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The Effect of Systemic Magnesium on Postsurgical Pain in Children Undergoing Tonsillectomies

A Double-Blinded, Randomized, Placebo-Controlled Trial

Benzon, Hubert A. MD, MPH*; Shah, Ravi D. MD*; Hansen, Jennifer MD*; Hajduk, John BS*; Billings, Kathleen R. MD*; De Oliveira, Gildasio S. Jr. MD, MSCI; Suresh, Santhanam MD*

doi: 10.1213/ANE.0000000000001028
Pain Medicine: Research Report
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BACKGROUND: Tonsillectomy is a frequently performed surgical procedure in children; however, few multimodal analgesic strategies have been shown to improve postsurgical pain in this patient population. Systemic magnesium infusions have been shown to reliably improve postoperative pain in adults, but their effects in pediatric surgical patients remain to be determined. In the current investigation, our main objective was to evaluate the use of systemic magnesium to improve postoperative pain in pediatric patients undergoing tonsillectomy. We hypothesized that children who received systemic magnesium infusions would have less post-tonsillectomy pain than the children who received saline infusions.

METHODS: The study was a prospective, randomized, double-blinded, clinical trial. Subjects were randomly assigned using a computer-generated table of random numbers to 1 of the 2 intervention groups: systemic magnesium infusion (initial loading dose 30 mg/kg given over 15 minutes followed by a continuous magnesium infusion 10 mg/kg/h) and the same volume of saline. The primary outcome was pain scores in the postanesthesia care unit (PACU) measured by FLACC (Face, Legs, Activity, Cry, Consolability) pain scores. Pain reduction was measured by the decrement in the area under the pain scale versus 90-minute postoperative time curve using the trapezoidal method. Secondary outcomes included opioid consumption in the PACU, emergence delirium scores (measured by the pediatric anesthesia emergence delirium scale), and parent satisfaction.

RESULTS: Sixty subjects were randomly assigned and 60 completed the study. The area under pain scores (up to 90 minutes) was not different between the study groups, median (interquartile range [IQR]) of 30 (0–120) score × min and 45 (0–135) score × min for the magnesium and control groups, respectively (P = 0.74). Similarly, there was no clinically significant difference in the morphine consumption in the PACU between the magnesium group, median (IQR) of 2.0 (0–4.44) mg IV morphine, compared with the control, median (IQR) of 2.5 (0–4.99) mg IV morphine (P = 0.25). The serum level of magnesium was significantly lower in the control group than in the treatment group at the end of the surgery (P < 0.001).

CONCLUSIONS: Despite a large number of studies demonstrating the efficacy of systemic magnesium for preventing postsurgical pain in adults, we could not find evidence for a significant clinical benefit of systemic magnesium infusion in children undergoing tonsillectomies. Our findings reiterate the importance of validating multimodal analgesic strategies in children that have been demonstrated to be effective in the adult population.

From the *Department of Anesthesiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, Illinois; and Department of Anesthesiology, Northwestern University, Chicago, Illinois.

Accepted for publication September 2, 2015.

Funding: Supported, in part, by 8UL1TR000150 from the National Center for Advancing Translational Sciences (NCATS) and National Institutes of Health.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Gildasio S. De Oliveira, Jr., MD, MSCI, Department of Anesthesiology, Northwestern University, 241 East Huron St., F5-704, Chicago, IL 60611. Address e-mail to g-jr@northwestern.edu.

Tonsillectomy is a frequently performed surgical procedure in children; however, achieving adequate postoperative pain control remains challenging.1 Being one of the most painful otorhinolaryngologic procedures, many patients have high postoperative analgesic requirements and poor postsurgical recovery, including functional limitations up to 1 week after surgery.2–4 Nonopioid analgesic strategies have been advocated as viable pathways to improve postsurgical pain and overall recovery in children undergoing tonsillectomies, but few interventions have been proven to be reliably useful.5–10 Despite having undesirable side effects (e.g., respiratory depression, nausea, and vomiting), opioid analgesics remain the mainstay of perioperative pain control for patients undergoing this surgical procedure.11,12

Magnesium alters the perception and duration of pain by serving as an antagonist of N-methyl-D-aspartate glutamate receptors.13 Several randomized clinical trials have demonstrated the efficacy of systemic magnesium for reducing postsurgical pain in adult patients. In addition, 3 recent meta-analyses have concluded that magnesium infusions improve pain control by decreasing opioid consumption, and a recent editorial endorsed the use of magnesium as a multimodal analgesia strategy in adult patients.14–17 In contrast, no studies have examined the efficacy of magnesium infusions to ameliorate postsurgical pain in pediatric patients.

