a b s t r a c t

Objective: This study aimed to clarify the efficacy of 2 therapies for patients with severe acute organophosphorus pesticide poisoning, including atropine adverse effects, the length of intensive care unit stay, complications, and mortality.

Methods: A retrospective cohort study of 152 cases collected from May 2008 to November 2012 at 2 urban university hospitals was conducted. Patients admitted to the hospital for organophosphate poisoning were divided into 2 groups with different therapeutic regimens: group A was administered a repeated pulse Intramuscular injection of pralidoxime chloride, and group B received the same initial dosage of atropine and pralidoxime chloride, but pralidoxime chloride intravenous therapy was administered for only 3 days, regardless of the length of atropine therapy. Subsequently, atropine adverse effects, length of ICU stay, complications, and mortality were statistically analyzed and compared between the 2 groups.

Results: The total dose of atropine was 57.40 +- 15.14 mg in group A and 308.26 +- 139.16 mg in group B; group A received less atropine than did group B (P = .001). The length of ICU stay in group A was reduced (P = .025), and group A had fewer atropine adverse effects (P = .002). However, there was no significant difference in the mortality or complication rate between the 2 groups (P N .05).

Conclusion: In patients with Severe poisoning, group A used less atropine, had fewer atropine adverse effects, and had a shorter ICU stay. We suggest that therapy should be started as early as possible using a sufficient amount of pralidoxime chloride started intramuscularly in combination with atropine and that the drugs should not be prematurely discontinued.

(C) 2013

Introduction

Organophosphorus pesticide poisoning causes approximately 200 000 deaths each year worldwide [1]. The standard treatment of acute organophosphorus pesticide poisoning (AOPP) involves the adminis- tration of intravenous (IV) atropine and pralidoxime to counter acetylcholinesterase (AChE) inhibition at the synapse, Symptomatic treatment, and supportive therapy. However, clinical trials have demonstrated the ineffectiveness of the Standard therapy, with a high mortality of 43.94% [2] in Southeast Asia and India. Different organophosphates have different mortality [3]. The major causes of mortality for Insecticide poisonings were the toxic effect of organo- phosphate, coma, and respiratory failure [4,5].

The standard therapy for poisoning with organophosphorus pesticides requires IV atropine and oximes [6]. The role of oximes as cholinesterase agents for the treatment of organophosphorus pesti- cide poisoning has been further studied. However, oximes may not be

? This work was supported by Shanghai ShenKang Hospital Development Center (SHDC12012226).

* Corresponding author. Tel.: +86 21 37798528.

E-mail address: [email protected] (R. Wang).

useful for several theoretical and practical reasons, particularly for the late presentation of patients with dimethyl organophosphorus poisoning and in those with a large excess of organophosphorus poisoning that simply reinhibits reactivated enzymes [7]. Therefore, it is important to explore and quantify the safest and most effective method of administering oximes to patients with AOPP [8-10]. Treatment with atropine, which inhibits the effects of acetylcholine at muscarinic receptors, is well established [11,12]. However, studies have suggested that oximes fail to benefit patients or decrease mortality [13,14]. Therefore, many physicians prefer using only atropine to improve symptoms. Unfortunately, using a Large dose of atropine has many adverse effects including increased mortality from atropine overdose.

This study aimed to determine the efficacy of 2 therapies in patients with severe AOPP and evaluated atropine adverse effects, the length of intensive care unit (ICU) stay, complications, and mortality.

Materials and methods

This retrospective study was conducted on patients with organ- ophosphorus poisoning admitted to 2 ICUs between May 2008 and

0735-6757/$ – see front matter (C) 2013 http://dx.doi.org/10.1016/j.ajem.2013.03.012

X. Tang et al. / American Journal of Emergency Medicine 31 (2013) 946–949 947

November 2012. A total of 152 patients were enrolled. The diagnosis was based on information collected from either the patients or the family members regarding the agent involved in the exposure. We confirmed the diagnosis with clinical manifestation and plasma cholinesterase levels.

General information

A total of 152 patients were hospitalized with AOPP between May 2008 and November 2012 aged 14 to 80 (40.49 +- 15.08) years. Fifty- four patients were male, and 98 were female.

Types of poisons involved in these AOPP cases observed included the following: 15 cases of methamidophos, 35 cases of dichlorvos, 16 cases of dimethoate, 19 cases of chlorpyrifos, and 67 unidentified other cases. Although 6 patients had an accidental cutaneous exposure to organophosphate, the remaining patients ingested organophosphate.

