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Magnesium as part of balanced general anaesthesia with propofol, remifentanil and mivacurium: a double-blind, randomized prospective study in 50 patients

Schulz-Stübner, S.; Wettmann, G.; Reyle-Hahn, S. M.; Rossaint, R.

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European Journal of Anaesthesiology: November 2001 - Volume 18 - Issue 11 - p 723-729

Abstract

Introduction

Magnesium ions are involved as a cofactor in about 300 known enzymatic reactions in the body and in several important processes such as hormone receptor binding, gating of calcium channels, transmembrane ion flux, regulation of the adenylcyclase system, muscle contraction, neuronal activity, vasomotor tone, cardiac excitability and neurotransmitter release [1]. As a pharmacological agent the use of magnesium sulphate is established for the treatment of supraventricular [2] and ventricular dysrhythmias [3], especially torsades de pointes [4], asthma [5], for tocolysis [6] and eclampsia [7,8]. The role of magnesium in the treatment of acute myocardial infarction remains unclear [1,9]. While many of the actions of magnesium sulphate are linked to its action as a physiological calcium antagonist [10], the proposed neuroprotective [11] and analgesic properties [12,13] might be explained by its antagonistic action at the N-methyl-D-aspartate (NMDA)-receptor. The effect of magnesium as a muscle relaxant [14] has been known since the 1950s. Other studies related to anaesthesia demonstrated a reduction of postanaesthetic shivering after treatment with magnesium sulphate [15] and the attenuation of the haemodynamic response to endotracheal intubation [16]. Besides a mild reduction of platelet function [17], there are no reports about major side-effects of magnesium treatment dosed in the range of 50 mg magnesium sulphate per kg body weight. Based on the literature and our clinical experience with magnesium sulphate we conducted this study to test the hypothesis that the addition of magnesium sulphate to a regimen of total intravenous (i.v.) anaesthesia with propofol, remifentanil and mivacurium should reduce the amount of the new opioid remifentanil needed to achieve haemodynamic stability. We also studied the effects on postoperative nausea and vomiting (PONV) and postoperative pain. We chose patients scheduled for elective pars plana vitrectomies, because this is a highly standardized procedure, performed by two surgeons at our institution with a comparable surgical stimulation and similar duration in each patient.

Materials and methods

The study was conducted according to the standards of good clinical practice of the European Union, the declaration of Helsinki and approved by the institutional review board. We studied 50 patients scheduled for elective pars plana vitrectomies in a double-blind randomized fashion. Patients with ASA grade IV and V, renal insufficiency (defined as a plasma creatinine concentration > 1.2 mg dL–1), neurological disorders (myotonia, myasthenia, Lambert–Eaton syndrome), bradycardia, AV conduction block, pregnancy or known chronic alcoholics or drug users were excluded from the study. Written informed consent was obtained the evening before surgery. Chronic medication remained unchanged, except for diabetic patients whose insulin or oral drugs were adjusted according to nil per mouth guidelines and the expected time of surgery in the morning. All patients received midazolam 3.75–7.5 mg orally, adjusted for age and body weight, 1 h before surgery. The patients were assigned to the magnesium or placebo group by a computer-generated block randomization list based on their study identification number.

When the patients arrived in the operating room monitoring consisting of electrocardiography, noninvasive arterial pressure (NIBP) and pulse oximetry was applied and baseline values obtained. Vital variables were recorded every 5 min during the procedure and in the recovery room. A pEEG™ monitor (Dräger, Lübeck, Germany) was used for continuous bi-hemispheric electrocencephalographic (EEG) monitoring to maintain a standard depth of anaesthesia during the procedure. This depth was defined as a spectral edge frequency (SEF 95) between 8 and 12 Hz recommended by the manufacturer. The degree of muscle relaxation was monitored with a Datex NMT™ Monitor (Datex-Ohmeda, Germany) using a mechanical accelerography device positioned on the patient’s thumb and stimulation of the ulnar nerve in the train-of-four (TOF) mode. A TOF count of 1 was maintained during the procedure.

Maintenance fluids were 1 mL kg–1 h–1 crystalloid solution and the calculated deficit since the last oral intake of fluids was replaced during the first hour of surgery.

