The key role of magnesium sulfate in the management of organophosphorus pesticide poisoning: a scoping literature review
Article information
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 [24,29,31–37].
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 [39–41]. 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 [1,7,10,16,38–49].
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
Article information Continued
Notes
Capsule Summary
What is already known
Organophosphate poisoning is potentially life-threatening. Standard management of organophosphate poisoning involves the use of antidotes such as atropine and oximes, which help to counteract the cholinergic crisis caused by acetylcholine accumulation.
What is new in the current study
The current study explores the use of magnesium sulfate as a potential adjunctive treatment for organophosphate poisoning. This study suggests that magnesium sulfate could be used as an adjunctive treatment in organophosphate poisoning, potentially improving outcomes. However, the evidence remains insufficient, indicating the need for further research to establish its effectiveness definitively.