Grouping criteria

Patients admitted to the hospital for organophosphate poisoning were categorized by poisoning severity score (PSS) [15]. The patients were then divided into 2 groups with different therapeutic regimens. Patients in group A were administered a different dose of pralidoxime chloride according to different PSS. Patients with severe (PSS 3-4) were administered 1 g intramuscularly (IM) every hour x 3, followed by 1 g IM every 2 hours x 3, and then 1 g IM every 4 to 6 hours (q4- 6h), with the daily total not exceeding 10 to 12 g on the first day. On the second day, pralidoxime chloride was reduced to 1 g IM q4-6h, according to the patient situation. Moderate patients (PSS 2) were administered 1 g IM q4-6h. Mild patients (PSS 0-1) were administered

0.5 g q4-6h. Patients in group A received pralidoxime chloride combined with a small dose of atropine. In group A, the initial atropine dose was administered according to the PSS as follows: 5 to 10 mg IV for severe poisoning (PSS 3-4), 2 to 4 mg for moderate poisoning (PSS 2), and 1 to 2 mg for mild poisoning (PSS 0-1). Atropine was reduced to 1 to 2 mg IV q2-3h after atropinization.

Atropine should be administrated along with pralidoxime chlo- ride, and atropinization should be achieved as early as possible. Patients in group B were given the same initial dose of atropine and pralidoxime; however, pralidoxime was given just 3 days along with a continuous IV infusion of atropine. The subsequent dose of atropine in group B is diversiform. The indication for discontinuing these 2 drugs included clinical signs of a cure without muscarinic, nicotinic, or central nervous system symptoms, and AChE activity increased to 50% to 60% of the normal value, with further observation for 24 hours. When patients presented with an intermediate syndrome in the treatment process, intensive pralidoxime chloride was used and combined with a small dose of atropine.

Oral poisoning patients with a PSS of 2 to 4 underwent gastric lavage. On admission to the emergency department, patients presenting with shock, cerebral edema, or pulmonary edema received airway protection before lavage. In addition, patients with oral poisoning received the established therapy: skin cleaning, gastric lavage, purges, catharsis, antidotes, and hemoperfusion, or hemodi- alysis when necessary.

Outcome measures

The primary outcome measurement was mortality from AOPP intoxication. The outcome measures also included the observed clinical manifestations, plasma cholinesterase activity [16,17], atropine adverse effects, complications (ie, liver, brain, kidney, and metabolic dysfunction), length of ICU stay, and the outcome for each patient. All patients were followed up for 4 to 8 weeks after discharge.

Statistical analysis

The measurement data were expressed as the mean +- SD. The count data were analyzed using the ?² test, and the measurement data were analyzed using a t test. All analyses were performed with SPSS 19.0 statistical software (Chicago, Illinois). P b .05 was considered statistically significant.

Results

Baseline characteristics of the 2 groups

The baseline characteristics of the patients in the 2 groups are illustrated in Table 1. There was no significant difference between the 2 groups regarding the total dose of pralidoxime chloride; the dose of atropine in group A was 57.40 +- 15.14 mg, and the dose in group B was

308.26 +- 139.16 mg, with the group A dosage being significantly lower (P = .001). The atropine withdrawal time was 3.98 +- 2.16 days in group A and 6.79 +- 4.19 days in group B. The withdrawal time was significantly shorter in group A (P = .003; Table 1). Dimethoate can present differently from other organophosphorus with Cardiovascular collapse before cholinergic crises. However, only 1 of the 16 dimethoate- Poisoned patients in our study demonstrated nodal tachycardia on an electrocardiogram. No patient presented with the clinical manifesta- tions of cardiovascular collapse. No patient vomited during therapy. Only 1 patient presented with an intermediate syndrome in group A and 1 patient with atropine intoxication in group B.

Atropine adverse effects in the 2 groups

Atropine adverse effects occurred in 3 of 36 severe cases in group A and 11 of 27 severe cases in group B; fewer patients with severe cases in group A had atropine adverse effects (P = .002; Table 2). Atropine adverse effects occurred in 5 of 48 (PSS 0-2) patients in group A and 6 of 51 in group B. In all group A patients, the rate of atropine adverse effects was 8 of 74, whereas it was 17 of 78 in group B. There was no significant difference between the 2 groups in the rate of atropine adverse effects in other patients (P = .831) or all patients (P = .068).

