Magnesium sulfate and calcium channel blocking drugs as antidotes for acute organophosphorus insecticide poisoning – a systematic review and meta-analysis

Figures & data

Figure 1. Flow diagram illustrating stages of the review process. The very large number of papers identified in the Chinese database screen, compared to PubMed that were considered not relevant was due to the common practice of giving magnesium sulfate in the gastric lavage for OP insecticide poisoning in China. As the magnesium was not given as an antidote, but as a cathartic, these papers were excluded from the analysis.

Table 1. Pre-clinical studies of MgSO₄ and CCB for acute organophosphorus insecticide toxicity.

Species and Ref.	OP	Treatment	Time point	Outcome	Side effects
Rat [22]	Paraoxon	Nimodipine 0.030–0.071 mg/kg IA	5 min after OP	Prolonged survival time after lethal dose; nimodipine with atropine and diazepamprevented lethality andprolongedsurvival time	NA
Rat & guineapigs [23]	Omethoate and dimethoate	Verapamil 1.25 mg/kg IP	5 min before OP	Elevated LD50 of dimethoate and omethoate (reduced toxicity); verapamil augmented the protection due to atropine against dimethoate and omethoate and delayed muscle fasciculation and convulsions	NA
Pig [24]	Paraoxon (150× LD50)	MgSO4 0.1 g/kg IV(6.7 ± 1.7 mg/kg/min)	After OP when MAP rose above 120 mmHg	Prevented death; prevented extreme hypertension and tachycardia	NA
Rat [25]	Dimethoate (70 mg/kg IP)	MgSO4 0.1 g/kg IV	30 min before OP	Improved Na^+/K^+ ATPase and Ca^2+ ATPase activities in OP poisoned skeletal muscles	NA
Rat [26]	Dichlorvos	MgSO4 0.2 g/kg IP	Just before OP	Trend toward decreasedmortality; increased cardiac tissue nitric oxide concentrations	MgSO4 furthersuppressed serum BuChE

IA: intra-arterial; IM: intramuscular; IP: intra-peritoneal; IV: intravenous; MAP: mean arterial pressure; NA: not available; OP: organophosphorus.

Figure 2. Assessment of sources of potential bias, using Cochrane Collaboration guidelines [41]. All studies were considered at risk of “other sources of bias” due to their small size, variation in the effect of the variable OP insecticides ingested, and lack of identification of the responsible insecticide by laboratory analysis.

Figure 3. Forest plots indicating impact of treatment with magnesium sulfate on (A) mortality and (B) need for intubation/ventilation in OP insecticide poisoned patients. Odds ratios with 95% confidence interval. The studies are ordered by their magnesium dose to allow visualization of a dose effect if one exists.

Table 2. Clinical studies of intravenous MgSO₄ treatment for acute organophosphorus insecticide poisoning.

