INTRODUCTION
Organophosphates are used as domestic and industrial pesticides since 1937.[1] Many opportunities for acute organophosphates (OP) poisoning are allowed due to its easy availability.[2] In 2014, more than 2900 cases of OP poisoning were reported to the American Association of Poison Control Centers with more than 700 cases had serious outcomes and three deaths.[3] In developing countries, pesticide poisonings were associated with high mortality rates, especially in rural areas.[4] In Egypt, more than 10% of the intoxicated cases consumed OP pesticides.[5]
Their acute toxic effects are related to irreversible inactivation of acetylcholine esterase enzyme (AChE) at a variety of neurotransmitter receptors; including sympathetic, parasympathetic, skeletal muscle, and central nervous system sites.[6]
Their nonpharmacologic treatment includes resuscitation and decontamination depending on the OP entrance route.[7]
However, their pharmacologic treatment includes symptomatic treatment, for example, atropine and diazepam, causal treatment, for example, AChE reactivators (oximes),[8] and other therapeutic toxicity ameliorating or reducing agents, for example, MgSO4 and clonidine.[910]
Magnesium is an essential cofactor in several enzymatic reactions and maintains cellular homeostasis.[11] The role of magnesium in OP poisoning is not yet fully understood, but it inhibits acetylcholine release through blocking calcium channel.[12]
The aim of this study is to elaborate the clinical benefits of MgSO4 in management of OP intoxicated patients.
MATERIALS AND METHODS
A case–control study was approved by the Ethical Committee, Faculty of Medicine, Cairo University and was done in line with the ethical principles set out in Declaration of Helsinki. It was conducted at National Egyptian Center for Toxicological Research (NECTR)-Cairo University from August 2014 to October 2016. According to the clinical condition of the patient, the patient himself or his/her relative signed a written informed consent.
Any adult patient diagnosed as OP poisoning based on the history of exposure to OP, presence of known nicotinic and/or muscarinic manifestations on examination, and/or reduced levels of AChE at the time of presentation was included in the study.[6] Patients who had any concomitant ingestion, chronic disease, or received advanced medical care before admission were excluded from the study.
Included patients were randomly allocated to routine treatment (Mg-nontreated patients) or to routine treatment in addition to MgSO4 in a dose 1 g (intravenous [IV])/6 h for 4 doses (total dose 4 g) (Mg-treated patients).[10] Randomization was done by a stratified allocation procedure designed to balance the two groups.
On admission to the emergency department, blood samples were withdrawn from patients, after detailed history and clinical examination, to determine Mg++ level using a flame atomic absorption spectrometric method[13] and plasma cholinesterase (PChE) level using a kinetic colorimetric method.[14]
Moreover, arterial blood gases using blood gas analyzer, Bayer 855;[15] liver function tests; including alanine aminotransferase and aspartate aminotransferase using NADH Kinetic UV method,[16] kidney function tests; including blood urea nitrogen and serum creatinine; using colorimetric method according to Houot;[17] and baseline 12-lead electrocardiography with a paper speed of 25 mm/s were performed for each patient.
All patients received routine nonpharmacological and pharmacological treatment; atropine (1 mg IV bolus every 5 min to 30 min time interval till resolution of muscarinic manifestations, for example, secretions, bradycardia, and miosis). Then, 10%–20% of the total amount of required atropine was continued as infusion and gradually reduced[18] and pralidoxime (30 mg/kg over 60 min followed by 8 mg/kg/h until recovery or death).[10]
The patients were monitored every 15 min in 1st h, then every 30 min in 2nd h, then every 1 h for 24 h after admission. A workup sheet [vital signs, nicotinic, muscarinic manifestations, signs of atropinization, biochemical, hematological investigations, medical, and pharmacological management] was used. Mg++ level was repeated 24 h after administration while PChE levels were repeated daily till normalization.
Statistical analysis
All statistical calculations were done using Statistical Package for the Social Science version 15 (IBM, Armonk, NY, United States of America). The data were statistically described in terms of mean ± standard deviation, frequencies and percentages. Comparison of numerical variables was done using Student's t-test for independent samples while comparison of categorical data was done using Chi-square test. P < 0.05 was considered statistically significant.
RESULTS
One hundred patients with acute OP poisoning presented to (NECTR) from August 2014 to October 2016. Fifty patients were allocated to be in Mg-treated group (25 males and 25 females). The main manner of intoxication was suicidal ingestion. Their mean age was 27.54 ± 11.71 years. Regarding demographic data, no significant difference was observed between two groups Table 1.
