Strategy for Calculating Magnesium Sulfate Dose in Obese Patients: A Randomized Blinded Trial

Background Magnesium sulfate has analgesic properties during the postoperative period. However, there is a knowledge gap in pharmacology related to the use of the real, ideal, or corrected ideal body weight to calculate its dose in obese patients. This trial compared postoperative analgesia using actual and corrected ideal body weight. Methods Seventy-five obese patients scheduled to undergo laparoscopic gastroplasty or cholecystectomy under general anesthesia were randomly assigned to three groups. The patients in the control group did not receive magnesium sulfate; the other two groups received magnesium sulfate at 40 mg·kg−1 of actual body weight or corrected ideal body weight. Results In patients with body mass index >30 mg·kg−2 (mean body mass index ranging from 32.964 kg·m−2 to 33.985 kg·m−2, according to the groups) scheduled for video laparoscopic cholecystectomy, there were no differences in the blood magnesium concentrations in the groups receiving magnesium sulfate throughout the study, regardless of whether the strategy to calculate its dose was based on total or corrected ideal body weight. Patients in the groups receiving magnesium sulfate showed a significant reduction in morphine consumption (p ≤ 0.001) and pain scores (p=0.006) in the postoperative period compared to those in the control group. There were no significant differences in morphine consumption (p=0.323) or pain scores (p=0.082) between the two groups receiving magnesium sulfate. There were no differences in the total duration of neuromuscular block induced by cisatracurium among the three groups (p=0.181). Conclusions Magnesium sulfate decreased postoperative pain and morphine consumption without affecting the recovery time of cisatracurium in obese patients undergoing laparoscopic cholecystectomy. Strategies to calculate the dose based on the actual or corrected ideal body weight had similar outcomes related to analgesia and the resulting blood magnesium concentration. However, as the sample in this trial presented body mass indices ranging from 30.11 kg·m−2 to 47.11 kg/m−2, further studies are needed to confirm these findings in more obese patients, easily found in centers specialized.

Worldwide, the increase in obesity prevalence [14] is associated with an increase in the frequency of obese patients in surgery rooms. Obese patients also receive MS in many situations [15]. It is necessary to adjust the dosage of some drugs in obese individuals because of pharmacokinetic changes caused by increased fat tissue [16,17]. However, to our knowledge, no study has analyzed the best way to calculate the MS dose in obese patients using actual, ideal, or corrected ideal body weight.
Tis trial compared the analgesic efects of MS in obese patients using two strategies to calculate the dose (real body weight and corrected ideal body weight). Te primary objective was to compare the blood magnesium concentrations in both groups. Te secondary objectives were to compare analgesia and the time frame to the recovery of 90% of the train of four (TOF) after cisatracurium administration. We recorded the blood magnesium concentration at planned moments, morphine consumption, pain scores during the postoperative period of 24 h, and total duration of onset and total neuromuscular blockade [18].

Materials and Methods
Tis is a randomized controlled trial with blinding of patients and clinical staf, carried out at the hospital of the Sociedade de Benefcência Portuguesa de Santos, SP. Data were collected from August 26, 2019, to November 12, 2020. Tis manuscript adheres to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Tis study was approved by the Institutional Review Board (IRB) of the Universidade de Taubaté, SP, Brazil (IRB number 09006119.2.0000.5501). Written informed consent was obtained from all participants prior to their participation in the study. Te trial was registered at clinicaltrials.gov (NCT04003688; principal investigator: Sebastião Ernesto da Silva Filho; registration date: June 24, 2019) before patient enrollment.

