduct sensitivity analyses on the effect of blinding (adequate or unclear/not done) and allocation concealment (adequate or unclear/not done), on the robustness of conclusions. As both included studies did not use blinding or allocation concealment, we did not perform sensitivity analyses.
Results
Description of studies
Results of the search
Our electronic search identified 303 studies, including 35 in English and 268 in Chinese. A total of 284 studies, including duplicate references, reviews, basic researches, case reports and non‐RCTs, were excluded after title and abstract examination. Full‐text of 19 studies that claimed to be randomised were retrieved for further assessment. However, none of the study reports described the procedure of randomisation. Of these studies, one historically controlled study was excluded. We successfully contacted seventeen study authors by telephone or e‐mail. Fifteen studies were excluded because true random allocation was not performed. Finally, two studies were identified as true RCTs and one further study was categorised as a study awaiting classification as we could not contact the study author to identify the randomisation method. The study selection process is outlined in Figure 1.
Study flow diagram.
Included studies
We included two studies of 84 patients in this systematic review. Both studies compared conventional care with conventional care plus Xuebijing injection for people with paraquat poisoning. All‐cause mortality at the end of the follow‐up period was the primary outcome in both studies. Study characteristics are shown in Characteristics of included studies.
Excluded studies
Sixteen studies were excluded because the study authors misunderstood true random allocation methods. Study characteristics and reasons for exclusion are shown in Characteristics of excluded studies.
Risk of bias in included studies
Allocation
Both studies claimed to be randomised, but none describe the methods used. After telephoning the study authors, we established that both studies used a random number table. Both studies provided no information about allocation concealment. After telephoning the study authors, we determined that both studies did not conceal the sequence.
Blinding
Both studies did not use blinding.
Incomplete outcome data
All‐cause mortality at the end of the follow‐up period was reported in full in both studies.
Selective reporting
There was no selective reporting of all‐cause mortality.
Other potential sources of bias
No other potential source of bias was found.
Effects of interventions
Both studies reported all‐cause mortality at the end of the follow‐up period. Although there were fewer deaths in people treated with Xuebijing, meta‐analysis showed that Xuebijing injection did not have a statistically significant benefit on reducing all‐cause mortality in people with paraquat poisoning (RR 0.71; 95% CI 0.48 to 1.04; P = 0.08) (Analysis 1.1). There was no heterogeneity between studies (Chi2=0.24, degrees of freedom (df)=1, (P=0.62); I2=0%).
Discussion
Summary of main results
Although there were fewer deaths in people treated with Xuebijing injection, meta‐analysis showed that it did not result in a statistically significant benefit by reducing all‐cause mortality in people with paraquat poisoning.
Overall completeness and applicability of evidence
Both included studies were certainly relevant to the review question. However, the number of studies that could be included in the review was limited by poor methodological quality in the majority of studies identified. Furthermore, information about participants such as weight, amount of toxin and exclusion criteria, was insufficiently reported. More high‐quality effectiveness studies are needed.
Quality of the evidence
Both included studies involved small numbers of participants and were considered to be of poor methodological quality. Both studies did not describe the randomisation procedure. We successfully contacted authors by telephone and established that two studies were RCTs as random number tables were used. However, allocation concealment and blinding were not used in both studies. This may lead to selection, performance and detection bias. There was no evidence of selective outcome reporting.
Potential biases in the review process
Study selection, assessment of the risk of bias, and data extraction were undertaken independently by two authors to reduce the risk of error and bias. Neither author declared a conflict of interest. The search for studies was extensive, and was conducted on English and Chinese language databases. Because only two studies are included in the review and thus we were unable to investigate publication bias using a funnel plot. However, publication bias is always a consideration in any systematic review.
Agreements and disagreements with other studies or reviews
As far as we are aware, this is the only systematic review on Xuebijing injection for paraquat poisoning.
Study flow diagram.
Comparison 1 All‐cause mortality at the end of the follow‐up period, Outcome 1 All‐cause mortality at the end of the follow‐up period.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause mortality at the end of the follow‐up period Show forest plot | 2 | 84 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.48, 1.04] |
