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Adverse drug events observed with intrathecal magnesium sulfate as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section: a meta-analysis

BMC Pharmacology and Toxicology volume 26, Article number: 96 (2025) Cite this article

Abstract

Introduction

Today, the number of cesarean section has drastically increased. Newer scientific reports have shown Magnesium sulfate (MgSO4) to have favorable outcomes for anesthesia. In this analysis, we aimed to systematically compare the adverse drug events observed with intrathecal MgSO4 as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section.

Methods

MEDLINE, EMBASE, Web of Science, Google scholar, http://www.ClinicalTrials.gov, and the Cochrane database were searched for relevant publications comparing the adverse drug events observed with intrathecal MgSO4 as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section. The RevMan software version 5.4 was used to analyze data in this analysis. Risk ratios (RR) with 95% confidence intervals (CIs) were used to represent analysis for the dichotomous data whereas weighted mean difference (WMD) with 95% CI was used to represent results using continuous data. Heterogeneity was assessed by the Q statistic and the I2 statistic tests.

Results

Eleven studies with a total number of 895 participants were included in this analysis whereby 466 patients were assigned to intrathecal MgSO4 and 429 participants were assigned to a control group. The main results of this analysis show that intrathecal MgSO4 as an adjuvant to bupivacaine was associated with a significantly lower risk of shivering (RR: 0.63, 95% CI: 0.48 – 0.83; P = 0.001). In addition, the risks for hypotension (RR: 1.11, 95% CI: 0.86 – 1.44; P = 0.40), nausea and vomiting (RR: 1.08, 95% CI: 0.76 – 1.54; P = 0.65), pruritus (RR: 0.77, 95% CI: 0.51 – 1.17; P = 0.22), and bradycardia (RR: 4.45, 95% CI: 0.97 – 20.36; P = 0.05) were not significantly increased. The sensory (WMD: 23.15, 95% CI: 7.83 – 38.48; P = 0.003), and motor block duration (WMD: 24.29, 95% CI: 16.36 – 32.23; P = 0.00001) and the duration of spinal anesthesia (WMD: 29.24, 95% CI: 13.61 – 44.87; P = 0.0002) were significantly in favor of MgSO4.

Conclusion

Intrathecal MgSO4 as an adjuvant to bupivacaine was associated with a significantly lower risk of shivering without causing any increase in other adverse drug events in patients undergoing elective cesarean section. Efficacy outcomes were also appreciated. Larger studies should be able to confirm this hypothesis.

Peer Review reports

Introduction

Today, even though the total number of pregnancies has decreased, the number of cesarean sections has drastically increased [1]. Thirty three percent (33%) of the deliveries done in the United States [2] are by cesarean section whereas in China, the rate has climbed to up to 35% [3]. Unfortunately, inadequate pain management has shown to be one of the contributing factors for morbidity, delayed recovery, chronic pain and post-traumatic distress syndrome [4]. Therefore, newer interventions are now focusing on how to reduce pain post-operatively [5].

New scientific reports have shown Magnesium sulfate (MgSO4) to have favorable outcomes for anesthesia [6]. Several benefits including shortening of anesthetic induction, decrease total post-operative analgesic requirements, reduction in anesthetic requirements, maintaining favorable hemo-dynamics and significantly lowering maternal and neonatal adverse effects have been observed [7].

Two meta-analyses based on the impact of intrathecal MgSO4 as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section have previously been published [8, 9]. However, both of the papers focused on post-operative analgesia only. No previous meta-analysis [8, 9] has yet reported adverse drug events following the use of intrathecal MgSO4 as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section.

Therefore, in this analysis we aimed to systematically compare the adverse drug events observed with intrathecal MgSO4 as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section.

Methods

Data sources, search strategies and searched terms

MEDLINE, EMBASE, Web of Science, Google scholar, http://www.ClinicalTrials.gov, and the Cochrane database were searched for relevant publications comparing the adverse drug events observed with intrathecal MgSO4 as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section.

Reference lists of selected articles were also verified for relevant publications.

The searched terms included:

  • ‘Magnesium sulfate, bupivacaine and cesarean section’;

  • ‘Magnesium sulfate, bupivacaine and spinal anesthesia and cesarean section’;

  • ‘Magnesium sulfate, spinal anesthesia and cesarean section’.

Criteria for inclusion

Studies were included if:

  1. (a)

    They were based on intrathecal MgSO4 as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section;

  2. (b)

    They reported adverse drug events with or without efficacy outcomes;

  3. (c)

    They included a control group;

  4. (d)

    They were published in English.

