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Clin Exp Emerg Med > Epub ahead of print
Nekoukar, Talabaki, Zakariaei, Mesri, and Azadeh: The key role of magnesium sulfate in the management of organophosphorus pesticide poisoning: a scoping literature review

Abstract

Organophosphorus agents are easily absorbed via respiratory, gastrointestinal, and dermal routes, and inhibit the acetylcholinesterase (AChE) enzyme, which is responsible for the majority of toxicity caused by organophosphates in the body. A comprehensive search was conducted across three prominent databases (Google Scholar, PubMed, and Science Direct) to identify relevant articles. The search focused on the keywords “MgSO4” or “magnesium sulfate” in conjunction with “organophosphate” or “organophosphate poisoning.” Inhibition of the AChE results in the accumulation of acetylcholine in synapses and the stimulation of cholinergic receptors. As several studies have shown that magnesium sulfate (MgSO4) can inhibit the release of acetylcholine in the central and peripheral sympathetic and parasympathetic synapses, this study reviews the role of MgSO4 in the treatment of organophosphorus poisoning. The intravenous administration of MgSO4 exhibits favorable tolerability and clinical efficacy in alleviating cardiac toxicity associated with organophosphorus poisoning.

INTRODUCTION

Organophosphorus agents continue to be used widely as agricultural pesticides, and their potential detrimental effects on health remain a significant concern, particularly with respect to occupational exposure. Intentional poisoning incidents involving these readily accessible pesticides have also been reported. Organophosphate poisoning (OP) accounts for approximately 50% of hospital admissions related to poisoning, particularly in developing countries [1,2].
Organophosphorus agents can be easily absorbed through multiple routes, including the respiratory, gastrointestinal, and dermal pathways, in which they inhibit various esterase enzymes. Among these enzymes, butyrylcholinesterase plays a role in the regulation of emotional behavior [3]. Organophosphorus agents also inhibit carboxylesterase, which is involved in the metabolism of numerous drugs [4]. However, the primary mechanism responsible for the majority of organophosphate-induced toxicity in the body is the inhibition of the acetylcholinesterase (AChE) enzyme, leading to impaired hydrolysis of acetylcholine (ACh). The structural similarity between organophosphates and ACh results in the formation of a covalent bond that inhibits the esteratic site of AChE [5]. Reactivation of the organophosphate-AChE complex, which is a potential treatment option in OP, is contingent upon the occurrence of the aging phenomenon. Aging refers to the stabilization of the organophosphate-AChE complex through dealkylation, rendering the complex resistant to hydrolysis (Fig. 1). This phenomenon has significant implications for the effectiveness of oximes in reactivating the complex [6].
The inhibition of AChE leads to the accumulation of ACh in synapses, which in turn stimulates both nicotinic and muscarinic receptors. During the initial hours after exposure to OP compounds, cholinergic overstimulation can become evident in the form of lacrimation, salivation, urinary and fecal incontinence, gastrointestinal cramping, vomiting, sweating, miosis, bradycardia or tachycardia, and hypotension. In less than half of cases of poisoning, an intermediate syndrome phase may develop within 24 to 96 hours. This phase is characterized by symptoms such as muscle fasciculations and weakness, pulmonary depression, and reduced deep tendon reflexes [7,8]. The primary research question in the current work is the role of magnesium sulfate as key antidote in the management of organophosphorus pesticide poisoning.

STUDY DESIGN AND SEARCH STRATEGY

The heterogenicity of data regarding the role of magnesium sulfate (MgSO4) in OP necessitated the selection of a scoping review methodology for this study. The scoping review adhered to guidelines outlined by the Joanna Briggs Institute for reviews [9], and no systematic reviews were performed. A comprehensive search was conducted across Google Scholar, PubMed, and Science Direct databases using the keywords “MgSO4” or “magnesium sulfate” in combination with “organophosphate” or “organophosphorus poisoning.” The search was limited to articles published between 2010 and 2023, and inclusion criteria involved the presence of these keywords in the titles, abstracts, or keywords of the articles. The obtained articles were imported into EndNote and, after removing duplicates, the remaining articles were independently screened by two researchers based on predefined inclusion and exclusion criteria. In the event of uncertainty regarding specific articles, a third investigator evaluated them. Data extraction, including author details, publication year, sample population characteristics, study design and setting (including dosage and duration of MgSO4 administration), initiation time of MgSO4 administration, and clinical outcomes, was conducted by the two independent investigators. The search process is illustrated in Fig. 2, which provides an overview of the study search details. The initial search using the specified keywords identified 176 articles. Following the application of exclusion criteria, which involved removing three unrelated and three duplicate articles, 47 papers were deemed relevant for further review. These 47 papers consisted of nine clinical trials, one case report, three animal studies, and 16 review articles. The remaining 12 papers encompassed various other types of publications, including observational studies, theses, books, and editorials (Fig. 2).

Ethics statement

This study was approved by the Ethics Committee of Mazandaran University of Medical Sciences (No. IR.MAZUMS.REC.1399.7850). The study was carried out in accordance with the principles of the Helsinki Declaration.

MANAGEMENT OF ACUTE POISONING

The first and most crucial step in successful management is the correct and timely diagnosis of OP. According to clinical guidelines, OP management can be divided into two steps: immediate administration of effective antidotes and supportive treatments. Both strategies are discussed below.

