Neuromuscular blocking drugs are the gold standard for facilitation of tracheal intubation. They significantly improve intubating conditions and reduce laryngeal morbidity.1,2 However, their inappropriate use may be associated with side-effects such as anaphylaxis, intraoperative awareness and complications of residual neuromuscular blockade.3 For these reasons, the concept of intubation without the use of a neuromuscular blocking drug has been developed and has become a part of clinical practice.4 The main indications for this technique are surgical procedures in which neuromuscular blockade is not required or there is a contraindication to these drugs (e.g. myopathy, allergy). Over the past few years, several studies have focused on the possibility of performing tracheal intubation without the use of neuromuscular blocking agents. It has been demonstrated that a combination of propofol and different opioids facilitates tracheal intubation.4–9 Various adjuvants such as lidocaine and midazolam have also been reported to improve intubating conditions.5,6 However, satisfactory intubating conditions are not obtained reliably in all patients; intubating conditions are inadequate in 30 to 50% of patients when no neuromuscular blocking drug is used.5,9,10
Magnesium is the fourth commonest mineral salt in the human organism and plays a fundamental role in many physiological processes, for example, neuronal activity, muscular contraction and control of vasomotor tone.11–13 There is increasing interest in this agent in anaesthetic practice.11 Magnesium is known to possess muscle relaxing effects, mostly by reducing acetylcholine release, and it seems to have antinociceptive and anaesthetic effects.11,12 Searching for possibilities to improve the anaesthetic technique for intubation without muscle relaxants, we hypothesised that the administration of magnesium sulphate with propofol and an opioid could act synergistically and, therefore, improve intubating conditions. This randomised double-blinded study was designed to evaluate the effect of magnesium sulphate on intubating conditions during induction of general anaesthesia without the use of a neuromuscular blocking drug.
Ethical approval for this study (Ethics Committee number 2010–04) was provided by the Ethics Committee of Hôpital Militaire Avicenne Marrakech (Chairperson Professor M. Janati Idrissi) on 8 April 2010.
After obtaining approval and written informed consent, we studied 60 American Society of Anesthesiologists (ASA) physical status 1/2 patients, aged 18 to 60 years and scheduled for elective surgery. Each patient's airway was assessed using the Mallampati test14 and patients were enrolled only if there was a class I or II view of the mouth and throat. Patients with a history of reactive airways disease, increased risk of regurgitation or anticipated difficult intubation, obese patients (BMI > 30 kg m−2) and those with an allergy to any of the study drugs were excluded from the study. Exclusion criteria included also hepatic, renal, cardiovascular or respiratory disease, treatment with calcium channel blockers and pregnancy.
No premedication was prescribed on the morning of surgery. In the operating room, monitoring of ECG, heart rate (HR), oxygen saturation and noninvasive blood pressure was started (Schiller Argus LCM, SCHILLER AG, Baar, Switzerland). An intravenous line was secured with an 18-gauge cannula and all patients received an infusion of 0.9% saline 5 ml kg−1 before the start of the study.
The patients were allocated randomly to one of two groups using a computer-generated list. The magnesium group (n = 30) received a 10-min infusion of magnesium sulphate 45 mg kg−1 in 100 ml of 0.9% saline (0.3 ml kg−1 of magnesium sulphate 15% in 100 ml of saline). The control group (n = 30) received a 10-min infusion of 100 ml of 0.9% saline. To maintain blinding, randomisation cards were placed in opaque envelopes and opened by an independent nurse who then prepared the study solution (saline or magnesium sulphate) in an unlabelled vial outside the operating theatre. In addition, all patients were advised of the possibility of the occurrence of minor symptoms related to the magnesium sulphate (heat sensation or burning in the arm). They had instructions not to report these symptoms to ensure that the intubating investigator remained blinded.