At the beginning of anaesthesia a remifentanil infusion was started with 0.1 μg kg–1> min–1 and anaesthesia was induced with propofol (1–2 mg kg–1). After the patient was asleep either magnesium sulphate (50 mg kg–1) or an equivalent volume of placebo (NaCl) was injected from a blindly labelled vial over 1 min. Mivacurium (0.25 mg kg–1) was given in divided doses to achieve muscle relaxation for tracheal intubation and after return of one twitch response administered by continuous infusion. Propofol infusion was used for maintenance of anaesthesia and adjusted to achieve a spectral edge frequency (SEF 95) between 8 and 12 Hz.

Remifentanil infusion was adjusted to keep heart rate and arterial pressure in a 20% corridor from baseline values. Episodes of hypo- or hypertension and brady- or tachycardia were recorded, when the values differed more than 20% from baseline. Oculocardiac reflex episodes (defined as sudden onset of bradycardia with surgical manipulation of an eye muscle and immediate restoration of normal heart rate after cessation of manipulation) were recorded separately.

Patients’ lungs were ventilated using a Cato™ anaesthesia machine (Dräger) with a tidal volume of 8 mL kg–1 and a positive end-expiratory pressure of 5 cmH2O using a mixture of air and oxygen. The minute volume was adjusted by changing the respiratory rate to maintain end-tidal CO2 between 4.7 and 5.3 kPa. Peak and plateau airway pressure and compliance were registered every 15 min as part of the standard monitoring program at our institution. The total amount of propofol, remifentanil and mivacurium was registered when the infusion was stopped at the end of surgery and calculated in mg kg–1> min–1.

For postoperative pain management, all patients received metamizol 10 mg kg–1 (Novalgin™, Aventis Pharma, Germany) slowly i.v. 30 min before the end of surgery. A first pain score using a numerical analogue scale (NAS) in the range of 0 to 10 [18] was obtained when the patient arrived in the recovery room, the second after 1 h and the third score 24 h after surgery. A verbal method – asking the patient – how their pain would be on a scale between 0 (no pain) and 10 (worst imaginable pain) was used, because they were not able to use common visual analogue scales after the eye surgery. The postoperative pain regimen was nurse controlled (checks every hour or on demand of the patient), starting with repeated doses of metamizol and nalbuphine as rescue drug in order to keep NAS scores below 3. The amount of pain medication required in the 24-h interval was obtained from the chart and calculated in mg kg–1. This was because a patient-controlled analgesia (PCA) device was unavailable at the time of the study and orally administered nonopioid analgesics seemed to be sufficient in most cases, based on our previous clinical observations with this type of surgery.

Episodes of PONV (defined as new onset of nausea or vomiting either after the procedure or successful treatment of a foregoing episode) during the 24-h interval were also recorded. Blood samples were taken to check the magnesium concentration before induction of anaesthesia, and 30 and 120 min after injection of the test drug. To keep the investigator blinded, only the first sample (baseline) was double analysed using an AVL-analyser (AVL, Germany) with an ion selective electrode and atomic absorption spectroscopy (AAS). The samples at 30 and 120 min were only analysed using AAS. The AAS samples were allowed to rest for 30 min and than placed into a free swinging centrifuge at 2500 g for 10 min and refrigerated at –20°C for later analysis.

For the analysis of cost effectiveness we created a 2-h case scenario with a 70-kg patient and calculated the necessary amount of drugs (remifentanil, mivacurium and propofol) based on our mean values. We excluded postoperative pain medicine and other variables and compared the anaesthesia drug costs only. A per-mg analysis was chosen, because the drugs can be diluted in different concentrations or are available in different sized vials so that a per-vial calculation might be misleading. For our hospital the costs in € (Euro) per mg for remifentanil are €5.6, for mivacurium €0.39 and for propofol €0.015. One gram of magnesium sulphate costs €0.14.

Statistical analysis

The statistical analysis was based on the intention-to-treat (ITT) population using an adaptive design [19]. For the interim analysis there were 25 patients in the placebo and 25 patients in the magnesium group. The Hypothesis H0 (reduction of remifentanil consumption) was described as H0: A1=A2 vs. A1> < A2 (A1 := μg kg–1 min–1 remifentanil with magnesium and A2 : = μg kg–1 min–1 remifentanil with placebo) and tested with the Wilcoxon rank sum test. There were three possible study scenarios:

(a) The lower limit for p1 was defined as a0=0.5, so the study could be stopped with the result H0 in case of P > 0.5.

(b) The next critical limit would be a1=0.0233 so the study could be stopped and H0 rejected in case of P < 0.0233.