Supportive therapy

The initial step involves assessment of the airway, breathing, and circulation. In-hospital poisoned patients are typically admitted to an intensive care unit (ICU), where they receive emergency medical support. High-flow oxygen supply and fluid replacement should be considered. Following establishment of intravenous (IV) access, volume resuscitation using 0.9% sodium chloride (NaCl) is initiated to maintain a urine output of 0.5 mL/kg/hr and a systolic blood pressure above 80 mmHg [10]. Close monitoring of physiological indicators, including blood pressure, pupil size, pulse rate, sweating, and auscultatory findings, is crucial to identify signs and symptoms resulting from cholinergic overstimulation [11]. If the tidal volume falls below 5 mL/kg or the vital capacity is below 15 mL/kg, or if the PaO2 level is below 60 mmHg, intubation of the poisoned patient may be necessary.
To prevent further or delayed complications patients must be decontaminated. In cases in which the poisoning route is ingestion, gastric decontamination should be contemplated once the patient is stabilized. The optimal time window for maximum effectiveness of gastric decontamination is within 1 to 2 hours following ingestion. However, when hospital admission is delayed, decontamination can still be beneficial up to 12 hours [7]. It is equally important to perform dermal decontamination to remove residual organophosphates. Washing the affected area with water and soap is a suitable approach for this purpose [10,12].

Effective antidotes

Known specific antidotes, including atropine and pralidoxime have long been used to treat OP. However, the search for other effective options is ongoing. The best known class of drugs used in selected cases of poisoning are benzodiazepines (e.g., diazepam), which are effective in reducing complications of the central nervous system (CNS) in OP. Acute intoxication with organophosphate cholinesterase inhibitors often leads to seizures, rapidly progressing to a life-threatening condition known as status epilepticus. Diazepam has traditionally been regarded as the standard treatment for seizure management [13]. In addition to its anticonvulsant properties, diazepam has shown efficacy in attenuating the elevation of ACh and choline concentrations in various brain regions [14]. Although the precise mechanism of action of diazepam in OP is not fully understood, it may be more effective than other anticonvulsants such as barbiturates.
Diazepam has been shown to be an effective adjunctive antidote in severe cases of poisoning, and it may even help alleviate certain CNS complications associated with atropine administration [15]. In the CNS, certain GABAergic pathways are secondarily activated by ACh, and diazepam can act as an antagonist to these GABAergic systems. Animal studies have also demonstrated that diazepam reduces cerebral morphological damage resulting from seizures induced by organophosphate compounds and helps prevent respiratory failure by attenuating the overstimulation of central respiratory centers, thereby preventing death [16,17]. However, little research has been conducted on the use of diazepam in humans for these purposes [10]. Recently, attention has been paid to the possible role of MgSO4 in reducing the complications of poisoning with organophosphates. In the following section, its effects will be discussed in detail. Due to the low cost and widespread availability of this compound in most medical centers, it can be included in OP treatment protocols once its beneficial effects have been demonstrated.

Atropine

According to numerous guidelines, atropine is the preferred treatment option for reversing the initial symptoms of OP through competitive antagonism at muscarinic receptors. In the hospital setting, IV administration is the preferred route for atropine. For adults affected by poisoning, the recommended initial dose is 2 mg. This dose can be repeated as necessary at intervals of 5 to 10 minutes until atropinization begins. The desired therapeutic effect of atropinization is often recognized by a reduction in body secretions [18].
While atropine is considered the primary treatment for OP, its efficacy is limited to muscarinic receptors, and it does not affect nicotinic receptors significantly. Its impact on CNS muscarinic receptors is also limited. Despite these limitations, there is a consensus among medical professionals regarding the critical role of atropine in the acute management of OP. It remains an essential component in treatment regimens due to its ability to counteract cholinergic overstimulation and mitigate potentially life-threatening symptoms associated with OP.

Oximes

Reactivating AChE with oximes can help alleviate the effects of overstimulation. Pralidoxime, the most commonly used oxime, facilitates AChE reactivation by accepting a phosphoryl group from AChE itself, thereby preventing its aging [19]. Although phosphoryl oximes themselves can inhibit AChE, their instability in aqueous environments generally results in a short duration of effect. Although initial exacerbation of the cholinergic crisis, which is sometimes observed during oxime therapy, is primarily due to AChE inhibition by the oxime, inhibition of the enzyme by phosphorylated oxime products is also possible if this treatment is not accompanied by administration of atropine [20]. Phosphorylated oximes can inhibit AChE more effectively than organophosphates, leading to greater toxicity instead of a cure [21]. Accordingly, oximes should not be used alone to treat OP.
Pralidoxime is typically administered with a loading dose of 2 g (or 30 mg/kg) IV over a period of 30 minutes, followed by a maintenance dose of 500 mg/hr (or 8–10 mg/kg/hr). If muscle weakness persists, the loading dose may be repeated after 1 to 2 hours, and subsequent repeat doses may be administered every 4 to 6 hours as necessary [18]. Studies have indicated that continuous infusion of oxime agents after the loading dose may be more effective in mitigating the adverse effects of OP [22]. However, certain limitations remain regarding the optimal timing of initial administration, the appropriate dose, treatment duration, and the ability to reach the CNS [23]. Some investigations have also suggested that the addition of oximes to the treatment of OP may yield little benefit due to underdosing of the oxime agents [15].