The main objective of the current investigation was to evaluate the use of systemic magnesium to improve postoperative pain in pediatric patients undergoing tonsillectomy. We hypothesized that children who received systemic magnesium infusions would have lower post-tonsillectomy pain than the children who received saline infusions.

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METHODS

The study was a prospective, randomized, double-blinded, clinical trial. Approval for the study was received by the IRB of the Ann and Robert H. Lurie Children’s Hospital of Chicago. The study was registered before patient enrollment at ClinicalTrials.gov, identifier: NCT02218424, Principal Investigator: Hubert Benzon, registration date: August 12, 2014. Written informed consent was obtained from parents or legal guardians of all participating subjects. Eligible subjects were children aged 4 to 10 years, with ASA physical status I to III, who were undergoing tonsillectomy by a single surgeon at our institution. Exclusion criteria included any patient with physical or developmental delay, psychiatric illness, current use of sedative or anticonvulsant medication, preexisting renal or cardiovascular disease, or regular use of analgesic medication.

Subjects were randomly assigned using a computer-generated table of random numbers to 1 of the 2 intervention groups: systemic magnesium infusion (initial loading dose of 30 mg/kg given over 15 minutes followed by a continuous magnesium infusion of 10 mg/kg/h) and the same volume of saline. The magnesium dose is consistent with previous clinical studies that examined the analgesic effects of the drug in adult patients.14–16 The study drug was prepared by the research pharmacy at the Ann & Robert H. Lurie Children’s Hospital of Chicago and was identical for both groups. A research associate and a research nurse from the clinical research unit blinded to group allocation were responsible for all data collection.

All children enrolled in the study received a standardized anesthetic regimen. Children were given oral midazolam as premedication, or a parent was present for induction if deemed clinically necessary. All patients were induced via inhaled induction with nitrous oxide mixed with oxygen and sevoflurane. Peripheral IV access was obtained, and patients were started on the study drug. Fentanyl 2 μg/kg, dexamethasone 0.1 mg/kg, and ondansetron 0.1 mg/kg were given IV before the start of surgery. Patients were tracheally intubated under a deep plane of anesthesia without muscle relaxant. Maintenance of anesthesia included nitrous oxide mixed with oxygen at a 1:1 ratio with sevoflurane. The same senior otolaryngology surgeon performed the surgery for all cases using the coblation device with standard settings. After completion of the surgery, a plasma magnesium level was obtained from each patient from an extremity different from the one with the IV in situ. The study drug infusion was stopped, and all patients were tracheally extubated “deep” while spontaneously ventilating.

Upon arrival at the recovery room, a research nurse from the clinical research unit at the Ann & Robert H. Lurie Children’s Hospital of Chicago was present, as well as a research associate, to collect postoperative pain scores and direct the administration of postoperative pain medication. FLACC behavioral pain assessment (Face, Legs, Activity, Cry, Consolability) scores were taken every 5 minutes for the first 30 minutes in recovery, then every 15 minutes until 1.5 hours after surgery. When a pain score of 4 or higher was determined, the patient was treated with a standardized dose of morphine 0.1 mg/kg. The pediatric anesthesia emergence delirium (PAED) scale was also measured every 5 minutes for the first 30 minutes, then every 15 minutes until 1.5 hours after surgery.18 All patients were monitored for at least 4 hours before discharge. A dosing regimen of ibuprofen 10 mg/kg/dose alternating with hydrocodone with acetaminophen 0.15 mg/kg/dose every 3 hours was recommended to all patients at discharge, and when the patient was feeling better, hydrocodone was switched to acetaminophen 10 mg/kg/dose.

