Effect of Intravenous Magnesium Sulfate on the Minimum Alveolar Concentrations of Desflurane Using Bispectral Index Monitoring: A Prospective Randomized Double-blind Controlled Study.

BACKGROUND: Magnesium sulfate has been implicated to influence the minimum alveolar concentration (MAC) of various volatile anesthetics, but its effect on desflurane remains unanswered so far. AIM: To study the effect of perioperative intravenous magnesium sulfate on MAC of desflurane using bispectral index (BIS) monitoring. SETTINGS: Operating room of a tertiary care hospital.
DESIGN: A prospective, randomized, controlled, double-blind clinical trial.
METHODS: Sixty American Society of Anesthesiologists Physical Status I/II patients aged 18-65 years and scheduled for breast conservative surgeries were randomized into three groups of 20 each. Control group (Group 1) was administered 100 ml normal saline (NS) as bolus followed by NS infusion. Magnesium (Mg) was administered as bolus of 40 mg/kg in 100 ml NS followed by NS infusion in Group 2 and as bolus of 40 mg/kg followed by infusion of 10 mg/kg/h of Mg in NS in Group 3. Anesthesia was induced with propofol, fentanyl, and atracurium. Dial setting of desflurane was adjusted to target a BIS of 45-55. Time from cessation of desflurane to beginning of spontaneous movement, time taken to respond to verbal commands, time of extubation, and time taken to reach BIS value of 70 were recorded. STATISTICAL ANALYSIS: Statistics was done using SPSS program using ANOVA and the Chi-square test for variables and a P < 0.05 was taken to indicate a significant difference.
RESULTS: No significant difference was present in MAC, end-tidal desflurane, and cumulative consumption of morphine. Recovery was similar in Group 2 and Group 3, but time to eye opening (P = 0.011), time to respond to verbal commands (P < 0.001), and time to extubate (P < 0.001) were significantly delayed when compared with patients in Group 1. Hemodynamic changes were comparable among three groups.
CONCLUSIONS: From this study, we conclude that MACs of desflurane using BIS as a guide remains unaffected by perioperative infusion of magnesium sulfate.

INTRODUCTION

Magnesium sulfate has the potential to treat and prevent pain by acting as an antagonist on N-methyl-D-aspartate receptors.[1] It has been reported to supplement the analgesic potential of opioids and decrease cumulative morphine consumption by 30% in the postoperative period.[23] It attenuates presser response to endotracheal intubation by inhibiting release of catecholamines[4] and also reduces intraoperative requirements of propofol.[5] Administration of magnesium sulfate before induction of anesthesia has been reported to increase minimum alveolar concentration (MAC) of sevoflurane.[6] However, effect on MAC of desflurane has not been studied till date.

Bispectral analysis of the electroencephalogram (EEG)[78] is a signal processing technique that has been proposed as a pharmacodynamic measure of anesthetic effects on the central nervous system (CNS). The bispectral analysis decomposes the EEG signal into its component sine waves using a Fourier transformation. A set of bispectral features is calculated by analyzing the phase relations between the component waves. These bispectral features are combined with other EEG features into a single measurement, the bispectral index (BIS), which is a numeric index ranging from 0 to 100.[9] The BIS correlates well with sedation and is a good indicator of a patient's response to stimulus.[91011] The BIS has also been validated as a measure of anesthetic effect for a number of anesthetic agents, including isoflurane, sevoflurane, and propofol.[912] Titration of volatile anesthetics including desflurane using BIS as a guide has been done previously by a number of studies.[1314]

We conducted a prospective, randomized, controlled, double-blind clinical trial to study the effect of perioperative intravenous magnesium sulfate on MAC of desflurane using BIS monitoring. Secondary objectives were to study the effect of magnesium sulfate on patient recovery, hemodynamic response to laryngoscopy and intubation, and postoperative analgesic requirement.

METHODS

After approval from the hospital ethics committee and informed consent, sixty American Society of Anesthesiologists Physical Status I/II patients aged 18–65 years and scheduled for breast conservative surgeries were randomized into three groups of 20 each.

Group 1: 100 ml normal saline (NS) as bolus followed by NS infusion

Group 2: 40 mg/kg magnesium sulfate in 100 ml NS bolus followed by NS infusion

Group 3: 40 mg/kg magnesium sulfate bolus in 100 ml NS followed by magnesium sulfate infusion at 10 mg/kg/h.