Criteria for exclusion

Studies were excluded if:

  1. (a)

    They were reviews (systematic reviews, brief reviews, literature reviews);

  2. (b)

    They were meta-analyses, network analyses;

  3. (c)

    They did not report adverse drug reactions;

  4. (d)

    They did not include a control group;

  5. (e)

    They were published in a different language except English;

  6. (f)

    They were duplicated studies from the same trial.

Data extraction, quality assessment and risk of bias

The authors independently extracted data after carefully assessing the selected studies. The total number of pregnant women who were assigned to MgSO4 and the control groups respectively, the adverse drug events and/or the efficacy outcomes which were reported, the endpoints which were assessed, the type of study and the participants’ enrollment time period, the gestational weeks, the body mass index, the weight and height of the participants as well as the type of participants, and the methodological features of the original studies were all carefully extracted.

Any disagreement which followed during this data extraction process was carefully discussed among the authors and a consensus was finally reached.

The quality assessment of the trials was carried out based on the recommendations suggested by the Cochrane database [10]. This Risk of Bias (RoB) tool was used to assess the methodological quality of the trials. The bias assessment report was generated through the RevMan software.

Statistical analysis

This is a meta-analysis and heterogeneity is obvious in such studies. The RevMan software version 5.4 (The Cochrane Collaboration, United Kingdom) was used to analyze data in this analysis. First of all heterogeneity was assessed by the Q statistic test whereby a p value less than 0.05 was considered significant statistically and a p value greater or equal to 0.05 was considered insignificant. Heterogeneity was also assessed by the I2 statistic test whereby a subgroup analysis with an I2 value less than 50% was considered to have a low heterogeneity and a subgroup analysis with an I2 value greater than 50% was considered to have a higher heterogeneity. A fixed effect statistical model was used for lower heterogeneity (I2 < 50%) whereas a random effect statistical model was used for an increasing I2 value.

Risk ratios (RR) with 95% confidence intervals (CIs) were used to represent data following analysis of dichotomous data.

For the continuous data, weighted mean difference (WMD) with 95% CI was used to represent the data. This was calculated using the mean, standard deviation and the number of participants in each related original study.

Sensitivity analysis was also carried out whereby each trial was excluded one at a time and a new analysis was carried out each time to verify for any significant change from the main results.

Publication bias was visually estimated through funnel plot which was generated by the Revman software.

Ethical approval

Ethical approval was not required for this study. This study did not involve experiment on animals or humans carried out by any of the authors.

Results

Search outcomes

A total number of 109 publications were obtained through this search process which followed the PRISMA (Preferred Reporting Items in Systematic Reviews and Meta-Analyses) guideline [11]. After carefully reviewing the titles and abstracts, as well as going through the data given in the abstracts, irrelevant studies were eliminated and at last, 57 full texts articles were assessed for eligibility.

While going through the 57 full texts articles, further eliminations were carried out based on the following reasons:

  1. (a)

    Meta-analyses (2);

  2. (b)

    Adverse drug events were not reported (6);

  3. (c)

    Case studies (3);

  4. (d)

    Repeated studies obtained from different search databases (35).

Finally, only 11 studies [12,13,14,15,16,17,18,19,20,21,22] were included in this analysis. The flow diagram for the study selection has been illustrated in Fig. 1.

Fig. 1
figure 1

Flow diagram showing the study selection for this analysis

Full size image

This Risk of Bias (RoB) assessment has been presented in Fig. 2.

Fig. 2
figure 2

Risk of bias assessment

Full size image

All the studies had low risk of bias as shown in the Figure. The randomization sequence generation, the allocation concealment, the blinding of participants and personnel, the blinding of outcome assessment were all well carried out and reported. Other bias was not reported in the studies.

Endpoints to be assessed

This analysis involved patients who underwent elective cesarean section. The adverse drug events which were reported in the original studies have been listed in Table 1.

Table 1 The endpoints which were reported
Full size table

The endpoints which were studied included:

  1. (a)

    Shivering;

  2. (b)

    Hypotension;

  3. (c)

    Nausea and vomiting;

  4. (d)

    Pruritus;

  5. (e)

    Bradycardia.

The efficacy outcomes, which were also listed in Table 1, have also been assessed and included:

  1. (a)

    Sensory block onset time (minute);

  2. (b)

    Sensory block duration time (minute);

  3. (c)

    Onset of motor block time (minute);

  4. (d)

    Duration of motor block (minute);

  5. (e)

    Time to first request of anesthesia (minute);

  6. (f)

    Duration of spinal anesthesia (minute).