Study Population.
Te inclusion criteria were as follows: patients aged 18-60 years, with American Society of Anesthesiologists physical status II and body mass index (BMI) >30 kg·m −2 , scheduled for video laparoscopic cholecystectomy. Te exclusion criteria were as follows: history of allergy to any component of the study protocol, refusal to participate or sign the informed consent form, neuromuscular disorders, cardiac conduction block other than frstdegree atrioventricular block, illicit drug use, psychiatric disorders that compromise the assessment of symptoms, use of calcium channel blockers, and renal failure.
Te sample was based on a trial by Kizilcik and Koner [15]; they administered MS 30 mg·kg −1 in obese patients with less pain than the control group (9.50 ± 2.98 vs. 12.65 ± 2.34) 60 min postoperatively. Te mean diference between the actual and corrected ideal body weights of the obese population in our hospital over the last 3 months was approximately 20%. To our knowledge, no study has compared the actual and corrected ideal body weights to calculate the MS dose in obese patients. Terefore, we used this 20% diference as a surrogate for the diference between the means and estimated; for a confdence level of 95% and a power of 80%, a sample of 19.43 participants [19] per group was needed. We increased the number to 25 to compensate for possible losses.
Among the patients who agreed to participate in the study, 75 individuals were selected and divided electronically into three groups using https://www.random.org/, which provides truly random numbers originating from atmospheric noise. In the control group (CG), 25 patients received general anesthesia (GA) only. In the real body weight group (RWG), the patients received GA and MS at a dose of 40 mg·kg −1 of their real body weight. In the corrected ideal body weight group (CWG), the patients received GA and MS at a dose of 40 mg·kg −1 of their corrected ideal body weight, Te electronic drawing allowed 75 envelopes with information about the related groups and procedures performed by a professional blinded to the study protocol. Another team member, not involved in any other task of this trial, prepared the concealed solutions.

Anesthetic Technique.
Te participants were monitored with continuous electrocardiography, pulse oximetry, noninvasive blood pressure on a multiparameter monitor (Mindray, model IPM-9800, China), and hypnosis level (patient state index, SedLine ® Sedation Monitor, USA) before receiving any medication. Te patients were also connected to a neuromuscular function (NMF) monitor (TOF-Watch SX; Ireland).
Te study included a group of 10 patients with a BMI of 20-30 kg·m 2 who received 40 mg·kg −1 MS and underwent the same protocol as participants in the RWG. Tis group, called the nonobese group (NOG), provided the standard magnesium concentration generated after MS administration in nonobese patients, and we could see how diferent the outcomes would be in each group of obese participants. Te participants in this group followed the same inclusion and exclusion criteria as the obese patients in the study, except for their weight.
To prevent nausea and vomiting and reduce postoperative pain, patients were also administered dipyrone 15 mg·kg −1 , clonidine 2 μg·kg −1 , dexamethasone 4 mg, ketoprofen 100 mg, ondansetron 4 mg, and lidocaine 1.5 mg·kg −1 just before anesthetic induction. Simultaneously, the patients received the concealed solution, followed by preoxygenation with a fraction of inspired oxygen � 1 for 3 min, and propofol in target-controlled infusion (TCI) to reach a concentration of 4 μg·mL −1 , guided by a hypnosis monitor. After appropriate hypnosis (Patient State Index (PSI) < 50), calibration of the neuromuscular function monitor was performed using TOF monitoring, followed by 0.15 mg·kg −1 cisatracurium intravenously and remifentanil infusion through TCI until 5 ng·mL −1 efect target concentration was reached. Anesthesia was maintained with propofol in TCI to maintain a PSI of 25-50, remifentanil in TCI (target of 3 to 5 ng·mL −1 , according to cardiac rate and blood pressure), and cisatracurium 0.03 mg·kg −1 if TOF > 2 count. Administration of cisatracurium was avoided during the last 20 min of surgery. At the end of the surgery, patients with TOF > 2 were administered 20 μg·kg −1 atropine and 40 μg·kg −1 neostigmine.
Before extubation, all patients were administered morphine (0.05 mg·kg −1 ) and dipyrone (15 mg·kg −1 ). Five min after anesthetic recovery and every 30 min thereafter, patients received another dose of morphine if the pain score was greater than 3 points on the verbal numeric scale (VNS: 0 (no pain) to 10 (the highest possible pain) points). In the ward, they received 1 g of dipyrone intravenously (every 6 h), 0.05 mg·kg −1 of morphine if their pain score was greater than 3 points in the VNS. All patients were discharged from the hospital the morning after the surgery.