;)
Table 1: Demographic data of the studied patients
The clinical presentation in the studied groups was presented in Table 2. Constricted pupils (89%), muscle fasciculation (79%), chest crepitation (64%), normal blood pressure (75%), and vomiting (87%) were the most prominent presentations among studied patients [Figures 1-3].
Table 2: Prevalence of complication among the studied patients
Figure 1: Prevalence of the central nervous system and pupillary manifestations among the studied groups
Figure 2: Prevalence of cardiovascular and respiratory manifestations among the studied groups
Figure 3: Prevalence of gastrointestinal and urinary manifestations among the studied groups
During the hospitalization, both groups developed many complications. The hospitalization period and complications, especially cardiac arrhythmias (e.g., premature ventricular contraction, premature atrial contractions, and ventricular tachycardia), respiratory failure, and death were significantly lower in Mg-treated patients [Table 2].
In both groups, plasma cholinesterase level was <3000 U/L and Mg++ serum level was within normal range. In Mg-treated group, the difference in Mg++ level before and after Mg infusion did not show any significant difference (P < 0.05) [Table 3].
Table 3: Laboratory results, given medication among the studied patients
Mg-treated group required less frequent doses of atropine and pralidoxime; 4 ± 1.01 mg and 690 ± 170 mg, respectively. The difference between two groups was statistically significant [Table 3].
DISCUSSION
Acute OP poisoning is an important cause of morbidity and mortality worldwide.[19] Treatment of OP poisoning conventionally involves atropine for reduction of muscarinic signs and oximes to increase the activation of (AChE) enzyme before aging.[20] It is documented that hypomagnesemia could cause cell resistance to atropine.[21] Thus, MgSO4 could be considered as a pharmacotherapeutic agent that could prevent or ameliorate the toxicity of OP insecticides.[22]
This study among adult patients (28.11 ± 11.5 years) with acute OP poisoning explored the ability to use MgSO4 as pharmacotherapeutic agent to ameliorate the OP toxicity.
Most of the patients were intentionally poisoned. On admission, there was no statistical difference between the Mg-treated and Mg-nontreated patients in plasma cholinesterase level as it is considered as a marker of exposure to OP compounds. We were inconsistent with Leibson and Lifshitz.[23]
Plasma magnesium level was within normal range in both groups and did not vary significantly before and after Mg treatment within Mg-treated group.
These results can be explained as stated in a previous study that the presence of normal range of plasma magnesium (1.8–2.4 mg/dl) did not exclude magnesium deficiency and insignificant difference within Mg-treated group was related to short half-life of magnesium.[10]
Regarding the pupil size, results in the current study are consistent with some previous researches,[24] while other studies reported that patients with severe OP poisoning showed pupil dilatation (mydriasis) due to excessive nicotinic stimulation.[25] However, pupil constriction (miosis) that reverses following atropine administration appears to be a reliable indicator of OP poisoning.[26]
As regards chest manifestations, crepitation was the most prominent finding followed by wheezes and MgSO4 significantly reduced incidence of respiratory failure in patients with OP poisoning. To the best of our knowledge, no study addressed the respiratory effects of MgSo4 in treatment of the OP-poisoned patients. Magnesium causes bronchodilation through modulation of calcium ion flow, which inhibits the release of acetylcholine from nerve terminals. Magnesium stabilizes T-cells, preventing their activation, and inhibits mastocyte degranulation, therefore, limiting the production of inflammatory mediators. It also acts to stimulate nitric oxide and prostacyclin production, possibly reducing the severity of bronchial constriction.[11]
As regards nervous and musculoskeletal manifestations, 79% of admitted patients had fasciculation, 7% had seizures, and 9% presented with disturbed conscious level.
Fasciculation is a part of nicotinic manifestations of OP poisoning. Reactivation of the cholinesterase enzyme either spontaneously or by oximes administration can resolve it.[27] Magnesium sulfate (MgSO4) has precurarization effects that reduce fasciculation and increases in serum potassium concentration.[28] Moreover, it could reverse the neuroelectrophysiological effects, for example, seizures of organophosphate poisoning.[29]
Concerning cardiovascular system, most of the patients (75%) were normotensive. This finding favored MgSO4 usage. In addition, incidence of arrhythmia, for example, premature ventricular contraction, premature atrial contraction, and ventricular tachycardia were significantly reduced in Mg-treated patients (16%). Shock was found only in 3 patients; one of them was in Mg-treated group.
