Efficacy of pralidoxime in organophosphorus poisoning: Revisiting the controversy in Indian settingI Banerjee1, SK Tripathi2, A Sinha Roy3
1 Department of Pharmacology, Murshidabad Medical College, Behrampore, West Bengal, India
2 Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India
3 Department of Medicine, Radha Gobinda Kar Medical College, Kolkata, West Bengal, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.128803 Clinical trial registration CTRI/2013/05/003628.
Source of Support: None, Conflict of Interest: None
Clinical trial registration CTRI/2013/05/003628.
Context: Poisoning with organophosphorus (OP) compounds constitutes a global public health problem. Standard treatment of OP poisoning involves use of atropine and pralidoxime. While efficacy of atropine is well-established, clinical experience with pralidoxime in management of OP poisoning is controversial. Aims: To explore the efficacy of add-on pralidoxime with atropine over atropine alone in the management of OP poisoning. Settings and Design: An open-label, parallel-group, randomized clinical trial was conducted in a tertiary care district hospital in West Bengal. Materials and Methods: Patients presenting with features of OP poisoning were randomly allocated to receive atropine or atropine-plus-pralidoxime. Efficacy was assessed by analyzing mortality, requirement for ventilator support and the duration of stay in hospital. Statistical analysis: Chi-square test was done to compare the efficacy parameters between the two groups. A two-tailed P-value <0.05 was considered as statistically significant. Results: During the study period, 150 patients were screened following which 120 patients were randomized to either of the treatment arms. Add-on pralidoxime therapy did not offer any appreciable benefit over atropine alone in terms of reducing mortality (18.33% (11/60) versus 13.33% (8/60)) and ventilator requirement (5% (3/60) versus 8.33% (5/60)). However, patients randomized in the add-on pralidoxime arm experienced longer duration of hospital stay (7.02 ± 1.12 days) than those receiving atropine-alone therapy (5.68 ± 1.87 days) (P < 0.001). Conclusion: The present study suggested that add-on pralidoxime with atropine therapy did not offer any appreciable benefit over atropine alone in management of OP poisoning. However, further trials are needed to explore different dosing regimens of pralidoxime in order to determine its efficacy in OP poisoning.
Keywords: Atropine, clinical trial, organophosphorus poisoning, pralidoxime
Poisoning with organophosphorus (OP) compounds is a global public health problem. According to World Health Organization (WHO), 3 million cases of pesticide (mainly OP compounds) poisoning occur every year, resulting in an excess of 250,000 deaths.  India is a predominantly agrarian country where pesticides are widely used for farming. As per estimates of National Crime Bureau of India, suicides by consumption of pesticides account for 19.4 and 19.7% of all cases of suicidal poisoning in the year 2006 and 2007, respectively. 
OP compounds inhibit acetylcholinesterase in the cholinergic synapses resulting in accumulation of acetylcholine (ACh) and consequent uncontrolled activation of these synapses.  The current management protocol of OP poisoning includes resuscitation, administration of the antimuscarinic agent atropine, an acetylcholinesterase reactivator such as pralidoxime, and assisted ventilation, if necessary.  While the efficacy of atropine has been well-established, clinical experience with pralidoxime has led to widespread doubt about its efficacy in treatment of OP poisoning.  It has been suggested in an earlier study that in Indian hospitals, a dose of 1 g pralidoxime every 4-6 h for 3-5 days has been frequently used though efficacy of such regimen is shrouded with controversy.  In fact, the abovementioned dose of pralidoxime is used routinely for management of OP poisoning patients in present study setting. Since OP poisoning accounts for a high incidence of mortality in rural India, it was essential to test the efficacy of such regimen in Indian setting.
Since early 1990s, several clinical trials have been conducted worldwide to explore the efficacy of pralidoxime in OP poisoning with variable results. ,,,,,,,, However, only a few studies have considered the abovementioned dose of pralidoxime. We earlier conducted one pilot study with add-on pralidoxime in OP poisoning where it was revealed that add-on pralidoxime therapy did not offer any advantage over atropine monotherapy. However, being a pilot study it was inadequately powered, apart from the fact that the dose of pralidoxime used in the study varied according to the judgment of the treating physician. In this backdrop, we conceived the present study with the objective of exploring the efficacy of add-on pralidoxime over atropine monotherapy in the management of OP poisoning.