General and baseline features of the studies and participants respectively

The general features of the selected studies have been listed in Table 2. Most of the studies which were included were prospective randomized studies which enrolled patients during years 2010 – 2015. A total number of 895 participants were included in this analysis whereby 466 patients were assigned to intrathecal MgSO4 and 429 participants were assigned to a control group as shown in Table 2.

Table 2 General features of the studies
Full size table

The baseline features of the participants have been listed in Table 3. The mean age of the participants was 23.0 to 35.0 years. The body mass index of the participants varied from 24.0 to 29.7 Kg/m2 whereas the mean gestational age varied from 36.0 to 39.0 weeks as shown in Table 3.

Table 3 Baseline features of the participants
Full size table

Main results of this analysis

The main results of this analysis show that intrathecal MgSO4 as an adjuvant to bupivacaine in patients undergoing elective cesarean section was associated with a significantly lower risk of shivering (RR: 0.63, 95% CI: 0.48 – 0.83; p = 0.001) as shown in Fig. 3. In addition, the risks for hypotension (RR: 1.11, 95% CI: 0.86 – 1.44; p = 0.40), nausea and vomiting (RR: 1.08, 95% CI: 0.76 – 1.54; p = 0.65), pruritus (RR: 0.77, 95% CI: 0.51 – 1.17; p = 0.22), and bradycardia (RR: 4.45, 95% CI: 0.97 – 20.36; p = 0.05) were not significantly higher compared to the control group as shown in Fig. 3.

Fig. 3
figure 3

Adverse drug events observed with intrathecal magnesium sulfate as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section

Full size image

The efficacy outcomes were also reported. The sensory block duration as well as the motor block duration time were significantly in favor of intrathecal MgSO4 with (WMD: 23.15, 95% CI: 7.83 – 38.48; p = 0.003) and (WMD: 24.29, 95% CI: 16.36 – 32.23; p = 0.00001) as shown in Fig. 4. The duration of spinal anesthesia was also in favor of MgSO4 with (WMD: 29.24, 95% CI: 13.61 – 44.87; p = 0.0002). However, no significant difference was observed in sensory block onset (WMD: −0.54, 95% CI: −2.27 – 1.18; p = 0.54), motor block onset (WMD: 0.89, 95% CI: −0.50 – 2.27; p = 0.21) and time to first request of analgesia (WMD: 135.14, 95% CI: − 23.42 – 293.70; p = 0.09) as shown in Fig. 4.

Fig. 4
figure 4

Efficacy outcomes observed with intrathecal magnesium sulfate as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section

Full size image

Consistent results were obtained throughout during sensitivity analysis. Publication bias was visually observed through funnel plot which was generated by the RevMan software and based on this visual assessment, there was little evidence of publication bias across all the studies that were involved in assessing the adverse drug events. The funnel plot has been illustrated in Fig. 5.

Fig. 5
figure 5

Funnel plot showing publication bias

Full size image

The results have been tabulated (Table 4).

Table 4 Results of this analysis
Full size table

Discussion

In this analysis, we aimed to compare the adverse drug events observed with intrathecal MgSO4 as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section and our current results showed that intrathecal MgSO4 was associated with a significantly lower risk of shivering without causing any increase in other adverse drug events in patients undergoing elective CS. The risks of hypotension, bradycardia, pruritus, nausea and vomiting were not significantly increased with MgSO4. In addition, intrathecal MgSO4 was significantly effective when compared to a control group. It was associated with a significantly longer duration of sensory as well as motor blockade. The duration of spinal anesthesia was significantly longer with intrathecal MgSO4 when compared to the control group.

In another study, MgSO4 was added to ropivacaine in local infiltration for post-operative pain following cesarean section [23]. Results of the study showed the analgesic effects to have been prolonged without any increase in adverse effects. Similarly, in a retrospective analysis [24], whereby 32 patients received MgSO4 infusion after cesarean section, the authors demonstrated that MgSO4 decreased total analgesic requirements and pain during the first 24 hrs after surgery.