At the end of the infusion of the study solution, anaesthesia was induced with fentanyl 3 μg kg−1 followed 3 min later by propofol 2.5 mg kg−1. Injections were made over a period of 20 to 30 s. When consciousness was lost, the ease of ventilation using a facemask was assessed as easy, difficult or impossible. Laryngoscopy was performed 60 s after the administration of propofol using an appropriate size of Macintosh blade. The same experienced physician (Y.A.), blinded to group assignment, performed and scored laryngoscopy and tracheal intubation. Cuffed tracheal tubes of internal diameter 7 and 7.5 mm were used in female and male patients, respectively. The cuff of the tracheal tube was inflated gently to the minimum pressure required to prevent a gas leak on positive pressure ventilation. Anaesthesia was maintained with 1% isoflurane and 50% nitrous oxide in oxygen.
The view of the larynx was assessed using the modified Cormack and Lehane classification.15 We evaluated intubating conditions using the Copenhagen score which takes into account ease of laryngoscopy, position and/or movements of the vocal cords and reaction to intubation (diaphragmatic movement/coughing).16 Laryngoscopy was considered as easy (jaw relaxed, no resistance to laryngoscope blade), fair (jaw not fully relaxed, slight resistance to blade) or difficult (poor jaw relaxation, active resistance of the patient to laryngoscopy). Intubating conditions were classified as excellent (all qualities were excellent), good (all qualities were either excellent or good) and poor (the presence of a single quality listed under poor). Excellent or good intubating conditions were regarded as clinically acceptable; poor intubating conditions were regarded as clinically unacceptable.16 The duration of laryngoscopy was also recorded (the time from the start of laryngoscopy until tracheal intubation and removal of the laryngoscope blade from the mouth). If at least one unacceptable condition was present on intubation, cisatracurium 0.15 mg kg−1 was administered. To avoid airway complications, tracheal intubation was not attempted if the vocal cords were closed. If cisatracurium was administered, the train-of-four ratio was monitored in the ulnar nerve to ensure complete recovery from neuromuscular blockade at the end of the procedure. Intubation failure was defined as the failure of insertion of the tracheal tube after three attempts.
Mean arterial pressure (MAP) and HR were recorded at five predetermined times: T1, at baseline; T2, after infusion of the study drug; T3, after induction of anaesthesia (30 s after the bolus injection of propofol); T4, 1 min after tracheal intubation; and T5, 5 min after tracheal intubation. Ephedrine was administered in 6-mg increments if MAP decreased by more than 30% of baseline and atropine 500 μg was given if HR was less than 50 beats min−1. Adverse events such as laryngospasm or bronchospasm were recorded.
The sample size calculation was based on previous research performed by Jabbour-Khoury et al.5 In that study, anaesthesia was induced with fentanyl, propofol and lidocaine. The percentage of acceptable intubating conditions was 60%. To detect a clinically significant improvement of acceptable intubating conditions from 60 to 90%, it was necessary to recruit 30 patients per group (5% level of significance with 80% power). The sample size calculation was made using Primer of Biostatistics Statistical Software, version 4.02 (McGraw-Hill, San Francisco, California, USA).
Results are expressed as mean ± SD for quantitative variables and as number and percentage for categorical variables. Qualitative variables were compared using the χ2-test or Fisher's exact test as appropriate. Quantitative variables were compared using Student's unpaired t-test. The Gaussian distribution of these variables was verified using the Shapiro–Wilk test. The Cormack grade was compared with the Mann–Whitney U-test. The haemodynamic variables (HR and MAP) were analysed using repeated measures analysis of variance (ANOVA). If ANOVA was significant, the Bonferroni post-hoc test was used. Significance for all statistical tests was set at P value of 0.05. Analysis of data was performed using SPSS for Windows (version 10.0, SPSS Inc., Chicago, Illinois, USA).
Between June 2010 and March 2011, 60 patients were enrolled and randomised (Fig. 1). Their characteristics are shown in Table 1. The Mallampati class was comparable in the two groups. Ventilation using a face mask was easy in all patients.