Length of ICU stay in the 2 groups

The length of ICU stay in group A was 4.89 +- 2.89 days, and in group B, the length of stay was 6.52 +- 5.10 days. Group A had a significantly shorter length of stay than group B (P = .025; Fig.).

Table 1

Baseline characteristics of patients in groups A and B with AOPP at admission

Characteristics	Group A	Group B	P	Power
	(n = 74)	(n = 78)		analysis
Age (y)	39.57 +- 16.32	40.72 +- 15.63	.86
Female	46 (62.16%)	52 (66.67%)	.336
Chronic disease	19 (25.67%)	12 (15.38%)	.116
Level of AChE (U/L)	1381.61 +- 2414.60	1780.82 +- 2872.32	.867	1390
Empty stomach	44 (59.46%)	47 (60.26%)	.922
Hemoperfusion	27 (36.49%)	20 (25.64%)	.148	564
Atropine withdrawal	3.98 +- 2.16	6.79 +- 4.91	.003	62
time (d)
Mortality in 24 h	0 (0%)	0 (0%)	–
Total dose of	12.56 +- 9.00	14.02 +- 9.91	.521	1322
pralidoxime chloride Total dose of atropine	57.40 +- 15.14	308.26 +- 139.16	.001	10

Power analysis: ? = .05, 1 – ? = 0.8. There was no significant difference between the 2 groups regarding the pralidoxime chloride dose, general patient condition, age, sex, chronic diseases, level of AChE, or withdrawal time. However, group A had a shorter withdrawal time and received a lower dose of atropine (P b .05).

948 X. Tang et al. / American Journal of Emergency Medicine 31 (2013) 946–949

Table 2

Atropine adverse effects in the 2 groups

Table 3

Mortality in the 2 groups

PSS	Group A	Group B	P	Power analysis		PSS	Group A	Group B	P	Power analysis
3-4	3/36	11/27	.002	40		3-4	8/36	5/27	.133	3716
0-2	5/48	6/51	.831	18 258		0-2	0/48	0/51	–
Total	8/74	17/78	.068	352		Total	8/74	5/78	.332	1274

Power analysis: ? = .05, 1 – ? = 0.8. Atropine adverse effects occurred less frequently in group A patients with severe organophosphate poisoning (P = .002). There was no significant difference between the 2 groups for nonsevere cases.

Power analysis: ? = .05, 1 – ? = 0.8. There was no significant difference in mortality between the 2 groups (P N .05).

Mortality and complications in the 2 groups

In group A, 8 of 36 patients with severe cases (PSS 3-4) died, whereas 5 of 27 died in group B. For all patients in group A, the mortality rate was 8 of 74, and the rate in group B was 5 of 78. The mortality rate did not significantly differ between the 2 groups (Table 3). In group A, 1 patient died of dimethoate, 2 patients died of methamidophos, 2 patients died of dichlorvos, and 3 patients died of other organophosphorus. In group B, 2 patients died of dichlorvos and 3 patients died of other organophosphorus. Complications (ie, liver, brain, kidney, and metabolic dysfunction) occurred in 15 of 36 severe cases in group A and 14 of 27 severe cases in group B. For all patients, the mortality of group A was 15 of 74, and the mortality of group B was 14 of 78. There was no significant difference between the 2 groups in patients with serious complications (Table 4). No delayed adverse events or neurologic complications were noted in either group.

Discussion and conclusions

The repeated pulse IM injection of pralidoxime chloride may be suitable in patients with severe AOPP. For more than 5 decades, pyridinium oximes have been used as therapeutic agents in the treatment of organophosphorus poisoning [18]. The oximes represent important medical countermeasures to nerve agent poisonings [19]. Pralidoximes are enzyme reactivators that reactivate phosphorylated AChEs by binding to the organophosphorus molecule. The use of oximes in the treatment of acute organophosphorus poisoning has been controversial for more than 2 decades [20]. A meta-analysis [4] of 7 Randomized controlled trials of pralidoxime found that 3 RCTs involving 366 patients studied pralidoxime vs placebo, and 4

Fig. Length of ICU stay in the 2 groups (**P b .01). The length of ICU stay in group A was

4.89 +- 2.89 days, and it was 6.52 +- 5.10 days in group B, with group A having a significantly shorter stay than group B (P = .025). Power analysis: ? = .05, 1 – ? = 0.8, n = 206.