Bolus injection was given over 15 min after shifting the patient to the operation theater and attaching routine monitors such as noninvasive blood pressure, electrocardiograph, and pulse oximetry. Infusion was started after induction of anesthesia.

Patients with hepatic, renal, respiratory, or cardiac dysfunction, atrioventricular block, body mass index >30, age >65 years or <18 years, pregnancy, abnormal serum magnesium (Mg) levels, drug allergy, neuromuscular disease, treatment with calcium channel blockers or abnormal serum Mg levels were excluded.

Anesthesia was induced with propofol (2 mg/kg), fentanyl (2 μg/kg), atracurium (0.5 mg/kg); tracheal intubation was done at train-of-four (TOF) of 0. Lungs were ventilated using air/oxygen, and anesthesia was maintained with desflurane. Dial setting of desflurane was adjusted to target a BIS of 45–55; increased or decreased if BIS value fell out of range for >10 s. The fresh gas flow was set at 6 L for 5 min (or till end-tidal desflurane [EtDEs]/desflurane inspired fraction equalized to about 80%), and after equilibrium, flows were reduced to 600–800 ml/min. EtDES and MAC were monitored continuously and recorded every 5 min.

Fentanyl boluses of 0.5 mg/kg were given on hourly basis or on increase of heart rate (HR) or mean arterial pressure >20% of baseline. Atracurium boluses 0.15 mg/kg were given when more than two responses were detected on TOF stimulation. Desflurane was discontinued at skin closure, and muscle relaxant was antagonized using glycopyrrolate (0.01 mg/kg) and neostigmine (0.05 mg/kg).

Time from cessation of desflurane to beginning of spontaneous movement, time taken to respond to verbal commands, time of extubation, and time taken to reach BIS value of 70 were recorded. All infusions were discontinued after 2 h and patients were observed for 4 h after cessation of infusion for possible residual effects. Postoperative pain was assessed by visual analog score (VAS), and morphine bolus was used for pain management. Total morphine requirements were recorded during 1st, 2nd, and 4th h after surgery.

Statistical analysis was carried out using IBM SPSS Statistics for Windows, (Version 17.0. Armonk, NY: IBM Corp). Continuous variables are presented as mean ± standard deviation, and categorical variables are presented as absolute numbers and percentage. Data were checked for normality before statistical analysis using Shapiro–Wilk test. Normally distributed continuous variables were compared using ANOVA. If the F value was significant and variance was homogeneous, Tukey multiple comparison test was used to assess the differences between the individual groups; otherwise, Tamhane's T2 test was used. The Kruskal–Wallis test was used for those variables that were not normally distributed and further comparisons were done using Mann–Whitney U-test. Categorical variables were analyzed using the Chi-square test. For all statistical tests, a P < 0.05 was taken to indicate a significant difference.

RESULTS

The groups did not differ with respect to age and weight [Table 1]. Statistically, significant difference was reported in mean total atracurium consumption; it was maximum in Group 1 with the minimum mean time for first repeat dose. Highest requirement of fentanyl was also reported in Group 1; the difference was however not statistically significant. There was no significant difference in the cumulative consumption of morphine in the three groups.

Table 1

Demographic and anesthetic drug data

MAC values did not demonstrate significant differences between the groups [Figure 1]. The EtDES values were also comparable [Figure 2].

Figure 1

Comparison of minimum alveolar concentration of desflurane (calculated)

Figure 2

Comparison of end-tidal desflurane among three groups

Recovery profile is summarized in Table 2. Time to eye opening, time to respond to verbal commands, and time to extubate were significantly prolonged in patients administered Mg (Groups 1 vs. 2 and Groups 1 vs. 3). However, the difference between Group 2 and Group 3 was not statistically significant.

Table 2

Recovery profile

Presser response to intubation was not observed in any group. Intergroup comparisons of HR at 2 min reported significantly higher values for the control group. However, variations in HR at all time intervals were <20% of baseline [Figure 3]. Significant fall in systolic blood pressure from the baseline was noted 2 min after intubation in all the three groups (P < 0.001 in Group 1 and 2; P < 0.005 in Group 3). Systolic blood pressures were comparable in all the groups at all times except at 20 min (P = 0.01) [Figure 4]. Diastolic blood pressures were comparable at all time intervals [Figure 5]. None of the patients demonstrated hypoxia (<95%) or hypoventilation (respiratory rate <12/min) during the postoperative period.