Study design: An open-label, parallel-design, randomized, clinical trial was conducted in a tertiary care district hospital for a period of two years commencing from June 2008.
Ethics : The study was approved by institutional ethics committee and was conducted in accordance with the principles of the Declaration of Helsinki, Indian Good Clinical Practice guidelines, and other applicable regulatory mandates of the country. Informed consent was obtained from eligible patients or the legally authorized representatives, if patient was unconscious before screening the patient for participating in the study. The trial was registered duly in the Clinical Trial Registry of India, No. CTRI/2013/05/003628.
Study procedure : All consecutive patients, presenting in the emergency department of the hospital during the study period, with history and clinical evidence of OP poisoning were screened for eligibility in the study. Patients of either sex and of age more than 12 years, who presented within 24 h following exposure to OP compounds, and had taken an OP compound other than a carbamate, were considered eligible for participation. All eligible patients were assessed by a poison severity scoring scale - Peradeniya Organophosphorus Poisoning (POP) Scale,  the details of which is given in [Table 1]. Patients, on presentation, underwent clinical examination and resuscitation following which they were randomized into one or the other study arm as mentioned below.
Group 1: Atropine was administered in the dose of 2 mg intravenous (i.v.) stat and then 2 mg i.v. every 5-10 min till the signs of atropinization appeared. Criteria used for assessing adequate atropinization included: Clear chest on auscultation, heart rate >80/min, systolic BP >80 mmHg, pupils no longer pinpoint, and dry axillae. At least four end-points were achieved, including all of the first three, before considering a patient atropinized.  After achieving atropinization, the interval between the doses was so increased as to just maintain adequate atropinization. Atropine was slowly withdrawn over a period of 5 days. Group 2: Atropine was used in the same manner as in Group 1 and pralidoxime chloride was given in a dose of 1 g i.v. every 6 h for a period of 5 days.
Patients were randomly assigned to either of the treatment groups following simple randomization procedure. Randomization sequence was created by an independent statistician using a computer generated randomization list. The treating physician was responsible for enrolling the patients in the study. Allocation sequence was concealed from the treating physician by placing them in sequentially numbered, sealed, and opaque envelope.
During the course of treatment, patients with clinical evidences of respiratory failure were urgently shifted to the intensive care unit (ICU). Those requiring mechanical ventilation were put on ventilator and the support was continued till they fulfilled the criteria of weaning. Patients who did not require mechanical ventilation were treated with oxygen supplementation and other routine care until stabilized.
Outcome assessment: Efficacy outcome in either arm was analyzed through finding out: Mortality, requirement for ventilator support, and the duration of stay in hospital (expressed in days).
Statistical analysis: On critical examination of earlier hospital records, it was found that atropine therapy caused 80% survival in OP-poisoned patients. We assumed that pralidoxime and atropine combination will increase the survival rate to 90%. A noninferiority margin of 10% was set at 5% significance level and 90% power. This led to a sample size of 108 patients with 54 patients in each treatment group. However, as this study was conducted among inpatients, we assumed the dropout rate to be 10%. The total calculated sample size was 118 which was rounded off to 120, that is, 60 patients in each group. Data were analyzed using descriptive and inferential statistics. Interval data have been expressed as mean ± standard deviation (SD). Chi-square test was done to compare the efficacy parameters between the two groups. A two-tailed P-value <0.05 has been considered as statistically significant. Data analysis was done using Statistical Package for Social Sciences (SPSS; version 11, Chicago IL, USA).
During the study period, 150 patients with history of OP poisoning were screened in emergency department. A total of 30 patients were excluded from the study in 17 patients, more than 24 h had elapsed following exposure; six patients were of <12 years; the other seven patients were considered asymptomatic and discharged following few hours observation in hospital. Thus, a total of 120 patients were considered eligible and randomly assigned into two groups of 60 patients each. No patients withdrew from the study and all 120 patients were available for analysis. The details of the flow of participants through each stage of the trial are shown in [Figure 1]. The baseline demographic characteristics of patients in two treatment groups are summarized in [Table 2].