Postoperative phone calls were conducted after 24 hours, and families were asked, by phone interview using the parents postoperative pain measure scale, a validated 15-question tool, about satisfaction with overall anesthetic care (scale 0–10, where 0 means very unsatisfied and 10 means very satisfied), and also about the frequency of the use of oral pain medication at home.19

The primary outcome was pain scores in the postanesthesia care unit (PACU) measured by FLACC pain scores. Pain reduction was measured by the decrement in the area under the pain scale versus 90-minute postoperative time curve using the trapezoidal method (GraphPad Prism version 5.03; GraphPad Software, Inc., La Jolla, CA).20 Secondary outcomes included opioid consumption in the PACU, emergence delirium scores (measured by the PAED scale),18 and parent satisfaction.

Group sample sizes of 28 and 28 achieve 81% power to show a difference in means when there is a difference of 1.0 between the null hypothesis mean difference of 0.0 and the actual mean difference of −1.0 at the 0.050 significance level (α) using a 2-sided Mann-Whitney-Wilcoxon test and a 1.3 SD. SD was obtained from a previous study evaluating postoperative pain in children undergoing tonsillectomies.21 These results are based on 2000 Monte Carlo samples from the null distributions.

The Shapiro-Wilk and Anderson-Darling tests were used to test the assumption of normal distribution (P > 0.1). Normally distributed interval data are reported as mean (SD) and were analyzed using the independent Student t test. Non-normally distributed interval and ordinal data are reported as median (range or interquartile range [IQR]) and were analyzed using the Mann-Whitney U test. The Wilcoxon-Mann-Whitney odds and 95% confidence interval (CI) for a random pair for pain score (area under the curve) and morphine consumption values from the magnesium and the saline group were determined from the area under the receiver operator characteristic curve from the binary logistic model.22,23 Categorical data are presented as counts (n) and were analyzed using the Fisher exact test. Data were analyzed using STATA version 12 (College Station, TX).

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RESULTS

Sixty children undergoing tonsillectomy with or without adenoidectomy surgery were recruited to the study between October 1, 2014, and April 30, 2015. The details of the conduct of the study are presented in Figure 1. There were no differences in baseline characteristics between the study groups (Table 1).

Table 1

Table 1

Figure 1

Figure 1

Table 2

Table 2

Figure 2

Figure 2

The serum level of magnesium was significantly different between the study groups at the end of the surgery (P < 0.001; Fig. 2). The area under pain scores (up to 90 minutes) was not different between the study groups, median (IQR) of 30 (0–120) score × min and 45 (0–135) score × min for the magnesium and control groups, respectively (P = 0.74). The Wilcoxon-Mann-Whitney odds for a random pair of pain score (area under the curve) values from a magnesium subject compared with a nonmagnesium subject was 0.89 (95% CI, 0.47–1.63; P = 0.71). Similarly, there was no clinically significant difference in morphine consumption in the PACU between the magnesium group, median (IQR) of 2.0 (0–4.44) mg IV morphine, compared with the control, median (IQR) of 2.5 (0–4.99) mg IV morphine (P = 0.25). The Wilcoxon-Mann-Whitney odds for a random pair of morphine consumption values from a magnesium subject compared with a nonmagnesium subject was 0.69 (95% CI, 0.37–1.43; P = 0.28). Other secondary outcomes also did not differ between the study groups (Table 2). No adverse events were observed in any of the study subjects.

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DISCUSSION

The most important finding of the current study was that a continuous intraoperative infusion of IV magnesium did not cause a clinically important decrease in postoperative pain scores or opioid consumption in children undergoing tonsillectomies. There was no clinically significant difference in postoperative pain scores during the first 90 minutes in the recovery room and no difference in total morphine consumption in the recovery room. Furthermore, no difference was noted in ibuprofen or hydrocodone with acetaminophen administration for the first 24 hours after surgery. Taken together, our results suggest that systemic magnesium infusion is not an effective strategy to reduce postsurgical pain in children undergoing tonsillectomies.

Our results are clinically important because magnesium infusions have been demonstrated to be an effective strategy to minimize postsurgical pain across multiple studies in adults.14–16 The difficulties in conducting randomized clinical trials in children often predispose pediatric practitioners to use multimodal analgesic strategies validated in adults but that lack confirmatory studies in children. The use of ineffective multimodal strategies in children undergoing tonsillectomies may lead to an increased use of opioids analgesics and the development of undesirable opioid-related side effects such as respiratory depression and vomiting.

