Magnesium sulfate in organophosphorus compound poisoning: A prospective open-label clinician-initiated intervention trial with historical controls.

Background: The addition of magnesium sulfate (MgSO4) to standard treatment has improved mortality and morbidity associated with organophosphorus compound (OPC) poisoning. We aimed to assess the effectiveness of adjunctive intravenous MgSO4 (IV MgSO4) in poisoning from OPCs.
Methods: Forty-seven cases and 72 controls were recruited to this prospective open-label clinician-initiated intervention trial after admitting OPC poisoning. All patients received standard treatment for anticholinesterase poisoning, and oximes were not used. Cases were divided into two groups. Group A (22 patients) received IV MgSO4 at 4 g/day in four divided doses (1 g every 6 h) on day 1. Group B (25 patients) received the same daily dose of IV MgSO4 throughout the hospital stay. Group C (72 patients) represents historical controls who did not receive IV MgSO4. The primary outcome was inhospital mortality. The secondary outcomes included the development of intermediate syndrome (IMS), the requirement of mechanical ventilation (MV), duration of MV, and length of hospital stay.
Results: Baseline parameters in both groups were comparable. There is no statistically significant difference in mortality among three groups (Group A: 2/22, 9.1%; Group B: 5/25, 20% and Group C: 6/72, 8.3%). Results were similar for the development of IMS, the requirement of MV, length of MV, and duration of hospital stay.
Conclusion: IV MgSO4 did not result in better outcomes compared with standard care alone in OPC poisoning. Copyright:

INTRODUCTION

Agriculture is a significant source of income for large-scale Asian populations. The pesticides are readily available in rural areas, making them the most frequent poisoning cause after intentional ingestion.[1234] In India, acetylcholinesterase (AChE)-inhibiting compounds, including organophosphorus compound (OPC) and carbamate, account for the highest number of pesticide poisoning cases.[5]

These pesticides inactivate the enzyme AChE by alkyl phosphorylation of a serine hydroxyl group, which results in the inability to hydrolyze acetylcholine to acetic acid and choline, which further prevents neurotransmission.[6] The clinical features of OPC poisoning are mainly due to the accumulation of endogenous AChE of cholinergic transmission. Treatment with atropine reverses the cholinergic effects of OPC (such as bradycardia, increased trachea-bronchial secretions, lacrimation, and urination).[7] Oximes, such as pralidoxime and obidoxime, have been used to reactivate the inhibited enzyme by removing the phosphoryl group. However, recent studies have questioned their effectiveness in OPC poisoning.[89] Given high mortality rates despite the standard management, new treatment options have been evaluated, including magnesium sulfate (MgSO 4), sodium bicarbonate, fresh frozen plasma, N-acetyl cysteine, clonidine, and hemoperfusion.[10]

Magnesium has shown variable success in small-scale studies in OPC poisoning. The physiological basis of magnesium comes from the observation in animal studies.[1112] It reversed the decrement in the force of contraction and compound muscle action potential in rats treated with diisopropyl fluorophosphate.[13] A similar effect was also observed in humans in whom magnesium reversed OPC poisoning's neuro-electrophysiological effect.[14] Studies have also shown the role of magnesium in controlling premature ventricular contractions in OPC poisoning.[15] Small randomized controlled studies have claimed a mortality benefit or reduction in the intensive care unit stay.[16] One of the surveys has showed decreased atropine requirement, need for intubation, and intensive care stay.[17] A recent meta-analysis on magnesium sulfate as adjunctive in OPC poisoning management has shown benefit in mortality.[18]

These studies have used pralidoxime and MgSO4 along with the usual treatment. In this study, we have used MgSO4 in OPC-poisoned patients in two different dose regimens. We have studied its effect on morbidity and mortality.

METHODS

Our study is a prospective open-label clinician-initiated intervention trial with historical controls, conducted at a tertiary care center in North India from July 1, 2012, to December 31, 2013. Ethical clearance was obtained from the Ethical Review Committee of the institution.

Patients aged between 18 and 60 years presenting with a history of OPC consumption and clinical features of cholinergic toxidrome of typical anticholinesterase poisoning were recruited. Informed written consent was obtained in all the cases from the patient or their relatives. Patients with doubtful history, poisoning with unknown compound, treatment initiated before admission, history of allergic reactions to magnesium, and those who refused to consent were excluded. Decontamination of the gastrointestinal tract and skin was performed as per standard protocol followed in the institute.