In our analysis, MgSO4 significantly reduced the risk of shivering. In another double-blind controlled study [13], the latter reported similar result as shown in this analysis by reducing the risk of shivering peri-operatively. Other studies have shown intravenous MgSO4 to be beneficial post-operatively following any surgery highlighting the potential of MgSO4 as a valuable adjunct for multimodal anesthesia and enhanced recovery [25]. The mechanism that causes shivering following administration of spinal anesthesia is related to the vasodilatation of vessels, which in turn, facilitates rapid heat loss therefore causing a redistribution of heat from the core to peripheral tissues, ending with shivering [26]. Other mechanisms could be related to reflexes of spinal cord, reduction of sympathetic stimulation, inhibition of the adrenal gland, pyrogenic production and post-surgical pain [27]. MgSO4 induces thermoregulation tolerance which could explain how it reduced shivering in patients post spinal anesthesia [28]. Prevention of shivering by magnesium could also be explained by its ability to modulate serotoninergic and noradrenergic neurons enhancing to the effect of N-methyl-D aspartate receptors in the dorsal raphe nucleus [29], and also decreases the gain of shivering by peripheral muscle relaxation via calcium antagonist [30]. The lowest recommended and effective dosage of intravenous MgSO4 is 50 mg/kg for the prevention and treatment of shivering without any significant adverse event [31].

The efficacy of MgSO4 as adjuvant to the anesthetic agent has been proven in several studies. When compared to a control group, intrathecal MgSO4 could prolong the duration of spinal anesthesia without causing any rise in adverse drug events thus favoring its use [20]. Another example showing better efficacy of intrathecal MgSO4 following cesarean section was the fact its use prolonged the duration of sensory and motor nerve blocks as well as the duration of spinal anesthesia without any significant adverse events [22].

However, other studies showed different results. For example, a randomized, prospective, double-blind, case-control clinical trial based on the addition of intrathecal MgSO4 to bupivacaine for spinal anesthesia in cesarean section did not show desirable outcomes due to the delayed onset of sensory blockade and the reduced effects of MgSO4 on post-operative pain [32]. In addition, there are other more potent drugs. Intrathecal dexmedetomidine showed superiority to intrathecal MgSO4 based on analgesia duration, severity of pain, onset duration, and duration of effects of the drug during cesarean section [33]. In a double-blind randomized clinical trial, where the effects of intrathecal dexmedetomidine versus MgSO4 were compared following cesarean delivery [34], the former showed to have a better effect on reducing shivering and its severity post-operatively demonstrating that dexmedetomidine might be a better option than MgSO4.

Limitations

One major limitation is the fact that the total number of participants was less compared to other studies. However, less research has been carried out based on this scope and since our task was to collect data on previously published studies, we could only extract whatever data are available. Publication bias which has been observed across the studies that were involved in carrying out this analysis could also be a limitation of this analysis. Another limitation could be the fact that several outcomes such as respiratory depression and dizziness were reported in only one study and therefore, the data for that specific outcome could not be used for comparison. In addition, a higher heterogeneity was observed during analysis of the efficacy outcomes and this could be another limitation. Moreover, even though registration of manuscript is not compulsory, this manuscript was not registered with PROSPERO during its protocol stage. This could also be a limitation of this study.

Conclusions

Intrathecal MgSO4 as an adjuvant to bupivacaine was associated with a significantly lower risk of shivering without causing any increase in other adverse drug events in patients undergoing elective cesarean section. Efficacy outcomes were also appreciated. Larger studies should be able to confirm this hypothesis.

Data availability

All data and materials used in this research are freely available in electronic databases (MEDLINE, EMBASE, http://www.ClinicalTrials.gov, Web of Science, Cochrane database, Google scholar). References have been provided.

Abbreviations

MgSO4:

Magnesium sulfate

SA:

Spinal anesthesia

CS:

Cesarean section

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Funding

There was no external source of funding for this research. This research was funded by the authors.

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Author notes

  1. Yuanhui Zhang and Yan Huang contributed equally to this work and they are the first co-authors of this study.

Authors and Affiliations

  1. Department of Anesthesia, The First People’s Hospital of Xianyang, Shaanxi, Xianyang, 712000, PR China

    Yuanhui Zhang

  2. Department of Anesthesiology, The First People’s Hospital of Jiangxia District, Wuhan, Hubei, 712000, PR China

    Yan Huang

  3. Department of Anesthesiology, Chongqing Jiangjin Central Hospital, Chongqing, 402260, PR China

    Jun Li

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Contributions

Dr Yuanhui Zhang, Dr Yan Huang, and Dr Jun Li were responsible for the conception and design, drafting the initial manuscript and revising it critically for important intellectual content. Dr Yuanhui Zhang and Dr Yan Huang wrote the final draft. All the authors approved the final manuscript as it has been written.

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Correspondence to Jun Li.

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Zhang, Y., Huang, Y. & Li, J. Adverse drug events observed with intrathecal magnesium sulfate as an adjuvant to bupivacaine for spinal anesthesia in patients undergoing elective cesarean section: a meta-analysis. BMC Pharmacol Toxicol 26, 96 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40360-025-00933-z

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BMC Pharmacology and Toxicology

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