Study	Patients	Treatment	Time of Rx	Outcomes and comments
Dong, China, 1993 [36] Case series	n = 19 (Mg 11, control 8)	MgSO4 2.5–5 g daily for 2–3 d	NA	Median atropine requirement for first 24 h: NA Need for intubation and ventilation: NA Median duration of ventilation in survivors: NA Median ICU stay: NA Median hospital stay: NA Mortality: Mg 0/11 (0%) vs. NoMg 1/8 (12.5%) Adverse effects of therapy: none noted Study limitations: small, not an RCT, basis for allocation unclear
Pajoumand, Iran, 2003–4 [37] Single blind prospectivecontrolled trial. Openallocation 1:3	n = 45 (Mg 11, control 34) Ward patients Poisoned by: ND	MgSO4 4 g over 24 h	On presentation to hospital. Timing: NA	Mean atropine requirement per day: Mg 3.4 (SE 0.8) mg vs. NoMg 4.7 (SE 1.0) mg (p > .05) (use of mean [SE] data)^a Need for intubation and ventilation: NA Median duration of ventilation: NA Median ICU stay: NA Mean hospital stay: Mg 2.9 (SE 0.7) vs. NoMg 5 (SE 0.8) days (p < .01) (use of mean [SE] data)^a Mortality: Mg 0/11 (0%) vs. NoMg 5/34 (14.7%) (p < .01) Adverse effects of therapy: none noted Study limitations: small, not a RCT
Basher, Bangladesh, 2006–7 [38] Phase II sequential doseescalation study 4:1 allocation	n = 50 (16 × 4 g Mg, 8 × 8 g Mg, 8 × 12 g Mg, 8 × 16 g Mg; 10 controls within cohorts) Ward patients. Poisoned by: malathion, chlorpyrifos, fenthion	MgSO4 4 g over 10–15 min every 4 h, to a maximum of 4 doses	On presentation to hospital, 1.5–19 h post poisoning.	Median atropine requirement during resuscitation: Mg: 6.7–12.2 mg for different Mg doses (no dose-response), NoMg: 28.9 mg. (Total atropine requirement: no difference, p > .05) Need for intubation and ventilation: 3/16 for 4 g Mg, 1/8 for 8, 1/8 for 12, 1/8 for 16 g; 4/10 for NoMg (p > .05). Median hospital stay: NA Mortality: 3/16 for 4 g Mg, 2/8 for 8, 1/8 for 12, 0/8 for 16 g; 6/10 for NoMg (p>.05). Adverse effects of therapy: none noted Study limitations: small study; higher proportion of severe toxicity in control group; limited critical care capacity to maintain ventilator support to all patients with GCS ≤8/15
Dawson, Sri Lanka, 2007–8 Dawson et al, unpublished data RCT, 2:1 allocation	n = 49 (Mg 36, control 13) Ward patients, Poisoned by: chlorpyrifos (∼50%), dimethoate (∼25%). Well balanced between groups.	MgSO4 4 g over 1 h, then 1 g per hour, up to a maximum of 28 g over 25 h. Note: 9/36 patients did not receive their full 25 h Mg Rx (loading dose was not completed in one due to hypotension)		Median atropine requirement for first 24 h: Mg 28.2 (IQR 14.4–29.1) mg vs. NoMg 28.8 (IQR 14.6–41.1) mg (p = .485) Need for intubation and ventilation: Mg 12/36 (33.3% [95% CI 20.1–49.7]) vs. NoMg 3/13 (23.1% [95% CI 7.5–50.9]) (p = .727) Median duration of ventilation in survivors: Mg 98.7 (IQR 42.9–391.9) h vs. NoMg 294.1 (IQR 40.8–547.5) h (p = .909) Median ICU stay: NA Median hospital stay: Mg 7.5 (IQR 5.0–10.8) d vs. NoMg 7.0 (IQR 5.0–8.0) d (p = .616) Mortality: Mg 7/36 (19.4% [95% CI 9.5–35.3]) vs. NoMg 2/13 (15.4% [95% CI 3.1–43.5]) (p  =  1.000) Adverse effects of therapy: transient hypotension noted in four patients (11.1%) Study limitations: finished early due to logistic reasons; insufficiently powered
Khurana, India 2009 Khurana, unpublished data Case-control study	n = 15 (Mg 7, control 8) Emergency dept/ward patients	MgSO44 g over 10–15 min every 6 h for 48 h	On presentation to hospital, within the first 24 h post poisoning.	Median total atropine requirement: NA Need for intubation and ventilation: Mg 5/7 vs. NoMg 6/8 (p = .88) Median duration of ventilation: Mg 24 (IQR 18–66) h vs. NoMg 30 (IQR 12–84) h (p = .93) Median ICU stay: NA Median hospital stay: NA Mortality: 0/7 Mg vs. 0/8 NoMg (p  =  1.00) Adverse effects of therapy: none noted Study limitations: smallsample size
Vijayakumar, India, 2014–5 [39] Double-blind RCT (per-protocol analysis, 10 excluded)	n = 100 (Mg 50, control 50) ICU patients.	MgSO4 4 g over 30 min	On admission to ICU (time since poisoning not described)	Median atropine requirement per day: Mg 40.9 (IQR 20.9–70.3) mg vs. NoMg 53.3 (IQR 37.4–82.0) mg/d (p < .001) Need for intubation and ventilation: Mg 23/50 vs. NoMg 33/50 (p = .043) Median duration of ventilation: Mg 3 (IQR 0–8) d vs. NoMg 4 (IQR 0–14) d (p = .45) Median ICU stay: Mg 4.5 (IQR 3–10) d vs. NoMg 6 (IQR 4–16) d (p = .026) Mean hospital stay: NA Mortality: Mg 3/50 vs. NoMg 4/50 (p =  .695) Adverse effects of therapy: none noted Study limitations: only ICU patients; no follow up after ICU discharge; insufficiently powered for mortality.
Philomena, India, 2015–6 [40] Case series, before & after study	n  =  133 (Mg 69, control 64) ICU patients.	MgSO4 4 g over 1 h	Within first 24 h after admission	Median atropine requirement per day: NA Need for intubation and ventilation: Mg 23/69 vs. NoMg 30/64 (p = .156) Median duration of ventilation: NA Median ICU stay: NA Median hospital stay: NA Mortality: 11/69 Mg vs. 20/64 NoMg (p = .042) Adverse effects of therapy: none noted Study limitations: cohort study, small sample size, atropine dose was not described, magnesium was not measured
Ghimire, Nepal, 2017. Ghimire et al, unpublished data Case series, before and after study	n  =  30 (Mg 15, control 15) Ward patients	MgSO4 4 g as bolus	Within the first 24 h after admission	Median total atropine requirement: Mg 50.0 (38.7–59.4) mg vs. 46.0 (40.8–72.6) mg (p>.05) Need for intubation and ventilation: 0/15 Mg vs. 0/15 NoMg Median duration of ventilation: NA Median ICU stay: NA Median hospital stay: Mg 6 (5–7) d vs. NoMg 6 (6–7) d (p>.05) Mortality: 0/15 Mg vs. 0/15 NoMg. Adverse effects of therapy: none noted Study limitations: small sample size

^a Use of mean (SE) values for one study for which primary data were not available.