ROLE OF MAGNESIUM SULFATE IN OP

Numerous studies have demonstrated that MgSO4 has an inhibitory effect on the release of ACh in both the CNS and in peripheral sympathetic and parasympathetic synapses. This interference with calcium channels in presynaptic nerve terminals, which are responsible for the release of ACh, leads to increased hydrolysis of certain pesticides. The administration of MgSO4 has been shown to reduce arrhythmias associated with organophosphates and atropine, mitigating hyperstimulation of organophosphates in the CNS, and acting on N-methyl-D-aspartate (NMDA) receptors to reverse neuromuscular syncope in the peripheral nervous system [24]. Based on these mechanisms and the findings from animal and human studies, the present study aims to review the role of MgSO4 in the treatment of OP.

Animal studies

An animal study conducted on rats that aimed to compare the anticonvulsant effects of MgSO4 with midazolam and caramiphen in the context of sarin poisoning found that all three agents were effective in resolving the induced tonic-clonic seizures [25]. However, a closer examination revealed that only midazolam and caramiphen were able to completely halt cortical convulsive activities, while MgSO4 was not able to achieve the same level of cessation. Additionally, after 1 week of sarin exposure, the MgSO4 group exhibited a significant increase in markers of brain damage, mirroring the pattern observed in the group treated solely with atropine. Rats in the MgSO4 group exhibited weight loss, restlessness, and reduced motor activity, indicating the persistence of subtle seizures in the CNS despite control of overt seizures. This study concluded that the use of MgSO4 to treat seizures induced by organophosphates such as sarin may not be a reliable option for mitigating subsequent cognitive impairment.
In addition to the previously mentioned animal study, two additional animal studies focusing on the cardiac effects of using MgSO4 in OP poisoning yielded similar findings. Shafiee et al. [26] evaluated the preventive effect of magnetic magnesium-carrying nanoparticles on rat cardiac cells’ mitochondrial energy depletion and free-radical damage induced by malathion exposure. The study revealed that, compared with MgSO4, this particular formulation exhibited superior efficacy in reducing cardiac cell lipid peroxidation and reactive oxygen species, improving the adenosine diphosphate to adenosine triphosphate ratio, and increasing intracellular magnesium levels. This suggests that magnetic magnesium-carrying nanoparticles may be more effective in mitigating cardiac damage caused by OP poisoning when compared to conventional MgSO4 treatment.
A separate study conducted by Mohammadi et al. [27] found that the administration of magnetic magnesium to rats poisoned with malathion resulted in improvements in blood pressure, heart rate, and arrhythmia, while also reducing cell lipid peroxidation. The findings indicate that magnetic magnesium is more effective than both MgSO4 and atropine in restoring AChE activity. Moreover, in the context of the neuromuscular junction, magnesium isotopes outperformed MgSO4 in inhibiting the release of ACh and appeared to be more effective than MgSO4 under hypoxic conditions.

Human studies

The clinical studies evaluated in this review consistently indicated the efficacy of MgSO4 in the acute management of OP. These studies, which were published from 2013 to 2019, revealed several benefits associated with the use of MgSO4 in the acute setting of OP. These benefits included a reduction in hospitalization duration and ICU stays, decreased reliance on mechanical ventilation, and a lower requirement for total doses of atropine and oxime, which are known antidotes for OP toxicity. Administration of MgSO4 also reduced mortality rates in OP cases. One trial conducted by Costa [28] specifically investigated the effects of MgSO4 at a dose of 4 g/day, when administered concurrently with conventional therapy, in individuals poisoned with OP substances. These findings emphasize the beneficial impact of MgSO4 in terms of reducing hospitalization duration and decreasing mortality.
Basher et al. [29] conducted a study that reported magnesium was well-tolerated in patients, with no observed adverse effects attributable to intermittent bolus injections of magnesium doses, even at doses as high as 16 g. Furthermore, a case study suggested that MgSO4 can effectively reduce the intensity of contractions in women experiencing hypertonic uterine contractions [30]. The occurrence of acute organophosphorus pesticide poisoning–induced uterine contractions is a rare complication that may result in abortion. However, the precise mechanisms by which MgSO4 inhibits uterine contractility induced by OP are not yet fully understood.
In a clinical trial conducted by Jamshidi et al. [31], the administration of MgSO4 was found to be beneficial in the treatment of acute organophosphate toxicity, resulting in a decrease in the duration of hospitalization. The protocol involved the intravenous infusion of 2 g of MgSO4 50% (4 mL) in a total volume of 100 mL over 30 minutes, followed by three successive injections of 2 g of MgSO4 at intervals of 2 hours. The treatment group receiving MgSO4 exhibited lower diastolic blood pressure and heart rate compared with the placebo group. The specific data from this clinical trial, along with other relevant clinical trials, are presented in Table 1 [24,29,3137].