Intravenous atropine was administered by doubling the dose every 5 min (2 mg initial dose) until the patient is atropinized.[19] Atropinization is defined as the absence of lung secretions (absence of crackles on chest auscultation): dry axilla and mouth: adequate heart rate and blood pressure (80 beats/min and 80 mmHg, respectively). After atropinization with bolus doubling dosing, an infusion of atropine at a rate of 10%−20% of the total dose of the required atropine was started. Oximes were not used. Other supportive care was given as per standard institute protocol. The patients were under observation for their vital signs, pupil size, reflexes, muscle fasciculation, respiratory crackles, amount of oral secretions, and tracheal secretion (if intubated).

Patients were enrolled in the prospective group (cases) during the study period based on the history of exposure and the presence of cholinergic toxidrome at presentation. Alternate cases were divided into two groups, Group A and Group B. Group A received IV MgSO4 at 4 g/day in four divided doses (1 g IV every 6 h) on day 1. Group B received IV MgSO4 at a dose of 4 g/day in four divided doses (1 g IV every 6 h) throughout the hospital stay (for at least five days). Serum magnesium levels were checked at admission and 24, 48, and 72 h after the entry. OPCs have an average half-life ranging 3−33 h depending on the type of compound. Hence, it has a prolonged effect on the myocardium, resulting in increased morbidity and mortality; therefore, we administered MgSO4 for a prolonged duration (5 days), covering at least four half-lives. The retrospective group of historical controls who did not receive IV MgSO4 was Group C. These were admitted cases of OPC poisoning in the last 3 years in the hospital. All the clinical details were obtained from the case records of the medical records department of the institution with coding T 60.0 according to the International Classification of Diseases-10. Similarly, to Groups A and B, Group C did not receive any oxime.

Cases were compared with controls for the inhospital mortality rate. Development of intermediate syndrome (IMS), the requirement of mechanical ventilation (MV), duration of MV, and length of hospital stay were the secondary outcomes. IMS was diagnosed clinically by development of motor weakness in the ocular, neck, bulbar, proximal limb, and respiratory muscles during resolution of the cholinergic symptoms, usually 12−96 h after OPC poisoning.[17] All clinical symptoms, signs, and interventions (including invasive ventilation, if used) were recorded. Routine investigations were performed as and when required. Patients were monitored for magnesium toxicity by observing variation in pulse rate, blood pressure, deep tendon reflexes, respiratory rate, and urine output, along with serum magnesium level.

The data were entered into Microsoft Excel and were analyzed using the Statistical Package for the Social Sciences (IBM SPSS Statistics, version 22.0. IBM Corp, USA). Descriptive statistics were used for summarizing the characteristics of study groups. Categorical variables were presented as numbers (percentages) and continuous variables as mean ± standard deviation. Differences between the three groups were tested by Chi-square test and analysis of variance for categorical and continuous variables, respectively. The P value for significance was set at ≤0.05.

RESULTS

A total of 55 patients were enrolled in the prospective group (the cases) during the study period, of which 8 did not meet the inclusion criteria. Forty-seven cases were further divided into two groups: Group A, n = 22, and Group B, n = 25. Retrospective data of 90 patients (historical control group) were taken as the control group, of which 18 patients were excluded due to inclusion criteria. The rest comprised Group C. The demographic variables and other baseline characteristics are presented in Table 1. Most patients were young; students and homemakers constituted more than half of the cases. The most common mode of exposure was by the oral route, and most cases were suicidal. All patients had clinical features of acute cholinergic crisis during admission, nausea and vomiting were the most common symptoms on admission (in >2/3 patients). Respiratory distress was seen in more than half of the patients. Miosis and bradycardia were the most common signs at presentation. A low Glasgow Coma Scale score (<9) was found in 47.9% of the patients.

Table 1

Baseline characteristics, symptom profile, and investigations of the organophosphorus compound poisoning patients included in the current study population