RCTs involving 479 patients compared 2 or more different doses. These trials found disparate results, with treatment effects ranging from benefit to harm. However, many studies did not consider several issues important to the outcomes. In particular, baseline character- istics were not equalized, oxime doses varied widely, there were substantial delays to treatment, and the type of organophosphate was not considered. These factors all affected the results. However, an RCT

[21] in 2010 found that patients receiving a high-dose regimen of pralidoxime (24 g/d) experienced fewer deaths (1% vs 8%) and fewer cases of pneumonia (8% vs 35%) compared with patients administered 6 g/d.

The World Health Organization recommended regimen (a 30-mg/ kg pralidoxime chloride bolus followed by an 8-mg kg^-1 h^-1 infusion) was not supported by our data [4]. In our study, critical patients (PSS 3-4) were administered a much higher dose of pralidoxime 1 g IM every hour x 3, followed by 1 g IM every 2 hours x 3 and 1 g IM q4-6h, with the daily total not exceeding 10- to 2 g on the first day. On the second day, pralidoxime chloride was reduced to 1 g q4-6h according to the patient situation. The total mortality rate was 10.81%, and in patients with severe cases, the mortality rate was 22.22%. Most of patients died of multiple-organ dysfunction syndrome or very severe situation (PSS 3-4) on admission. Only 1 of the patients presented with intermediate syndrome and that patient survived.

Oxime cholinesterase reactivators are rapidly metabolized by the liver, and 83% are excreted by the kidney within 4 hours after IV administration. Rapid Bolus injection can cause explosive vomiting, respiratory muscle inhibition, and arrhythmia resulting in crises [6,22]. The rapid administration of pyridine-2-aldoxime methyl chloride IV frequently causes explosive vomiting [23,24]. However, in our study, patients neither vomited nor had crises. The rapid metabolism of IV oximes after their administration has received more attention in the treatment of AOPP [25]. An animal study confirmed that approximately 90% of a single IM dose of oximes was present in the plasma 180 minutes after administration [26]. Therefore, IM administration was able to maintain a sustained plasma concentration and resulted in fewer adverse effects.

A sufficient amount of pralidoxime chloride and a smaller dose of atropine should be used in combination for the treatment of organophosphorus pesticide poisoning. There is a substantial mortal- ity rate associated with atropine overdose when treating patients with AOPP [22]. In our study, group A used less atropine and had fewer atropine adverse effects and a significantly shorter atropine withdrawal time and ICU length of stay. Therefore, a sufficient amount of pralidoxime chloride combined with a smaller dose of atropine is could also reduce the possibility of atropine overdose.

Table 4

Complications in the 2 groups

PSS	Group A	Group B	P	Power analysis
3-4	15/36	14/27	.422	750
0-2	0/48	0/51	–
Total	15/74	14/78	.133	9150

Power analysis: ? = .05, 1 – ? = 0.8. There was no significant difference between the 2 groups in patients with serious complications (P N .05).

X. Tang et al. / American Journal of Emergency Medicine 31 (2013) 946–949 949

Based on the literature and our clinical experience, there are many advanced alternatives in place of the traditional approach. In this retrospective study, 152 cases were reviewed, and the toxicity of the different treatments was analyzed. The patients were subsequently divided into 2 groups: severe cases (PSS 3-4) and others (PSS 0-2). Although there were no significant differences at baseline between the 2 groups, the proposed therapy of repeated pulse IM administered pralidoxime chloride with a smaller dose of atropine (group A) showed a significant reduction in the length of ICU stay and atropine-related adverse effects compared with the standard treatment (group B).

We suggest that therapy should be started as early as possible using a sufficient amount of pralidoxime chloride delivered IM in combina- tion with small dose of atropine for patients with severe AOPP. In the same time, treatment should not be discontinued too early.

Limitations

Some limitations of this study may have affected the results, including the small size of the study sample and the inclusion of different types of toxic organophosphorus poisonings, which may have skewed the distribution.

Acknowledgments

We thank Nick Kwan, MD; Xiaopeng Guo; Binbin Wang; and Huifang Zhang for their comments on this manuscript and the medical nursing staff in the ICU who cared for the patients and collected the data.