Figure 3

Heart rate at various intervals

Figure 4

Systolic blood pressure at various intervals

Figure 5

Diastolic blood pressure at various intervals

Ramsay and VAS scores and episodes of nausea and vomiting did not differ between groups.

DISCUSSION

Numerous studies have tried to investigate the anesthetic properties of magnesium sulfate. Peck and Meltzer have reported its use as a “sole anesthetic” in humans in 1916.[15] Thompson et al.[16] reported a 60% reduction in MAC of halothane in Mg-treated rats. However, experimental animal studies cannot be extrapolated to humans. This is the first prospective, randomized, controlled, double-blind clinical trial to study the effect of perioperative intravenous magnesium sulfate on the MACs of desflurane using BIS monitoring.

We did not observe any significant difference in the requirement of desflurane in the three groups. Results of our study are in contrast to the study by Durmus et al.,[6] who demonstrated an increase in MAC for endotracheal intubation and surgical incision (MAC) of sevoflurane with the administration of magnesium sulfate. The increase was 10% and 15%, respectively, at dose of 50 mg/kg followed by infusion of 10 mg/kg of magnesium sulfate. Incidence of side effects was 50%, and this has been postulated to be responsible for the increased MAC levels. They also reported attenuation of presser response to laryngoscopy and intubation. Lower doses were used in our study (40 mg/kg), and thus, we did not report any side effect or any significant difference in the hemodynamic parameters among the three groups. Most of the studies demonstrating attenuation of presser response with Mg have been conducted on hypertensive patients, and this may also account for the difference in our results as none of our patients were hypertensive.[1718]

BIS monitoring has been used in our study to assess depth of anesthesia. Durmus et al.[6] recorded the incidence of “purposeful movements” to intubation and skin incision at different dial settings of sevoflurane and then calculated MAC of sevoflurane using logistic regression analysis. They did not administer any intravenous induction agent, muscle relaxant, or opioid. However, clinically, we administer “balanced anesthesia” to patients scheduled for operative interventions, and thus, we have administered propofol, fentanyl, and atracurium in our study.

NMDA receptor is responsible for excitatory synaptic transmission in the CNS and has modulatory sites for Mg. Analgesic action of Mg is due to voltage-dependent blockade of these channels and hence prevention of nociception-associated central sensitization.[19] Calcium channels are involved in the modulation of nociceptive transmission, Mg is an antagonist of calcium, and this could also explain its analgesic properties. We did not report a statistically significant difference in the opioid consumption in our study. This could be attributed to the type of surgery chosen for our study, breast conservation surgeries which usually involve lumpectomy which is a less radical surgery. Studies reporting an analgesic sparing action of magnesium sulfate include patients undergoing laparotomies[23] and thoracotomies.[420]

Significant reduction in total consumption of atracurium was observed in the presence of magnesium sulfate infusion in our study. Mg is known to decrease the presynaptic release of acetylcholine and reduce the sensitivity of the postjunctional membrane. It potentiates the effects of all nondepolarizing muscle relaxants and use of a peripheral nerve stimulator is advocated to guide further dosing.

Mg has been known as a CNS depressant, but certain properties of this ion need to be reconsidered, and its anesthetic potency needs to be re-investigated. Blood–brain barrier limits the transport of Mg, and thus, its concentration in cerebrospinal fluid is well controlled.[21] Perioperative administration of magnesium sulfate (50 mg/kg bolus and 15 mg/kg/h continuous infusion) has no effect on cerebrospinal fluid Mg concentrations and thus no analgesic effect.[22]

We did not measure serum Mg levels and this is one of the limitations of our study.

CONCLUSION

Perioperative intravenous magnesium sulfate did not affect the MACs of desflurane or perioperative opioid consumption. There was no advantage in terms of hemodynamic stability, but recovery was delayed. Thus, there is no advantage in perioperative administration of magnesium sulfate to patients anaesthetized with desflurane for breast conservation surgeries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.