Variables	Received MgSO4 for 1 day (n=22)	Received MgSO4 entire hospital stay (n=25)	Historic controls with no MgSO4 (n=72)	P
Age (years)*	29.7±11.6	30.7±14.9	25.6±8.4	0.071
Male sex	8 (36.4)	14 (56)	42 (58.3)	0.189
Mode of ingestion
Self-harm	20 (90.9)	21 (84)	60 (83.3)	0.323
Accidental	2 (9.1)	3 (12)	12 (16.7)
Route of exposure
Oral	21 (95.5)	24 (96)	68 (94.4)	0.948
Inhalational	1 (4.5)	1 (4)	4 (2.8)
Symptom profile
Vomiting	17 (77.3)	15 (60)	52 (72.2)	0.384
Blurred vision	0	2 (8)	13 (18.1)	0.061
Diarrhea	4 (18.2)	5 (20)	9 (12.5)	0.604
Salivation	9 (40.9)	15 (60.9)	48 (66.7)	0.096
Lacrimation	8 (36.4)	13 (52)	39 (54.2)	0.338
Abdominal pain	2 (9.1)	2 (8)	9 (12.5)	0.787
Sweating	13 (59.1)	18 (72)	35 (48.6)	0.119
Urinary incontinence	14 (63.3)	13 (52)	25 (34.7)	0.037
Muscle fasciculations	2 (9.1)	1 (4)	13 (18.1)	0.166
Muscle weakness	4 (18.2)	4 (16)	16 (22.2)	0.774
Seizures	1 (4.5)	3 (12)	3 (4.2)	0.342
Wheeze	12 (54.5)	8 (32)	49 (68.1)	0.007
Miosis	16 (72.7)	14 (56)	41 (56.9)	0.383
Tachycardia	6 (27.3)	10 (40)	31 (43.1)	0.415
Hypotension	1 (4.5)	2 (8)	5 (6.9)	0.888
GCS <9	7 (31.8)	13 (52)	28 (38.9)	0.343
Investigations
Hemoglobin (g/dL)*	13.0±1.9	12.1±2.4	12.4±2.1	0.319
TLC (×109 cells per liter)*	12.28±0.51	13.64±0.63	13.03±0.49	0.674
Platelet count (×109 cells per liter)*	187±66	226±97	215±84	0.260
Sodium (mEq/L)*	139±4	138±5	144±7	0.000
Potassium (mEq/L)*	3.9±0.5	4.2±0.6	4.0±0.8	0.515
Blood urea (mg/dL)*	27.3±8.1	38.3±47	35.7±22.2	0.361
Serum creatinine (mg/dL)*	0.53±0.27	0.85±0.73	0.93±0.95	0.137
AST (units/L)*	58±45	53±20	69±69	0.435
ALT (units/L)*	60±56	43±21	50±38	0.367
Alkaline phosphatase (units/L)*	87±21	105±55	100±52	0.432
Total bilirubin (mg/dL)*	0.5±0.2	0.7±0.5	0.9±0.8	0.100
Albumin (g/L)*	3.9±0.7	3.8±0.6	3.9±0.6	0.585

The parameters are presented as n (%) or *mean±SD. AST: Aspartate transaminase, ALT: Alanine transaminase, GCS: Glasgow Coma Scale, TLC: Total leukocyte count, SD: Standard deviation, MgSO4: Magnesium sulfate

The type of OPC consumed was not known in more than half of the patients. Dimethyl compounds were more commonly used than diethyl compounds among the known. Dichlorvos was the most common OPC used in poisoning, followed by chlorpyriphos [Table 2].

Table 2

Type of organophosphorus compound exposed to among the study population involved in the current study

Type of organophosphorus compound	Received MgSO4 for 1 day (n=22)	Received MgSO4 entire hospital stay (n=25)	Historic controls with no MgSO4 (n=72)	Total (n=119)
Chlorpyriphos	1 (4.5)	4 (16)	10 (13.9)	15 (12.6)
Dichlorvos	3 (13.6)	8 (32)	20 (27.8)	31 (26.1)
Malathion	0	0	2 (2.8)	2 (1.7)
Not known	18 (81.8)	13 (52)	40 (55.5)	71 (59.7)

The parameters are presented as n (%). MgSO4: Magnesium sulfate

Serum magnesium levels were monitored from baseline until day 5 of hospital stay. Baseline magnesium levels were significantly on the lower side among cases than controls, although they were within normal limits [Table 3]. No statistical differences were observed between the groups regarding the clinical and laboratory profiles, except for urinary incontinence (P = 0.037), wheezing (P = 0.007), and blood Sodium levels [P < 0.001; Table 1].

Table 3

Serial serum magnesium levels (mg/dL) in the three different study groups

	Received MgSO4 for 1 day (n=22)	Received MgSO4 entire hospital stay (n=25)	Historic controls with no MgSO4 (n=72)	P
Day 1	1.7±0.34	1.8±0.5	2.0±0.4*	0.005
Day 2	2.0±0.3	1.9±0.4	1.9±0.3#	0.852
Day 3	2.0±0.4	2.1±0.2	1.9±0.3^	0.702

The parameters are presented as mean±SD. The values were available for *n=64, #n=24, ^n=9. SD: Standard deviation, MgSO4: Magnesium sulfate

The mortality was 8.3% among the patients who received no MgSO4 compared to 9.1% among those who received MgSO4 on day 1 and 20% among those who received MgSO4 throughout the hospital stay. There was no statistically significant difference (P = 0.261). IMS incidence was 22.7% among patients in Group A and 12% in Group B compared to 15.3% among the controls. MV was required in 40.9% of Group A, 60% in Group B, and 51.4% among the patients in Group C. The total number of days on MV was 4.4, 6.8, and 4.0 days in Groups A, B, and C, respectively. The mean of the total number of days of hospital stay was 7.8 days in Group A, 9.8 days in Group B, and 9.8 days in Group C. There was no statistically significant difference in the development of IMS, the requirement of MV, duration of MV, and length of hospital stay among the three groups [Table 4].