Expert opinion

The review articles obtained in this research consistently found that, while MgSO4 has been considered as a potential adjuvant therapy for OP, its effectiveness has not been firmly established. These review articles acknowledged MgSO4 can be a potential adjunctive therapy, and that its role in the treatment of OP is still being investigated. Although MgSO4 has shown potential benefits in various studies, the review articles emphasized the need for further evidence to support its use [38].
In a systematic review conducted by Eddleston et al. [19], an extensive search was performed across preclinical and clinical studies to evaluate the role of MgSO4 in the context of OP. The collected data indicate that administration of MgSO4 subsequent to organophosphorus insecticide poisoning effectively mitigates tachycardia and hypertension by diminishing cholinergic stimulation. It was also found to enhance skeletal muscle adenosine triphosphatase activity. In one rat study, MgSO4 suppressed mean serum butyrylcholinesterase activity. Among the eight clinical studies included, a meta-analysis revealed a pooled odds ratio for MgSO4 compared with placebo in terms of mortality and the need for intubation and ventilation of 0.55 (95% confidence interval [CI], 0.32–0.94) and 0.52 (95% CI, 0.34–0.79), respectively. However, no evidence of a dose-effect relationship was reported across the studies. A small dose-escalation study did suggest a potential benefit from higher doses of MgSO4. A phase II dose-response study, which involved groups of 10 patients poisoned with organophosphorus insecticides, compared 4, 8, 12, and 16 g of MgSO4 with placebo. All doses were well-tolerated, and there was a trend toward reduced mortality with larger doses [3941]. The diverse outcomes obtained from these studies can be attributed to several factors, including the risk of bias, lack of randomization, inadequate MgSO4 dosage, small sample sizes, and variations in the timing of drug administration following exposure. The authors conducted a risk-of-bias analysis to address these issues [1].
Another review reported that MgSO4, when acting as a ligand-gated calcium channel blocker, can alleviate the release of ACh from presynaptic terminals. Additionally, MgSO4 has been observed to mitigate CNS overstimulation mediated through NMDA receptor activation. However, caution should be exercised in its administration due to the presence of ambiguous outcomes resulting from inadequately conducted studies regarding the dosage of MgSO4 and other methodological aspects. One trial demonstrated a reduction in the mortality rate when MgSO4 was administered to individuals poisoned with organophosphorus compounds [10].
Narang et al. [42] conducted another review, which recommended the inclusion of MgSO4, along with antioxidants and other standard therapies, in the management of OP. However, the review was unable to establish the efficacy of MgSO4 due to the limited availability of evidence-based data.
MgSO4 may alleviate the risk of ventricular tachycardia in patients experiencing tachycardias caused by nicotinic stimulation, and it has shown promise in improving neuromuscular function [39]. Adjunctive use of MgSO4 has also been demonstrated to decrease the required dosage of atropine for intubation, leading to reduced overall time spent in the ICU and associated mortality rates [7]. The specific data from these review articles, along with other relevant review articles, are presented in the Table 2 [1,7,10,16,3849].
Numerous studies have been conducted to explore alternative effective options in the management of OP, despite the longstanding use of atropine and oximes. Among these options is MgSO4, which is utilized as a nonstandard therapy and nonregular antidote for OP poisoning. The aforementioned studies consistently recommend administering an infusion of 4 g of MgSO4 on the first day of hospital presentation, followed by a daily dose of 2 g as needed. The administration of this drug has shown various benefits, such as a decrease in hospitalization duration, shorter stays in the ICU, reduced mortality rates, decreased reliance on mechanical ventilation, and a reduced requirement for total doses of atropine and oxime. The outcomes of the patients in these studies did not differ significantly.

CONCLUSION

The outcomes of clinical trials investigating the effectiveness of MgSO4 in OP exhibit inconsistency. Presently, there is insufficient evidence to establish MgSO4 as a robust and effective antidote for OP management. However, satisfactory tolerability and clinical efficacy in mitigating the cardiac toxicity associated with OP has been reported when MgSO4 is administered by IV. Moreover, it has shown to be effective in reducing hospital stays, the need for critical care, and invasive mechanical ventilation support. The utilization of a magnetic MgSO4 formulation has also proven to effective in mitigating mitochondrial energy depletion caused by OP-induced free-radical damage in cardiac cells. Furthermore, it can reduce blood pressure, heart rate, and OP-related arrhythmias. The review of research data from 2010 to 2023 highlights the need for a clinical trial that addresses the optimal timing and dosage of MgSO4 in the context of OP.

NOTES

Conflicts of interest
The authors have no conflicts of interest to declare.
Funding
The study was funded by the Mazandaran University of Medical Sciences. The funder had no role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript.
Acknowledgments
The authors express their gratitude to Professor Mahdi Fakhar (Iranian National Registry Center for Lophomoniasis and Toxoplasmosis, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran) for his kind cooperation and critical appraisal of the manuscript.
Author contributions
Data curation: ZZ, ZN, HT; Formal analysis: ZZ, ZN, HT; Funding acquistion: all authors; Investigation: ZZ, ZN, HT; Methodology: HA, MM; Visualization: HA, MM; Writing–original draft: all authors; Writing–review & editing: ZZ, HA, MM. All authors read and approved the final manuscript.
Data availability
Data analyzed in this study are available from the corresponding author upon reasonable request.