(c) If P would have been in the interval [a1,a0] = [0.0233, 0.5] a power calculation using the program POWER™ using a2=0.0087 could be made and corrected according to the necessary number for block randomization. In this case, the global null hypothesis could be rejected if p1> × p2> < 0.0087 and H02 could be rejected if p2> < 0.05. A simple data pooling of phase I and phase II data is not possible.

For descriptive statistics regarding the other variables either a two-sided Wilcoxon test, contingency tables or Fisher’s exact test were used. Demographic data (age, gender, weight) and data from medical history (comorbidity, medication, preoperative lab values) were obtained for possible subgroup analysis. Values are given as mean ± standard deviation whenever necessary.

Results

Demographic variables such as age, gender and weight and the medical history (comorbidity, medication and laboratory values) showed no significant differences between the magnesium and placebo group (Table 1), nor did the chronic medication (consisting of digoxin, b-adrenoceptor blocking drugs, or ACE inhibitors and calcium channel blocking drugs). Two patients screened for the study needed to be excluded due to renal insufficiency. The study could be stopped after the interim analysis and enrolment of 50 patients because the null hypothesis could be rejected with P < 0.01 for the amount of remifentanil needed.

Table 1
Table 1:
Demographic parameters of the study population

The results for remifentanil, propofol and mivacurium are shown in Table 2. While the reduction of mivacurium was also significant, there was only a trend of reduced consumption of propofol.

Table 2
Table 2:
Results for consumption of remifentanil, mivacurium and propofol

The magnesium concentration (AAS) increased from a mean baseline level of 0.79 to 1.62 mmol L–1 after 30 min and decreased to 1.29 mmol L–1 after 120 min in the magnesium group. It remained stable (0.78 ± 0.04 mmol L–1) in the placebo group. There was no case of hypomagnesemia at the outset.

The pain scores showed a trend toward a reduction in the magnesium group after 24 h without statistical significance. Although the trend of reduced consumption of pain medication in the magnesium group (Figure 1) is more obvious, statistical significance was also not reached.

Figure 1.
Figure 1.:
Postoperative pain medication. Open squares = magnesium; closed squares = control.

The incidence of PONV was not significantly changed, although there is a trend towards less severe PONV as shown in Table 3.

Table 3
Table 3:
Episodes of PONV

A significant reduction (P < 0.05) could be demonstrated for the incidence of oculocardiac reflex episodes in the magnesium group (Figure 2).

Figure 2.
Figure 2.:
Incidence of oculocardiac reflex episodes. Open squares = magnesium; closed squares = control.

Routinely measured ventilatory variables (mean airway pressure, plateau airway pressure and compliance) showed no significant differences in both study groups.

The incidence of hypotensive episodes were equally distributed as well as the incidence of tachycardia or bradycardia. Hypertensive episodes during the case as defined in the methods section were significantly reduced in the magnesium group.

In four patients of the magnesium group, surgery lasted longer than 2 h and we measured a significant increase of remifentanil consumption at this time (Figure 3). We observed no severe side-effects of the magnesium treatment during the study period.

Figure 3.
Figure 3.:
Four cases (a, b, c and d) lasting more than 2 h in the magnesium group. a = diamonds; b = squares; c = triangles; d = crosses.

In our drug cost analysis scenario, a 2-h anaesthetic without magnesium would cost €57.87 whereas the same case in the magnesium group costs €45.52, i.e. 21.35% less.

Discussion

Demographic data from both study groups were comparable so we did not perform a subgroup analysis, which would have been of limited value anyway owing to the small sample size of the subgroups. Our data demonstrated a significant reduction in remifentanil and mivacurium consumption during general anaesthesia, lasting less than 2 h, supplemented with 50 mg kg–1 body weight magnesium sulphate at induction. The effect on mivacurium consumption is not surprising, because the muscle relaxing effect of magnesium is well known and described in the literature [14], although not yet used in anaesthesia practice routinely. The mechanism by which magnesium reduces opioid consumption during general anaesthesia in this study is less clear. Hints for an analgesic or coanalgesic effect of magnesium are reported in studies examining postoperative pain in patients treated with magnesium. An explanation might be its action at the NMDA-receptor site [20]. We could show at least a trend in reduction of postoperative pain too, which was most obvious in the pain scores 24 h after surgery where magnesium concentrations are surely not therapeutically elevated. This observation supports the hypothesis that magnesium prevents central sensitization beside possible direct analgesic properties. Because we could not use a PCA device at the time the study was conducted, the amount of pain medication generated by chart analysis is a criticism of our methodology, but showed a trend towards less pain medication in the magnesium group. The statistical relevance of both postoperative pain-related observations might also be influenced by the small number of patients, because the power analysis was only performed for the main hypothesis.