Outcomes Measured.
Immediately after venipuncture, the frst blood sample (2 mL) was collected to measure blood magnesium concentration. Te concealed solution was then infused for 10 min. Te concealed solution consisted of 100 mL of saline solution or saline solution with MS, for a total of 100 mL, depending on the group.
Blood samples were collected to measure the blood magnesium concentration in the arm contralateral to the arm receiving the medication while maintaining an indwelling catheter. Te collection times were as follows: venipuncture (before any medication) and 15, 30, 60, 120, and 240 min. Magnesium concentrations were measured in the hospital laboratory using mg·dL −1 as the unit of measurement. Patients and everyone involved in the research were blinded to Mg levels.
Te analgesic efect of diferent doses of MS was assessed using the following outcomes: VNS at 5 min after extubation; at 30, 60, 120, and 240 min; the highest pain score in the perioperative period during hospital stay (VNS); and morphine consumption during the hospital stay. Morphine was administered on demand or when the pain score was greater than 3 points (VNS).
Te efects of MS on cisatracurium pharmacology were evaluated using the onset time (TOF � 0) and total duration (time to TOF T4/T1 � 90%). Diferences in blood magnesium concentrations between groups were compared using the concentrations verifed at the collection times defned in the study protocol. Te NOG (BMI of 20-30 kg·m 2 ) was used as a reference to show how close or far the average magnesium concentration in obese patients receiving diferent doses of MS was from the average concentration in nonobese patients at those times.

Statistical Analysis.
Te hypotheses of interest were tested using parametric analysis of variance (ANOVA) or repeated-measures ANOVA when observations were taken over time. Normality was verifed using the Shapiro-Wilk test, and samples without a normal distribution were compared using the Kruskal-Wallis test. Results with a descriptive level of less than 5% (p < 0.05) were considered signifcant. When comparisons between groups showed a diference, we applied the Bonferroni post hoc test.
Blood magnesium concentrations during the perioperative period were tested using two-way ANOVA for repeated measurements. Violation of sphericity was demonstrated using Mauchly's test. Te Greenhouse-Geisser method was used to correct this bias.

Results
One patient was excluded from the study (CONSORT fowchart; Figure 1). Table 1 shows similar durations of anesthesia, weight, height, and BMI.
As expected, the analysis showed similar blood magnesium concentrations in all measurements performed in the CG (Figure 2). RWG and CWG showed concentrations similar to those of CG at time zero. However, they showed an increase in the Mg concentration at 15 min, with a progressive decay in the subsequent moments. Tere were no signifcant diferences in the blood magnesium concentrations between the RWG and CWG at the collection times provided by the study protocol. Te blood magnesium concentration in the MS-treated obese group was similar to that in the NOG (Table 2 and Figure 2).
In the CWG, the participants' average real body weight (92.54 kg) was compared to their average corrected ideal body weight (73.54 kg), with a mean diference of 18.72 kg. Terefore, these participants received a 21.6% lower MS dose than they would have received if the dose had been calculated based on their actual weight.
None of the patients reported any pain upon awakening. Data on the highest postoperative pain scores and morphine consumption during their hospital stay were not normally distributed (Shapiro-Wilk test). Te pain scores at 30, 60, 120, and 240 min were normally distributed.
Regarding the highest postoperative pain scores during their hospital stay, the comparison between the groups showed a signifcant diference (p � 0.006, Kruskal-Wallis test). Te post hoc test for multiple comparisons showed a statistical diference between the RWG and CG (p � 0.005, Bonferroni) and between the CWG and CG (p � 0.016, Bonferroni), but there were no statistical diferences between the RWG and CWG (p � 0.082, Bonferroni; Table 3).
Participants in the CWG had lower pain scores than those in the CG (p < 0.05) at 30 min (one-way ANOVA; Bonferroni). Participants in the RWG showed lower pain scores than those in the CG (p < 0.05) at 30 and 60 min (one-way ANOVA; Bonferroni correction). Tere were no statistical diferences between the groups at any other time point (Table 4).
Tere were diferences in morphine consumption during the hospital stay between the groups (p ≤ 0.001, Kruskal-Wallis test). Multiple post hoc comparisons adjusted by Bonferroni correction showed a similarity in morphine consumption between the RWG and CWG (p � 0.108; corrected p � 0.323). Te RWG (p ≤ 0.001; corrected p ≤ 0.001) and CWG (p � 0.013; corrected p � 0.040) had signifcantly lower morphine consumption than CG (Table 3).
Te latency (p � 0.651) and total duration of action (p � 0.181) of cisatracurium were independently analyzed using a one-way ANOVA (Welch's correction due to unequal variance). No statistical diferences existed between the groups in either of the two variables studied (Table 5).