REFERENCES

1. Eddleston M. Novel clinical toxicology and pharmacology of organophosphorus insecticide self-poisoning. Annu Rev Pharmacol Toxicol 2019; 59:341-60.
crossref pmid
2. Mohapatra S, Rath N. Mania following organophosphate poisoning. J Neurosci Rural Pract 2014; 5(Suppl 1):S86-7.
crossref pmid pmc
3. Brimijoin S, Chen VP, Pang YP, Geng L, Gao Y. Physiological roles for butyrylcholinesterase: a BChE-ghrelin axis. Chem Biol Interact 2016; 259:271-5.
crossref pmid pmc
4. Laizure SC, Herring V, Hu Z, Witbrodt K, Parker RB. The role of human carboxylesterases in drug metabolism: have we overlooked their importance? Pharmacotherapy 2013; 33:210-22.
crossref pmid pmc
5. Auf Der Heide E. Case studies in environmental medicine: cholinesterase inhibitors: including pesticides and chemical warfare nerve agents. Agency for Toxic Substances and Disease Registry; [cited 2007 Oct 17]. Available from: https://www.atsdr.cdc.gov/csem/cholinesterase-inhibitors/cover-page.html

6. Zhuang Q, Young A, Callam CS, et al. Efforts toward treatments against aging of organophosphorus-inhibited acetylcholinesterase. Ann N Y Acad Sci 2016; 1374:94-104.
crossref pmid pmc
7. Alozi M, Rawas-Qalaji M. Treating organophosphates poisoning: management challenges and potential solutions. Crit Rev Toxicol 2020; 50:764-79.
crossref pmid
8. Peter JV, Sudarsan TI, Moran JL. Clinical features of organophosphate poisoning: a review of different classification systems and approaches. Indian J Crit Care Med 2014; 18:735-45.
crossref pmid pmc
9. Peters MD, Marnie C, Tricco AC, et al. Updated methodological guidance for the conduct of scoping reviews. JBI Evid Synth 2020; 18:2119-26.
crossref pmid
10. Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning. Lancet 2008; 371:597-607.
crossref pmid pmc
11. In: Shannon MW, Borron SW, Burns MJ, editors. Haddad and Winchester’s clinical management of poisoning and drug overdose. 4th ed. Saunders Elsevier; 2007.

12. 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:R391-7.
crossref pmid pmc
13. Supasai S, Gonzalez EA, Rowland DJ, et al. Acute administration of diazepam or midazolam minimally alters long-term neuropathological effects in the rat brain following acute intoxication with diisopropylfluorophosphate. Eur J Pharmacol 2020; 886:173538.
crossref pmid pmc
14. Shih TM. Cholinergic actions of diazepam and atropine sulfate in soman poisoning. Brain Res Bull 1991; 26:565-73.
crossref pmid
15. Johnson MK, Jacobsen D, Meredith TJ, et al. Evaluation of antidotes for poisoning by organophosphorus pesticides. Emerg Med 2000; 12:22-37.
crossref
16. Kaur S, Singh S, Chahal KS, Prakash A. Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity. Can J Physiol Pharmacol 2014; 92:893-911.
crossref pmid
17. Dickson EW, Bird SB, Gaspari RJ, Boyer EW, Ferris CF. Diazepam inhibits organophosphate-induced central respiratory depression. Acad Emerg Med 2003; 10:1303-6.
crossref pmid
19. Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute organophosphorus pesticide poisoning: a systematic review of clinical trials. QJM 2002; 95:275-83.
crossref pmid
20. Szinicz L. Non-reactivator effects of oximes; In: Szinicz L, Eyer P, Kilmmek R, editors. Role of oximes in the treatment of anticholinesterase agent poisoning. Spektrum Akademischer Verlag; 1996. p.53-68.

21. Eysoldt S, Paudel I, Chambers J. Phosphorylated oximes increase organophosphate toxicity. 2nd International Conference on Molecular Biology, Nucleic Acids & Molecular Medicine; 2017 Aug 31-Sep 1; Philadelphia, PA, USA.

22. Thiermann H, Mast U, Klimmek R, et al. Cholinesterase status, pharmacokinetics and laboratory findings during obidoxime therapy in organophosphate poisoned patients. Hum Exp Toxicol 1997; 16:473-80.
crossref pmid pdf
23. Worek F, Thiermann H, Wille T. Oximes in organophosphate poisoning: 60 years of hope and despair. Chem Biol Interact 2016; 259:93-8.
crossref pmid
24. Vijayakumar HN, Kannan S, Tejasvi C, Duggappa DR, Veeranna Gowda KM, Nethra SS. Study of effect of magnesium sulphate in management of acute organophosphorous pesticide poisoning. Anesth Essays Res 2017; 11:192-6.
crossref pmid pmc
25. Katalan S, Lazar S, Brandeis R, et al. Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity. Arch Toxicol 2013; 87:347-60.
crossref pmid pdf
26. Shafiee H, Mohammadi H, Rezayat SM, et al. Prevention of malathion-induced depletion of cardiac cells mitochondrial energy and free radical damage by a magnetic magnesium-carrying nanoparticle. Toxicol Mech Methods 2010; 20:538-43.
crossref pmid
27. Mohammadi H, Karimi G, Seyed Mahdi Rezayat, et al. Benefit of nanocarrier of magnetic magnesium in rat malathion-induced toxicity and cardiac failure using non-invasive monitoring of electrocardiogram and blood pressure. Toxicol Ind Health 2011; 27:417-29.
crossref pmid pdf
28. Costa LG. Organophosphorus compounds at 80: some old and new issues. Toxicol Sci 2018; 162:24-35.
crossref pmid
29. Basher A, Rahman SH, Ghose A, Arif SM, Faiz MA, Dawson AH. Phase II study of magnesium sulfate in acute organophosphate pesticide poisoning. Clin Toxicol (Phila) 2013; 51:35-40.
crossref pmid
30. Sun L, Li GQ, Yan PB, Liu Y, Li GF, Wei LQ. Clinical management of organophosphate poisoning in pregnancy. Am J Emerg Med 2015; 33:305.
crossref
31. Jamshidi F, Yazdanbakhsh A, Jamalian M, et al. Therapeutic effect of adding magnesium sulfate in treatment of organophosphorus poisoning. Open Access Maced J Med Sci 2018; 6:2051-6.
crossref pmid pmc pdf
32. Sriharsha J. A clinical study of intravenous magnesium sulphate in the treatment of acute organophosphate poisoning [Dissertation]. Rajiv Gandhi University of Health Sciences; 2016.