Table 4

Outcomes of the organophosphorus compound poisoning patients included in the current study

Outcome variables	Received MgSO4 for 1 day (n=22)	Received MgSO4 entire hospital stay (n=25)	Historic controls with no MgSO4 (n=72)	P
Inhospital mortality	2 (9.1)	5 (20)	6 (8.3)	0.261
Development of IMS	5 (22.7)	3 (12)	11 (15.3)	0.788
Need of MV	9 (40.9)	15 (60)	37 (51.4)	0.664
Duration of MV (days)*	4.38±3.42	6.8±4.28	4±6.3	0.621
Length of hospital stay (days)*	7.77±7.65	9.88±7.97	9.77±9.35	0.247

The parameters are presented as n (%) or *mean±SD. IMS: Intermediate syndrome, MgSO4: Magnesium sulfate, MV: Mechanical ventilation, SD: Standard deviation

No substantial adverse effects such as hypotension, bradyarrhythmia, respiratory depression, depressed tendon jerks, and decreased urine output were noted in trial patients. Magnesium levels were monitored daily for toxicity, and they remained within the normal reference range of 1.6−2.6 mg/dl. No mortality was noted in the study population related to magnesium toxicity.

DISCUSSION

IV MgSO4 did not result in better outcomes than standard care alone in a prospective open-label clinician-initiated intervention trial, including 47 cases and 72 historical controls with OPC poisoning. Most patients included in this study belonged to the younger age group. Most patients require hospitalization for more than 1 week. MV was required in almost half of the patients (61 of 119 patients), with no significant difference between the groups. The inhospital mortality was 10.92% (13/119) and was similar in the three groups.

Oximes are used to reactivate AChE inhibited by OPC. Recent research failed to demonstrate its effectiveness and benefit in OPC poisoning. In some studies, its use was associated with poor outcomes.[89] We did not use oximes in this study. To our knowledge, this is the first interventional trial to address the role of IV MgSO4 without using oximes.

IV MgSO4 in the first 24 h of admission has shown mortality benefit in a small randomized controlled trial (RCT) and a recent case−control study.[1617] An RCT of 100 OPC poisoning patients claimed a reduction in the requirement of intubation and hospital stay with a single bolus dose of IV MgSO4 in the first 24 h of hospitalization but without benefit in the mortality and duration of the MV.[17] A phase II trial has shown a reduction in mortality with an increasing dose of IV MgSO4.[20] Our study failed to show any benefit with IV MgSO4 used either in the first 24 h or during the entire hospital stay. Concurring with the other studies, IV MgSO4-related adverse events were not seen with a dose of 4 g/d.[16171820]

This study had the following limitations. First, the study sample size was small, and the design was not a RCT. Second, the facility for measuring the blood level of OPC and the red cell cholinesterase concentrations were not available in our institute; therefore, we were unable to confirm the suspected cases. Third, data on first aid, decontamination, and atropine requirement (per kg) are not available, which would have partially helped classify the severity of poisoning. Different dose regimens’ rationale was arbitrary, and half-lives of MgSO4 are variable when used for a prolonged duration.

CONCLUSION

In conclusion, although a single-center case−control study, we report no benefit from the addition of IV MgSO4 (either in the first 24 h of the admission or during the entire hospital stay, at a dose of 1 g every 6 h) to the atropine and supportive care in the management of OPC poisoning. As the MgSO4 is an inexpensive, easy to available, commonly used, and relatively safe drug, further large multicenter randomized trials are needed to define its role in the treatment and outcome of OPC insecticide poisoning. Although our study cannot answer for poor prognosis in OPC poisoning, it points to the necessity of assessing the novel treatment approaches in large trials to reduce the case fatality rate, especially in the resource constraint rural agricultural communities.

Research quality and ethics statement

This study was approved by the Institutional Ethics Committee at Postgraduate Institute of Medical Education and Research, Chandigarh (approval no: NK/372/MD/9976-77; approval date: December 5, 2013). The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the STROBE guidelines, during the conduct of this research project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.