Discussion
In this randomized trial, administering a bolus dose of MS increased serum magnesium levels and improved postoperative analgesia in obese patients with an average BMI of 33 kg·m  administration were similar in this population and compared to 10 controls with normal body mass index regardless of whether the dose was calculated using actual or corrected ideal body weight. An increase in adipose tissue and muscle mass modifes the pharmacokinetics of many drugs [16,17,21,22]. Furthermore, obesity-associated diseases reduce the physiological reserves in this population [23].
Despite the benefts of MS in various areas of medicine [1][2][3][4][5][6][7][8], it has side efects, such as the delayed recovery of neuromuscular function and orotracheal extubation [24]. For this reason, establishing the ideal dosing paradigm for MS in obese patients to maximize analgesia without resulting in unsafe serum levels or undesirable prolongation of neuromuscular blockade is important.
In this trial, there was a 22% diference between the actual body weight and the corrected ideal body weight in the CWG. However, investigators were surprised to note that the 22% diference in MS dosing did not result in diferences in the Mg concentration between the CWG and RWG groups, as shown in Table 2 and Figure 2. Even after receiving MS doses with a 21.6% diference, the MS groups had similar blood magnesium concentrations (Table 2 and Figure 2). Tese concentrations were similar to the blood magnesium concentrations in the NOG (10 patients). Tese concentrations were always within the safe values for study patients [25], as reported by Taheri et al. [10]. Although they did not analyze the analgesic properties, Brookfeld et al. [26] found that obese pregnant women needed a longer time to reach a therapeutic concentration of magnesium in the blood for seizure prophylaxis in preeclampsia, which was higher than the average concentration in the present trial and may be higher than the level needed to achieve postsurgical analgesia, which was higher than the average concentration in the present trial.
One gram of MS contains 98.6 mg of magnesium (Fresenius Kabi Canada, Toronto, ON). According to the mean actual body weight in the RWG (94.32 kg) and corrected ideal body weight in the CWG (73.54 kg), the participants received 3,772.8 and 2,941.6 mg of magnesium, respectively. Based on the calculated total blood volume of 70 mL·kg −1 of ideal body weight [27][28][29], we estimated an average plasma volume of 2700 mL in both groups. Terefore, participants in the CWG and RWG received 290 and 372 mg of Mg, respectively. Subsequently, ignoring the tissue distribution volume, there was an increase in blood magnesium concentration of 1.07 and 1.38 mg·mL −1 , respectively. Similar concentrations were reached 30 min after administration, and the highest peak was reached in the frst 15 min.
Te average body content of magnesium is 24 g in individuals weighing 70 kg [30,31]. Only approximately 0.3% of this content is distributed in the plasma [30,31]. Tis is a possible cause of the rapid balance in concentration and similar analgesia between the groups that received MS. Te     T0, T15, T30, T60, T120, and T240: baseline and 15,  30, 60, 120, and 240 min after magnesium sulfate administration. Two-wayrepeated-measures analysis of variance. Te control group was not represented here because there were no changes in this group over time. patients had an average increase in body Mg of 1.2% in the CWG and 1.55% in the RWG. Pascoal et al. [32] compared two groups of 31 patients who underwent MS treatment to prevent preeclampsia. After an initial MS dose of 6 g, patients received a continuous infusion of 1 or 2 g·h −1 . Te initial concentration was statistically equal between the groups (3.7 mEq·L −1 ; p � 0.96). Subsequently, the concentrations increased in the group that received an infusion of 2 g·h −1 and were relatively static in the group that received 1 g·h −1 . Te authors concluded that an infusion of 1 g·h −1 could be as efective as an infusion of 2 g·h −1 , with a small reduction in side efects. Tis knowledge