33. Afify T, El-Barrany UM, Elshikhiby H, Adly M, Fathy S. Effect of intravenous magnesium sulphate on atropine and oxime usage in acute organophosphate toxicity. Egypt J Forensic Sci Appl Toxicol 2016; 16:17-22.
crossref
34. Elbarrany UM, Mohamed MA, Ibrahim SF, Elshekheby HA, Afify T. Clinical benefits of magnesium sulfate in management of acute organophosphorus poisoning. Saudi J Forensic Med Sci 2018; 1:30-4.
crossref
35. El Taftazany E, Hafez R, Ebeid G. The potential role of intravenous magnesium sulfate administration on the outcome of acute organophosphorus toxicity. A prospective study in Poison Control Center Ain Shams University. Ain Shams J Forensic Med Clin Toxicol 2019; 32:40-6.
crossref
36. Kumar HM, Pannu AK, Kumar S, Sharma N, Bhalla A. Magnesium sulfate in organophosphorus compound poisoning: a prospective open-label clinician-initiated intervention trial with historical controls. Int J Crit Illn Inj Sci 2022; 12:33-7.
crossref pmid pmc
37. Mitra JK, Hansda U, Bandyopadhyay D, Sarkar S, Sahoo J. The role of a combination of N-acetylcysteine and magnesium sulfate as adjuvants to standard therapy in acute organophosphate poisoning: a randomized controlled trial. Heliyon 2023; 9:e15376.
crossref pmid pmc
38. Nurulain SM, Szegi P, Tekes K, Naqvi SN. Antioxidants in organophosphorus compounds poisoning. Arh Hig Rada Toksikol 2013; 64:169-77.
crossref pmid
39. Eddleston M, Chowdhury FR. Pharmacological treatment of organophosphorus insecticide poisoning: the old and the (possible) new. Br J Clin Pharmacol 2016; 81:462-70.
crossref pmid
40. Brvar M, Chan MY, Dawson AH, Ribchester RR, Eddleston M. Magnesium sulfate and calcium channel blocking drugs as antidotes for acute organophosphorus insecticide poisoning: a systematic review and meta-analysis. Clin Toxicol (Phila) 2018; 56:725-36.
crossref pmid
41. Aman S, Paul S, Chowdhury FR. Management of organophosphorus poisoning: standard treatment and beyond. Crit Care Clin 2021; 37:673-86.
pmid
42. Narang U, Narang P, Gupta O. Organophosphorus poisoning: a social calamity. J Mahatma Gandhi Institute of Medical Sciences 2015; 20:46-51.
crossref
43. Bajracharya SR, Prasad PN, Ghimire R. Management of organophosphorus poisoning. J Nepal Health Res Counc 2016; 14:131-8.
pmid
44. Blain PG. Organophosphorus poisoning (acute). BMJ Clin Evid 2011; 2011:2102.
pmid pmc
45. Husain K, Ansari RA, Ferder L. Pharmacological agents in the prophylaxis/treatment of organophosphorous pesticide intoxication. Indian J Exp Biol 2010; 48:642-50.
pmid
46. Kumar A, Margekar SL, Margekar P, Margekar V. Recent advances in management of organophosphate & carbamate poisoning. Indian J Med Spec 2018; 9:154-9.
crossref
47. Balali-Mood M, Saber H. Recent advances in the treatment of organophosphorous poisonings. Iran J Med Sci 2012; 37:74-91.
pmid pmc
48. Asalu A, Oloche J, Itodo SO, Arubi PO. Update on clinical evaluation and management of organophosphate poisoning. J Res Basic Clin Sci 2019; 1:116-21.