Magnesium deficiency is one of important pathogenetic factors responsible for supraventricular and ventricular arrhythmias. Magnesium, intracellular ion, plays a crucial role in the functioning of many ion channels, including cardiac potassium channels.[30] Despite normal magnesium blood levels, intracellular and systemic deficiency may occur. Hence, intravenous magnesium seems to be useful in prevention and treatment of various cardiac arrhythmias. Moreover, magnesium therapy is well tolerated, with sporadic, mild, and quickly subsiding adverse effects (heat, flushing, hypotension).[31] A research did not find any Mg adverse effects in OP-poisoned patients treated with high magnesium infusion up to 16 g.[10]
On studying the cardiotoxicity of OP poisoning, it was found that patients with OP poisoning had QTc prolongation that was correlated with patients' prognosis.[3233] Magnesium counteracts the direct toxic inhibitory action of organophosphate compounds on the heart and inhibits acetylcholine release.[31]
Most of admitted patients had vomiting, diarrhea, and abdominal pain, while 29% of them had urinary incontinence. These are consistent with adverse cholinergic actions of the cholinesterase inhibitors compounds.[6] Magnesium deficiency is linked to gastrointestinal problems. Drugs containing magnesium can improve gastrointestinal disorders.[34] In Mg-nontreated group, two patients had liver impairment and five patients had renal impairment. The incidence of liver impairment in this study was lower than its incidence in another study done by Wang et al.[35] This difference may be due to the formulation of consumed OP agent, impurities, and delay time. Renal impairment was consistent with other study stated that renal failure is rarely caused by OP poisoning,[36] but still its pathogenesis is unknown due to lack of experimental data;[37] however, it could be caused by direct toxic effect of OP agents rather than increase acetylcholine or oxidative stress[37]
The present study showed MgSO4 therapy to significantly reduce atropine and oxime requirements. These findings were inconsistent with some other studies.[1012] This difference may be due to careful observation and dose adjustment minimized overuse of these therapies.[2] Moreover, atropine infusion was largely determined by the initial loading dose.[10]
The duration of hospitalization and mortality rate were lower in Mg-treated patients that is in the same line with other studies[1012]
These findings could be explained by ability of Mg to inhibit acetylcholine release from motor nerve terminals, to antagonize the effects of OP, to control premature ventricular contractions, and to counteract the direct toxic inhibitory action of OP on sodium–potassium ATPase,[38] hence Mg-nontreated patients showed higher incidence of complications.
Magnesium has many side effects including respiratory depression and peripheral vasodilatation resulting in sudden drop of blood pressure, but we tested the least effective dose to prevent undesirable toxic effects. Moreover, careful monitoring and calcium gluconate can reverse these effects.[10]
CONCLUSION AND RECOMMENDATION
MgSO4, when given to OP-intoxicated patients within 24 h of admission as a total 4 g dose, reduces the requirement of atropine and oximes, duration of hospital stay, and incidence of cardiac and respiratory complications. The results of the present study suggest that magnesium could ameliorate organophosphorus toxic effects. However, for these results to be generalized, there should be more studies with large sample size and studies to determine the most appropriate durations and doses for MgSO4 administration with different types and amounts of consumed OP.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Petroianu GA. Poisoning with organophosphorus compounds Middle East J Emerg Med. 2006;6:64–71
2. Roberts DM, Aaron CK. Management of acute organophosphorus pesticide poisoning BMJ. 2007;334:629–34
3. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American association of poison control centers' national poison data system (NPDS): 32nd Annual Report Clin Toxicol (Phila). 2015;53:962–1147
4. Cha ES, Khang YH, Lee WJ. Mortality from and incidence of pesticide poisoning in South Korea: Findings from national death and health utilization data between 2006 and 2010 PLoS One. 2014;9:e95299
5. NECTR. Annual Statistics Sheet from National Environmental and Clinical Toxicology Research Center. NECTR. 2013
6. Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetylcholinesterase inhibitors: Pharmacology and toxicology Curr Neuropharmacol. 2013;11:315–35
7. Clark RGoldfrank LR, Flomenbaum NE, Lewis NA. Insecticides: Organic phosphorus compounds and carbamates Goldfrank's Toxicologic Emergencies.. 20068th ed. New York McGraw-Hill:1498–512