may be applied to the use of MS for analgesic purposes. In this trial, patients who received MS had lower mean postoperative pain scores and lower morphine consumption. Tese results, which have been reported in other studies [9][10][11][12][13], are attributed to the action of magnesium on calcium channels and NMDA receptors [4,5]. We compared pain at planned moments (30, 60, 120, and 240 min; Table 4) when patients were asked about pain. At 30 min, both groups that received MS experienced less pain than the CG. At 60 min, the RWG experienced less pain. After 30 min, there were no diferences in the pain scores among the three groups. When asked about the highest pain during hospitalization, participants in the RWG and CWG were similar, although the CWG received 21.6% less MS, and both groups showed similar morphine consumption rates. However, both patients experienced less pain and morphine consumption than patients in the CG. Maintaining an infusion of MS can produce prolonged analgesia.
MS did not alter the onset or duration of neuromuscular blockade induced by cisatracurium. Germano et al. [33] did not fnd any diference in the latency of rocuronium 0.6 mg·kg −1 after MS. Czarnetzki et al. [34] found a signifcant reduction in latency (average of 77 vs. 120 s) of rocuronium 0.6 mg·kg −1 after MS at higher doses than in the study by Germano et al. (60 mg·kg −1 ). Te diference in the time gap between the administration of MS and rocuronium might have interfered with these results. Czarnetzki [35] found a longer mean total recovery time after MS 60 mg·kg −1 (73.2 (SD � 22) vs. 57.8 (SD � 14.2) min in the CG). Te absolute onset times in the present study cannot be compared to those reported by Germano et al. [33] and Czarnetzki et al. [34] because they used diferent neuromuscular blockers. Czarnetzki et al. [35] used higher MS doses, excluding the comparison with the present trial.
Sugimoro et al. [36] reported a reduction in the production of infammatory cytokines (tumor necrosis factor and interleukin 6) in pregnant women who received MS. Tis mechanism should be investigated in the context of substance use for analgesic purposes.
Te strengths of this study include methodological caution and the fear of administering MS to an underexplored population regarding the analgesic and unwanted efects of this drug. Tus, it is safe to calculate the MS dose using total body weight, although this is not always necessary.
Te limitations of this study include the relatively low BMI range of participants. Te average BMI was 35 kg·m −2 (32.964 kg·m −2 to 36.478 kg·m −2 ). Tis is less than what is seen in several specialized centers that easily treat patients weighing >40−50 kg·m −2 . Although we observed a safe use of MS based on actual body weight, which increased the magnesium blood concentration in proportion to the increasing dose, more research is necessary for patients with a higher BMI. In addition, a larger sample size may bring in more normalized variables and give the test more power.
In patients with higher body mass indexes, dosing based on total body weight could result in toxic magnesium levels and should not be performed outside the protection of close monitoring and rigorous research protocol.

Conclusion
Magnesium sulfate decreased postoperative pain and morphine consumption without afecting the recovery time of cisatracurium in obese patients undergoing laparoscopic cholecystectomy. Strategies to calculate the dose based on the actual or corrected ideal body weight had similar outcomes related to analgesia and the resulting blood magnesium concentration. However, as the sample in this trial presented body mass indices ranging from 30.11 kg.m-2 to 47.11 kg/m-2, further studies are needed to confrm these Means and confdence intervals of pain scores (0, no pain; 10, worst imaginable pain) were recorded at four postoperative time points (in min). CG, control group; CWG, corrected ideal weight group; RWG, real weight group; Inf, lower limit; Sup, upper limit. One-way ANOVA. * p < 0.05 (Bonferroni comparisons): CWG < CG. * * p < 0.05 (Bonferroni comparisons)-RWG < CG.