Mortality rate: In the present study, 19 out of 120 patients died during hospital stay resulting in a mortality rate of 15.83%. Case fatality was higher (18.33%, 11/60) in Group 2 patients (add-on pralidoxime arm) as compared to those in Group 1 (13.33%, 8/60), that is, those receiving atropine.
Requirement of ventilator : A total of eight out of 120 patients (6.67%) were put on ventilator during treatment. Five patients in Group 1 (8.33%, 5/60) and three patients in Group 2 (5%, 3/60) required ventilatory support.
However, neither of these differences between the two groups were found to be statistically significant.
Duration of stay in hospital : The mean duration of stay in the hospital (in days) was 5.68 ± 1.87 (mean ± SD) in Group 1, that is, atropine only group as compared to 7.02 ± 1.12 (mean ± SD) in the Group 2 receiving both atropine and pralidoxime (P < 0.001).
Adverse reactions: No significant adverse reaction was reported in either of the treatment arms.
The management protocol of OP poisoning usually involves the use of atropine and pralidoxime. In the early nineties, clinicians started questioning the efficacy of pralidoxime in OP poisoning. The early research in this field was led by Duval et al.,  and De Silva et al.,  which was followed by trials of Samuel et al.,  Balali-Mood et al.,  Cherian et al.,  and Chabra et al.,  using a variety of dosing regimens of pralidoxime. All these studies revealed that either add-on pralidoxime therapy did not offer any added benefit ,,,, or was associated with worse outcome when compared to treatment with atropine.  Additionally, results of two meta-analyses concluded that pralidoxime caused more harm to these patients than benefit. , However, both nonrandomized historical studies as well as randomized controlled trials were considered in the meta-analysis. , In contrast, the proponents of oximes opined that the doses used in these trials were too low to be effective and recommended a higher dosing regimen as suggested by WHO, that is, at least 30 mg/kg pralidoxime salt, i.v., as a loading dose, followed by 8 mg/kg infusion. Eddleston et al., in 2009 in their study  used the WHO-recommended high-dose pralidoxime regimen and concluded that such regimen did not improve survival in all patients. However, majority of these studies primarily considered two efficacy parameters - mortality rates and ventilator requirement. In our present piece of work, we additionally considered duration of hospital stay as an efficacy parameter as in a resource-constrained setting like ours, prolonged hospital stay is associated with profound socioeconomic impact.
The results from the present study suggest that add-on pralidoxime therapy did not offer any appreciable benefit in terms of reducing mortality and ventilator requirement when compared with atropine monotherapy. This finding is in concordance with results observed in studies reported by Duval et al., (1991);  De Silva et al., (1992);  Chugh et al., (2005);  and Eddleston et al., (2009).  However, it did not support that pralidoxime in combination with atropine is associated with a significantly higher risk of death and increased need for ventilatory support as observed by Samuel et al.  In the present study, patients randomized in the pralidoxime add-on arm experienced longer duration of hospital stay than those receiving atropine monotherapy despite having comparable severity at baseline. This finding is in discordance with the results obtained in an earlier study by us where we found no statistically significant difference in duration of hospital stay between two treatment arms.  However, the study was a pilot one and both dose and duration of pralidoxime therapy were different from the present one.
The present study was not without its limitations that can be summarized as follows. The study could not measure RBC cholinesterase level in poisoned patients which has got significance in determining response to treatment with pralidoxime. Follow-up of the poisoned patients after being discharged from the hospital was also beyond the scope of the present study. The present study was conducted in a single center within a narrow time frame; hence the sample size calculation was based on noninferiority design and post hoc power calculation reveals it to be underpowered (70%). A well-designed adequately powered multicentric randomized controlled trial with larger sample size could definitely address the study objective in a more meaningful way. Any further work to address similar objective should take into account the above issues to provide a more convincing answer to the controversy of efficacy of add on pralidoxime therapy over atropine in OP poisoning management.
In conclusion, the results from the present study suggest that add-on pralidoxime therapy did not offer any appreciable benefit in terms of reducing mortality and ventilator requirement when compared with atropine alone. On the other hand, patients randomized in the add-on pralidoxime arm experienced longer duration of hospital stay than those receiving atropine monotherapy. Further trials to explore different dosing regimens of pralidoxime are required to assess the risk/benefit of pralidoxime in OP poisoning.
[Table 1], [Table 2]