49. Rafati Rahimzadeh M, Moghadamnia A. Organophosphorus compounds poisoning. J Babol Univ Med Sci 2010; 12:71-85.

Fig. 1.
Inhibition of acetylcholinesterase (AChE) by organophosphate poisoning (OP) and aging process.
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Fig. 2.
Flowchart of the study.
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Table 1.
Clinical trials of intravenous MgSO4 for acute OP
Study Patient Intervention Start intervention Outcome Comment
Basher et al. [29] (2013) Adult (12–60 yr) Atropinization First 24 hr Cholinergic crisis, IMS, median atropine requirement (NS) Cholinergic crisis, death, and intubation were lower with MgSO4
Daily MgSO4 in doses of 4, 8, 12, or 16 g Median of subsequent post atropine loading infusion doses (NS), intubation, death
Intermittent bolus IV (4 g over 10–15 min for 4 hr) Mean serum MgSO4 concentration before intervention (NS)
Mean serum MgSO4concentration 24 hr after intervention (NS)
24 hr Mean urine MgSO4 concentration (P=0.019)
Sriharsha [32] (2016) Adult 4 g MgSO4 over 4 hr First 24 hr Atropine load (P=0.01) MgSO4, in a dose of 4 g concurrent to conventional therapy, in OP acute human poisoning is beneficial by reducing the hospitalization days and rate of mortality
Total atropine dose (P<0.001)
No. of days of ventilation (P=0.04)
Days of ICU stay (P<0.001)
Mortality rate, (P<0.05)
Hospitalization days (P<0.05)
Afify et al. [33] (2016) Adult Group I (50 patients treated with atropine and oximes): MgSO4 1 g/6 hr for 24 hr Acutely poisoned ND Amount of atropine (P<0.001) MgSO4 decreases atropine and oxime use in acute OP
Group II (50 patients only treated with atropine and oximes) Amount of oxime (P=0.038)
Jamshidi et al. [31] (2018) - Case group: 2 g MgSO4 50% (4 mL) in 0.5 hr and 2 g over 2 hr for three times ND SBP in both groups during the first 24 hr of intervention (NS) The use of MgSO4 in OP reduces therapeutic costs an average hospital length of stay and mortality
Control group: 100 mL normal in the same manner DBP in 0 and 2 hr after intervention was higher in MgSO4 group (P=0.004) and insignificant statistical difference for the remaining hours
Heart rate was lower in MgSO4 group at 8 hr (P=0.028), 16 hr (P=0.001), and 24 hr (P=0.017) after intervention
Respiratory rate during the first 24 hr of intervention (NS)
Arterial oxygen during the first 24 hr of intervention (NS)
Intubation frequency during the first 24 hr of intervention (NS)
Lung secretions during the first 24 hr of intervention (NS)
Admission hours (P=0.006)
The amount of consumed pralidoxime (NS)
Pupil diameter during the first 24 hr of intervention (NS)
Vijayakumar et al. [24] (2017) Adult (18–60 yr) Case group: (1) atropine and pralidoxime; (2) 4 g MgSO4 20% over 30 min Admitted to ICU within 24 hr of ingestion The need for intubation (NS) 4 g of MgSO4 given to OPCP patients within 24 hr of admission to ICU, decreases atropine requirement, need for intubation, and ICU stay
Control group: normal saline in the same manner Requirement of atropine (P<0.001)
Duration of mechanical ventilation (NS)
Duration of ICU stay (P=0.026)
Effect on mortality (NS)
Elbarrany et al. [34] (2018) Adult Atropinization and pralidoxime ND The hospitalization period (P=0.05) The outcomes were significantly lower in MgSO4‑treated patients
Group I: nontreated patients Cardiac arrhythmias (e.g., PVC, PAC, and VT) (P=0.001)
Group II: 1 g MgSO4/6 hr for four doses Respiratory failure (P=0.001)
Death (P=0.008)
El Taftazany et al. [35] (2019) - Group I: atropine and oximes + normal saline ND Amount of atropine (P=0.040) Conflicting results: IV MgSO4 did not modify the total dose of atropine and oximes, and need for MV. Although MgSO4 had reduced the number of patients who developed IMS and CVS toxicity, duration of ICU stay, total duration of hospital stay, and mortality, but this reduction was statistically insignificant
Group II: atropine and oximes + 4 g MgSO4 only the first 24 hr Amount of oximes (P=0.374)
Death (NS)
Intermediate syndrome (NS)
Duration of hospital stay (NS)
Duration of ICU stay (NS)
Need for MV (NS)
CVS toxicity (NS)
Kumar et al. [36] (2022) Adult (18–60 yr) Atropine ND In-hospital mortality rate (P=0.261) No benefit from the addition of IV MgSO4 (either in the first 24 hr of the admission or during the entire hospital stay, at a dose of 1 g every 6 hr) to the atropine and supportive care in the management of OPC poisoning
Group I: 1 g MgSO4 every 6 hr for 24 hr Development of IMS (P=0.788)
Group II: 1 g MgSO4 every 6 hr for at least 5 days Requirement of MV (P=0.664)
Group III (control group): not receive MgSO4 Duration of MV (P=0.621)
Length of hospital stay (P=0.247)
Mitra et al. [37] (2023) Adult (18–80 yr) Case group: 600 mg NAC tab every 8 hr for 3 days and 4 g MgSO4 over 30 min only on day 1 On arrival to the emergency department Biochemical parameters before and after treatment completion (e.g., plasma pseudocholinesterase, plasma total malonaldehyde, free reduced glutathione level in plasma, serum MgSO4 levels) (NS) The combination of NAC and MgSO4 as adjuvants to standard therapy in the treatment of acute OP failed to significantly improve the clinical outcomes with respect to atropine requirements, ICU stay, mechanical ventilatory requirements, and mortality and did not offer protection against oxidative damage
Control group: 5 g sugar tab every 8 hr for 3 days and 50 mL of normal saline over 30 min only on day 1 Atropine requirements (NS)
ICU stay (NS)
Invasive MV (NS)
Median duration of hospital stay (NS)
Mortality (NS)
No. of cases with neurological sequalae (NS)

MgSO4, magnesium sulfate; OP, organophosphate poisoning; IV, intravenous; IMS, intermediate syndrome; NS, not significant; ICU, intensive care unit; ND, not defined; SBP, systolic blood pressure; DBP, diastolic blood pressure; OPC, organophosphorus compound; PVC, premature ventricular contraction; PAC, premature atrial contraction; VT, ventricular tachycardia; MV, mechanical ventilation; CVS, cardiovascular; NAC, N-acetylcysteine.