References

1. Gunnell D, Eddleston M, Phillips MR, et al. The global distribution of fatal pesticide self-poisoning: systematic review. BMC Public Health 2007;7:357.
2. Dash SK, Mohanty MK, Mohanty S, et al. Organophosphorus poisoning: victim specific analysis of mortality and morbidity. Med Sci Law 2008;48:241-5.
3. Kang EJ, Seok SJ, Lee KH, et al. Factors for determining survival in acute organophosphate poisoning. Korean J Intern Med 2009;24:362-7.
4. Chien WC, Chung CH, Jaakkola JJ, et al. Risk and prognostic factors of inpatient mortality associated with unintentional insecticide and herbicide poisonings: a retrospective cohort study. PLoS One 2012;7:e45627.
5. Munidasa UA, Gawarammana IB, Kularatne SA, et al. Survival pattern in patients with acute organophosphate poisoning receiving intensive care. J Toxicol Clin Toxicol 2004;42:343-7.
6. Eddleston M, Dawson A, Karalliedde L, et al. Early management after self- poisoning with an organophosphorus or carbamate pesticide–a treatment protocol for junior doctors. Crit Care 2004;8:391-7.
7. Buckley NA, Eddleston M, Li Y, et al. Oximes for acute organophosphate pesticide poisoning.Cochrane Database Syst Rev 2011;2 CD005085.
8. Lotti M. A critical review of oximes in the treatment of acute organophosphate poisoning. J Toxicol Clin Toxicol 2003;41:440441.
9. Peter JV, Moran JL, Graham P. Oxime therapy and outcomes in human organophosphate poisoning: an evaluation using meta-analytic techniques. Crit Care Med 2006;34:502-10.
10. Eyer P. The role of oximes in the management of organophosphorus pesticide poisoning. Toxicol Rev 2003;22:165-90.
11. Eddleston M, Eyer P, Worek F, et al. Pralidoxime in acute organophosphorus insecticide poisoning–a randomised controlled trial. PLoS Med 2009;6:e1000104.
12. Rahimi R, Nikfar S, Abdollahi M. Increased morbidity and mortality in acute human organophosphate-poisoned patients treated by oximes: a meta-analysis of clinical trials. Hum Exp Toxicol 2006;25:157-62.
13. Johnson S, Peter JV, Thomas K, et al. Evaluation of two Treatment regimens of pralidoxime (1 gm single bolus dose vs 12 gm infusion) in the management of organophosphorus poisoning. J Assoc Physicians India 1996;44:529-31.
14. Cherian AM, Peter JV, Johnson S, et al. Effectiveness of pralidoxime in the treatment of organophosphorus poisoning: a randomized, double blind, placebo controlled clinical trial. J Assoc Physicians India 1997;45:22-4.
15. Persson HE, Sjoberg GK, Haines JA, et al. Poisoning severity score. Grading of acute poisoning. J Toxicol Clin Toxicol 1998;36:205-13.
16. Eddleston M, Buckley NA, Eyer P, et al. Management of acute organophosphorus pesticide poisoning. Lancet 2008;371:597-607.
17. Hmouda H, Ben Salem C, Bouraoui K. Management of acute organophosphorus pesticide poisoning.Lancet 2008;371:2169-70 [author reply 2170-2171].
18. Jokanovic M, Prostran M. Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds. Curr Med Chem 2009;16:2177-88.
19. Kassa J, Musilek K, Karasova JZ, et al. Two possibilities how to increase the efficacy of Antidotal treatment of nerve agent poisonings. Mini Rev Med Chem 2012;12: 24-34.
20. Simkhada NR, Kafle KK, Prasad PN. Pralidoxime in organophosphorus poisoning. JNMA J Nepal Med Assoc 2010;50:300-2.
21. Pawar KS, Bhoite RR, Pillay CP, et al. Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial.Lancet 2007;369:1425-6 author reply 1427.
22. Husain K, Ansari RA, Ferder L. pharmacological agents in the prophylaxis/treat- ment of organophosphorous pesticide intoxication. Indian J Exp Biol 2010;48: 642-50.
23. Stephen S, Laura P, et al. The pharmacokinetics of continuous infusion pralidoxime in children with organophosphate poisoning. J Toxicol Clin Toxicol 1998;36: 549-55.
24. Lotti Marcello, Becker Charles E. Treatment of acute organophosphate poisoning: evidence of a direct effect on central nervous system by 2-PAM (pyridine-2- aldoxime methyl chloride). J Toxicol Clin Toxicol 1982;19:121-7.
25. Buckley NA, Eddleston M, Szinicz L. Oximes for acute organophosphate pesticide poisoning.Cochrane Database Syst Rev 2005;1 CD005085.
26. Karasova JZ, Chladek J, Hroch M, et al. Pharmacokinetic study of two acetylcholinesterase reactivators, trimedoxime and newly synthesized oxime K027, in rat plasma. J Appl Toxicol 2013;33:18-23.