Mg: MgSO₄ treatment arm; NA: not available; NoMg: control treatment arm.

Table 3. Serum Mg²⁺ concentrations in the clinical studies were reported.

Study	Treatment	Time point	Control arm [Mg^2+] (mmol/L) (median, IQR)	MgSO4 arm [Mg^2+] (mmol/L) (median, IQR)
Iran, 2003–4 [37]	MgSO4 4 g	After treatment	0.85 ± 0.02^a	0.93 ± 0.03^a (use of mean [SE] data)	p < .01
Bangladesh, 2006–7 [38]	MgSO4 4 g every 4 h, to a maximum of 4 doses	24 h after the first Mg dose	0.88 (0.86–0.91)	4 g Mg: 0.91 (0.88–0.94) 8 g Mg: 0.95 (0.88–0.98) 12 g Mg: 0.92 (0.90–0.98) 16 g Mg: 0.90^b	p > .05
Sri Lanka, 2007–8 Dawson et al, unpublished.	MgSO4 4 g over 1 h, then 1 g per hour, up to a max 28 g over 25 h.	24 h after the first Mg dose	0.88 (0.73–0.99)	1.54 (1.10–1.77)	p = .004
India, 2014–5 [39]	MgSO4, 4 g	24 h after the first Mg dose	0.82 (0.78–0.93)	0.91 (0.86–1.03)	p = .023
Nepal, 2017. Ghimire et al, unpublished	MgSO4 4 g	24 h after the first Mg dose	NA	1.05 (1.00–1.15)	NA

^a Use of mean (SE) values for one study for which primary data were not available.

^b Single patient measured.

In addition, the serum samples post-treatment was usually not taken at the end of the loading/first infusion when the Mg²⁺ concentration would be expected to be at its highest. Higher concentrations of magnesium might have occurred during the studies.

Trouve R, Nahas G. Nimodipine in combination with atropine and diazepam as an antidote to lethal organophosphorus intoxication. Br J Pharmacol. 1989;96:19P.

 Google Scholar

Li Y, Cai ZF, Zhao LH. Experimental treatment and protective effect of verapamil on organophosphate poisoning [in Chinese]. Occup Med. 1996;23:4–6.

 Google Scholar

Petroianu G, Toomes LM, Petroianu A, et al. Control of blood pressure, heart rate and haematocrit during high-dose intravenous paraoxon exposure in mini pigs. J Appl Toxicol. 1998;18:293–298.

 PubMed Web of Science ®Google Scholar

Li C, Zhao M, Yang L, et al. ATPase activities in skeletal muscle tissue after acute organophosphorus poisoning and the effects of magnesium sulfate [in Chinese]. Chinese J Emerg Med. 2005;14:276–278.

 Google Scholar

Gunay N, Kekec Z, Demiryurek S, et al. Cardiac effects of magnesium sulfate pretreatment on acute dichlorvos-induced organophosphate poisoning: an experimental study in rats. Biol Trace Elem Res. 2010;133:227–235.

 PubMed Web of Science ®Google Scholar

Cochrane Collaboration. Assessing risk of bias in included studies. In: Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions. Hoboken (NJ): John Wiley & Sons; 2011.

 Google Scholar

Dong X. Effect of magnesium sulfate on organophosphate pesticide poisoning in 11 cases [in Chinese]. Clin Focus. 1993;8:276–277.

 Google Scholar

Pajoumand A, Shadnia A, Rezaie A, et al. Benefits of magnesium sulfate in the management of acute human poisoning by organophosphorus insecticides. Hum Exp Toxicol. 2004;23:565–569.

 PubMed Web of Science ®Google Scholar

Basher A, Rahman SH, Ghose A, et al. Phase II study of magnesium sulfate in acute organophosphate pesticide poisoning. Clin Toxicol. 2013;51:35–40.

 PubMed Web of Science ®Google Scholar

Vijayakumar HN, Kannan S, Tejasvi C, et al. Study of effect of magnesium sulphate in management of acute organophosphorous pesticide poisoning. Anesth Essays Res. 2017;11:192–196.

 PubMedGoogle Scholar

Philomena J, Sathi V, Prathiba P. A case control study of intravenous magnesium sulphate in treatment of acute organophosphate poisoning. J Evol Med Dent Sci. 2016;5:2290–2294.

 Web of Science ®Google Scholar