Table 2.
Review articles of intravenous MgSO4 for acute OP
Study Outcome
Nurulain et al. [38] (2013) MgSO4 as nonstandard therapy and nonregular antidote.
Its effectiveness has not yet been sufficiently established.
Brvar et al. [40] (2018) OR for MgSO4 for mortality, 0.55 (95% CI, 0.32–0.94).
OR for MgSO4 for the need for intubation and ventilation for all eight studies, 0.52 (95% CI, 0.34–0.79).
There was no apparent evidence of a dose effect.
The most common dose of MgSO4 studied was 4 g.
MgSO4 doses such as 4 g every 4 hr might offer greater benefit.
Eddleston et al. [10] (2008) MgSO4 reduced ACh release from presynaptic terminals.
Reduced mortality with MgSO4 (0/11 [0%] vs. 5/34 [14.7%], P<0.01).
Bajracharya et al. [43] (2016) The use of MgSO4 in acute OP in humans has been reported in three small studies.
In the first study, IV administration of magnesium sulfate improved neuromuscular function.
The second and third studies reported that magnesium decreased mortality compared with usual care.
Aman et al. [41] (2021) Preclinical studies of rodents suggested that MgSO4 before or soon after OP exposure decreases mortality.
MgSO4 uses of managing cardiac dysrhythmias and hypertonic uterine contractions (MgSO4) occurring in OP poisoned patients.
A total of eight clinical studies or trials have now been performed with MgSO4 (239 patients receiving MgSO4 doses of up to 26 g/day and 202 control patients).
The dose most commonly used was 4 g, which is also the standard dose for treating cardiac dysrhythmias and needs no intensive monitoring of magnesium concentrate.
A small phase II study performed in Bangladesh that tested four escalating doses of MgSO4 (4, 8, 12, and 16 g) demonstrated good tolerance.
Eddleston [1] (2019) Interruption of the calcium flow through channels by magnesium may be sufficient to reduce the synaptic concentration of Ach.
Administration of magnesium to rodents before or soon after OP exposure, in addition to atropine and/or oxime, reduces mortality.
A nonrandomized Iranian clinical study of 4 g MgSO4 in acute OP during 2003–2004 suggested that it was effective in reducing mortality and length of hospital stay.
Narang et al. [42] (2015) MgSO4 blocks calcium channels and reduces ACh release.
Given in a dose of 4 g on first day of admission, it has been shown to decrease hospitalization period and improve outcomes in patients with OP poisoning.
Blain [44] (2011) The administration of MgSO4 to animals poisoned with organophosphorus pesticides improves outcome, possibly due to a favorable effect on neuromuscular junction block or increased hydrolysis of some pesticides.
In one study, intravenous administration of MgSO4 4 g to four people produced some improvement in neuromuscular function in two people.
Another nonrandomized comparative study reported that MgSO4 decreased mortality compared with usual care (0/11 [0%] vs. 5/34 [15%]).
Husain et al. [45] (2010) Beneficial effect of MgSO4 at a dose of 4 g/day concurrent with standard therapy, in OP acute human poisoning has been reported.
Eddleston and Chowdhury [39] (2016) Magnesium may reduce the risk of ventricular tachycardia in patients presenting with tachycardias due to nicotinic stimulation.
More recent phase II dose-response study compared 4, 8, 12, and 16 g of MgSO4 vs. placebo in groups of 10 OP insecticide-poisoned patients; MgSO4 at all doses was well-tolerated and there was a trend toward reduced mortality with larger doses.
Kaur et al. [16] (2014) It has been shown to be of benefit in animal models.
IV MgSO4 (4 g) given on the first day after admission have been shown to decrease hospitalization period, decreased mortality and improve outcomes in patients with OP.
MgSO4 may also provide protection by reducing the stimulatory effect of ACh on the muscle action potential and reversing the decrement in the force of contraction.
Kumar et al. [46] (2018) IV MgSO4 (4 g) was administered to the patient on the first day after admission, and was found to reduce the hospital stay and improve the outcomes in patients with OP.
Balali-Mood and Saber [47] (2012) IV MgSO4 (4 g) given in the first day after admission have been shown to decrease hospitalization period and improve outcomes in patients with OP.
Alozi and Rawas-Qalaji [7] (2020) A phase II study confirmed the safety of MgSO4 administration to OP poisoned patients, and several other trials recommended the infusion of 1 g of MgSO4 every 6 hr within the first 24 hr of admission.
Adjunctive MgSO4 was also shown to reduce the dose of atropine needed for intubation and the overall time spent in the ICU and associated mortality rates were reduced as well.
Asalu et al. [48] (2019) MgSO4 has been shown to decrease hospitalization period and improve patients’ outcomes in OP.
MgSO4 is given in a dose of 4 g on day 1of presentation at the hospital and subsequently 2 g daily when necessary.
MgSO4 acts by blocking calcium channels and thus reduces ACh release from the storage vesicles.
Rafati Rahimzadeh and Moghadamnia [49] (2010) Recommended the infusion of 1 g of MgSO4 every 6 hr within the first 24 hr of admission.
Magnesium also reduce the risk of ventricular tachycardia in patients presenting with tachycardias.

MgSO4, magnesium sulfate; OP, organophosphate poisoning; OR, odds ratio; CI, confidence interval; , Ach, acetylcholine; IV, intravenous; ICU, intensive care unit.

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