Our study design used haemodynamic variables as surrogates for intraoperative pain to adjust the administration of remifentanil. This is common practice among anaesthesiologists because there are no other clinical signs that can be easily measured. Using this design we cannot clearly distinguish between an analgesic effect and a sympatholytic effect of magnesium. By standardizing depth of the anaesthesia with continuous EEG monitoring and muscle relaxation with TOF monitoring, we could exclude these factors influencing haemodynamic performance of the patients. The demographics and data from the medical history (especially chronic medication with β-adrenoceptor blocking drugs, calcium antagonists, digoxin or ACE inhibitors) are also comparable between both groups, so that pain during the procedure seems to be the most suitable explanation for haemodynamic reactions. The effect of magnesium as a physiological calcium channel blocker is well-known and could be responsible for the observed reduction in remifentanil consumption by reducing heart rate and lowering arterial pressure directly. Moreover, magnesium inhibits the release of neurotransmitters and catecholamines. If these mechanisms and not an analgesic effect were responsible for our observation, we would also expect a higher incidence of hypotension and bradycardia in the magnesium group, especially shortly after induction, when there was no surgical stimulation and the patient was being transferred from the induction room to the operating room. In fact, we found no significant difference in haemodynamic stability between the two groups besides less hypertension in the magnesium group and even a lower incidence of episodes of the oculocardiac reflex. Differences in surgical stimulation can be excluded because all procedures were performed by two surgeons and equally distributed between the two groups. Because appropriate depth of anaesthesia and analgesia is accepted as a basic precaution to prevent oculocardiac reflex episodes [21], we believe more in a (co)analgesic effect of magnesium if used as a supplement of general anaesthesia. The thesis is supported by a study of Yamakura and his colleagues [22]: although not performed with remifentanil – and with a higher opioid concentration than in our study – they demonstrated for several opioids, including fentanyl, a direct inhibition of the NMDA-receptor channel by high concentrations of opioids at a site that overlaps that for magnesium. Another strong indicator of the analgesic effects of magnesium is a study by Chanimov and colleagues who could induce spinal anaesthesia with magnesium in rats [23].

A depression of the central nervous system by the dose of magnesium we used is unlikely because the propofol requirements between both groups did not change significantly and the maximum magnesium concentrations found in our study were far below those reported for depression of the central nervous system in the literature [1].

We do not believe that magnesium sulphate has antiemetic properties. The minimal reduction of PONV is most likely based on reduced opioid consumption.

The AAS magnesium concentrations were markedly elevated above normal range (0.75–1.2 mmol L–1) after 30 min in the treatment group and close to the upper normal value after 120 min, which indicates that a single bolus dose of 50 mg kg–1 is enough for procedures lasting for up to 2 h. In those cases in our study lasting longer than 2 h, we observed a steady increase in the amount of remifentanil needed for maintenance after the second hour, so we conclude that for longer procedures, either a continuous infusion or repeated bolus doses might be necessary.

With a cost reduction of 21.35% in our 2-h per case scenario, magnesium sulphate clearly proved to be a cost effective part of balanced anaesthesia with propofol, remifentanil and mivacurium.

Conclusion

Based on our observations, we can recommend the use of magnesium sulphate as a safe and cost effective supplement to a general anaesthetic regimen with propofol, remifentanil and mivacurium, although we cannot clearly distinguish between a mechanism as a (co)analgesic agent at the NMDA-receptor site or its properties as a sympatholytic. The effect of a single bolus dose of 50 mg kg–1 on induction lasts for about 2 h. For longer cases, either a continuous infusion or repeated bolus doses might be necessary.

Acknowledgments

We would like to thank Dipl. Math. Thorsten Rheineke and Nicole Heussen for their statistical advice and work with the SAS-Computer-program and Dr oec. troph. Anton Kraus for monitoring the study.

This work was made possible in part by a grant from Verla-Pharm Arzneimittelfabrik, Hauptstraße 98, 82324 Tutzing, Germany.

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Keywords:

ANAESTHESIA, INTRAVENOUS; MAGNESIUM; OPHTHALMOLOGICAL SURGICAL PROCEDURES, vitrectomy; REFLEX, OCULOCARDIAC

© 2001 European Academy of Anaesthesiology