8. Balali-Mood M, Saber H. Recent advances in the treatment of organophosphorous poisonings Iran J Med Sci. 2012;37:74–91
9. Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning Lancet. 2008;371:597–607
10. Basher A, Rahman SH, Faiz MA, Dawson AH. Efficacy of magnesium sulfate for treating the acute organophosphate pesticide poisoning. A pilot trial Clin Toxicol. 2013;51:35–40
11. Bittar TM, Guerra SD. Use of intravenous magnesium sulfate for the treatment of severe acute asthma in children in emergency department Rev Bras Ter Intensiva. 2012;24:86–90
12. Pajoumand A, Shadnia S, Rezaie A, Abdi M, Abdollahi M. Benefits of magnesium sulfate in the management of acute human poisoning by organophosphorus insecticides Hum Exp Toxicol. 2004;23:565–9
13. Abdulsahib HT. Determination of magnesium in whole blood and serum of ischemic heart disease (IHD) patients by flame atomic absorption spectrometry Am J Analyt Chem. 2011;2:996–1002
14. Waber H. Kinetic colorimetric method for detection of cholinesterase Dtsch Med Wochschr. 1996;91:127–9
15. Moran RF. Blood gases and other critical care analytes Clin Lab News. 2000:12–4
16. Huang X-J, Choi Y-K, Im H-S, Yarimaga O, Yoon E, Kim H-S. Aspartate Aminotransferase (AST/GOT) and Alanine Aminotransferase (ALT/GPT) Detection Techniques Sensors (Basel, Switzerland).. 2006;6:756–82
17. Houot OSiest G, Henny J, Schiele F, Young DS Interpretation of clinical laboratory tests. 1985 United States Biomedical Publications:220–34
18. Milby TH. Prevention and management of organophosphate poisoning J Am Med Assoc. 1971;216:2131–3
19. Jeyaratnam J. Acute pesticide poisoning: A major global health problem World Health Stat Q. 1990;43:139–44
20. Tafuri J, Roberts J. Organophosphate poisoning Ann Emerg Med. 1987;16:193–202
21. Sungur M, Güven M. Intensive care management of organophosphate insecticide poisoning Crit Care. 2001;5:211–5
22. Richard CD, Luke Y, Kathrene MH, Edwin KK Organophosphate insecticides. The 5-Minute Toxicology Consult. 2000 Philadelphia CT Lippincott Williams & Wilkins
23. Leibson T, Lifshitz M. Organophosphate and carbamate poisoning: Review of the current literature and summary of clinical and laboratory experience in Southern Israel Isr Med Assoc J. 2008;10:767–70
24. Slavica V, Biljana A, Bogdan B, Marijana C. Intensive care managament of acute organophosphate poisoning: clinical experience and the review of the literature Recent Adv Clin Med. 2008:74–9
25. Hirshberg A, Lerman Y. Clinical problems in organophosphate insecticide poisoning: The use of a computerized information system Fundam Appl Toxicol. 1984;4:S209–14
26. Garber M. Carbamate poisoning: The ‘other’ insecticide Pediatrics. 1987;79:734–8
27. Paudyal BP. Organophosphorus poisoning JNMA J Nepal Med Assoc. 2008;47:251–8
28. Sakuraba S, Serita R, Kosugi S, Eriksson LI, Lindahl SG, Takeda J. Pretreatment with magnesium sulphate is associated with less succinylcholine-induced fasciculation and subsequent tracheal intubation-induced hemodynamic changes than precurarization with vecuronium during rapid sequence induction Acta Anaesthesiol Belg. 2006;57:253–7
29. Singh G, Khurana D. Neurology of acute organophosphate poisoning Neurol India. 2009;57:119–25
30. Rude RK, Shils MEShike M, Ross AC, Caballero B, Cousins RJ. Magnesium Modern Nutrition in Health and Disease.. 200610th ed. Philadelphia, United States Lippincott Williams & Wilkins
31. Cieœlewicz A, Jankowski J, Korzeniowska K, Balcer-Dymel N, Jabecka A. The role of magnesium in cardiac arrhythmias J Elemntol. 2013;2:317–27
32. Abraham S, Oz N, Sahar R, Kadar T. QTc prolongation and cardiac lesions following acute organophosphate poisoning in rats Proc West Pharmacol Soc. 2001;44:185–6
33. Malik M. Drug-induced QT/QTc interval shortening: Lessons from drug-induced QT/QTc prolongation Drug Saf. 2016;39:647–59
34. Thukral C, Wolf JL. Therapy insight: Drugs for gastrointestinal disorders in pregnant women Nat Clin Pract Gastroenterol Hepatol. 2006;3:256–66
35. Wang WZ, Li YQ, Zhang JZ, Wang L, Ma GY, Cao SQ. Effect of the pre-hospital systematic treatment on prognosis patients of with severe acute organophosphorus pesticide poisoning Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2005;23:371–3
36. Cavari Y, Landau D, Sofer S, Leibson T, Lazar I. Organophosphate poisoning-induced acute renal failure Pediatr Emerg Care. 2013;29:646–7
37. Rubio CR, Felipe Fernández C, Manzanedo Bueno R, Del Pozo BA, García JM. Acute renal failure due to the inhalation of organophosphates: Successful treatment with haemodialysis Clin Kidney J. 2012;5:582–3
38. Sivagnanam S. Potential therapeutic agents in the management of organophosphorus poisoning Crit Care. 2002;6:260–1