Another interesting finding of our current investigation was the lack of a beneficial effect of systemic magnesium on the development of postoperative emergence delirium in children. There was no clinically significant difference in PAED scores between those treated with IV magnesium versus those treated with placebo at wake up, 5 minutes after wake up, and 30 minutes after wake up. These findings are very different than the ones presented by previous investigators. Abdulatif et al.,24 using a similar dosing regimen of magnesium (30 mg/kg bolus followed by a continuous infusion of 10 mg/kg/h), found a reduced incidence and severity of emergence agitation in pediatric patients undergoing tonsillectomies.

O’Flaherty and Lin25 evaluated the postoperative opioid use of IV ketamine, magnesium sulfate, or both, compared with placebo. Ketamine, magnesium, or ketamine plus magnesium did not provide any improvement in patients’ postoperative pain scores or analgesic consumption. Our study differed from the study by O’Flaherty and Lin because we included both an initial loading dose followed by an IV infusion of magnesium, whereas the study by O’Flaherty and Lin examined only a small dose of IV magnesium after induction and before surgical incision. This difference is important because the use of a single magnesium bolus has not been demonstrated to be effective for reducing postoperative pain in adults.26 To the best of our knowledge, our study is the first to examine the effect of a systemic infusion of magnesium on postoperative pain outcomes in children.

It is important to develop effective multimodal analgesic strategies to improve pain control in pediatric patients undergoing surgical procedures. We continue to use opioids as the mainstay treatment, particularly in patients undergoing tonsillectomy, because few other modalities have been proven to be effective. Specifically for pediatric patients undergoing tonsillectomies, the use of postoperative opioids may predispose patients with obstructive sleep apnea to death or severe neurologic impairment.27

Our study should only be interpreted within the context of its limitations. We have only examined patients undergoing a single surgical procedure; therefore, we cannot generalize our findings for children undergoing different surgical procedures. Studies that evaluate the analgesic benefit of magnesium in surgical procedures where the drug has been shown to be effective in adults are needed. Another limitation was that the magnesium infusion was only administered intraoperatively. It is possible that an infusion during the postoperative period may increase the analgesic effects of systemic magnesium. Nonetheless, the vast majority of studies that demonstrated the analgesic efficacy of systemic magnesium in adults used only an intraoperative infusion.14–16

It is possible that a higher dose of a magnesium infusion could have improved pain scores. Because we only tested the analgesic efficacy of a single infusion dose, we could not examine a potential dose-response effect of systemic magnesium on analgesic outcomes in children. The infusion rate of 10 mg/kg/h was extrapolated from the adult literature; however, to our knowledge, there is no literature evaluating the pharmacodynamic profile of systemic magnesium and pain control, so optimal dosing is still unclear at this time.

In summary, despite a large number of studies demonstrating the efficacy of systemic magnesium in preventing postsurgical pain in adults, we could not find evidence for a significant clinical benefit of a systemic magnesium infusion in children undergoing tonsillectomies. Our findings reiterate the importance of validating in children multimodal analgesic strategies that have been demonstrated to be effective in the adult population. Future studies to confirm or refute our current findings in different surgical procedures in children are warranted.

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DISCLOSURES

Name: Hubert A. Benzon, MD, MPH.

Contribution: This author contributed to study design, conduct of the study, and manuscript preparation.

Attestation: Hubert A. Benzon approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.

Name: Ravi D. Shah, MD.

Contribution: This author contributed to study design, conduct of the study, and manuscript preparation.

Attestation: Ravi D. Shah approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Jennifer Hansen, MD.

Contribution: This author contributed to conduct of the study and manuscript preparation.

Attestation: Jennifer Hansen approved the final manuscript.

Name: John Hajduk, BS.

Contribution: This author contributed to conduct of the study and manuscript preparation.

Attestation: John Hajduk approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Kathleen R. Billings, MD.

Contribution: This author contributed to conduct of the study and manuscript preparation.

Attestation: Kathleen R. Billings approved the final manuscript.

Name: Gildasio S. De Oliveira, Jr., MD, MSCI.

Contribution: This author contributed to study design, statistical analysis, and manuscript preparation.

Attestation: Gildasio S. De Oliveira Jr. approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Santhanam Suresh, MD.

Contribution: This author contributed to study design, conduct of the study, and manuscript preparation.

Attestation: Santhanam Suresh approved the final manuscript.

This manuscript was handled by: Spencer S. Liu, MD.

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