The number of patients presenting excellent or good intubating conditions was significantly higher in the magnesium group than in the control group according to the Copenhagen consensus conference scoring system (Table 2).16 Laryngoscopy was easy in 83% of the magnesium group vs. 30% in the control group (P < 0.0001). Seventy-four percent (22 patients) in the magnesium group had an optimal position of the vocal cords (i.e. vocal cords abducted) vs. 20% (six patients) in the control group (P < 0.0001). A higher percentage of patients in the control group had sustained coughing: 34 vs. 10% (P = 0.028). Clinically acceptable intubating conditions were observed more frequently in the magnesium group compared with the control group: 25 (83%) vs. 18 patients (60%) (P = 0.042). The addition of magnesium produced excellent conditions in 11 patients (37%) compared with two patients in the control group with excellent conditions.
Patients in the magnesium group had significantly lower Cormack grades than those in the control group (Table 2). The duration of intubation was also shorter in the magnesium group than the control group, but the difference was not significant: 15 ± 8 vs. 20 ± 10 s, P = 0.092). Administration of cisatracurium was necessary in one patient in the magnesium group and eight patients in the control group (P = 0.030). There was no intubation failure.
As shown in Figure 2, the haemodynamic variables at baseline and after the injection of the study drug were similar in the two groups. The significant decrease in MAP observed after induction was similar in both groups (23 mmHg in the magnesium group and 24 mmHg in the control group, P > 0.05). The decrease in HR observed after induction was also comparable in the two groups (16 beats min−1 in the magnesium group and 12 beats min−1 in the control group, P > 0.05). No laryngospasm or bronchospasm was observed in either group and no patient needed treatment for bradycardia. One patient in the magnesium group became hypotensive and was treated with ephedrine 6 mg. Peripheral oxygen saturation remained at pre-induction values (97 to 100%) throughout the study period.
This study shows that the addition of magnesium sulphate 45 mg kg−1 to fentanyl 3 μg kg−1 and propofol 2.5 mg kg−1 improved intubating conditions during induction of general anaesthesia without adverse haemodynamic effects.
The mechanism of action of magnesium as an adjuvant to intravenous induction appears to be multifactorial. Magnesium is an agent with analgesic, anaesthetic and muscle relaxant effects.11–13 Magnesium sulphate has a depressant effect on the central nervous system and is used in the treatment of eclampsia.12,13 Its anaesthetic effect is suggested by a number of studies which showed a significant reduction in anaesthetic requirements during both intravenous and inhalational anaesthesia.17–20 Magnesium sulphate also has an analgesic effect by interference with calcium channels and N-methyl-D-aspartate.11 This antinociceptive agent has been used as an adjuvant to intraoperative and postoperative analgesia.21–24 The hypothesis that magnesium sulphate could improve opioid analgesia and enhance the action of propofol may explain better relaxation of the pharyngeal and laryngeal muscles and, therefore, improved intubating conditions observed in the magnesium group in this study.
In our study, the most important effect of magnesium sulphate which could explain the improvement of intubating conditions is probably its effect on the neuromuscular junction. Magnesium is considered to be a ‘muscle relaxant’-like agent. Indeed, neuromuscular transmission is altered by a preponderant presynaptic effect: reduction in release of acetylcholine at motor nerve terminals.12 Moreover, it is known that magnesium sulphate potentiates the effect of nondepolarising neuromuscular blocking agents.25–27 Recently, a clinical study demonstrated that a rapid infusion of magnesium sulphate (50 mg kg−1) can re-establish a relevant degree of muscle paralysis in patients who have just recovered from nondepolarising neuromuscular blocking agents.28
Various techniques have been investigated in an attempt to improve intubating conditions when neuromuscular blocking drugs are not used.4–10 Propofol, which has a depressant effect on laryngeal reflexes, is usually combined with a rapid-onset and short-acting opioid (alfentanil or remifentanil).4,5,7,8 However, relatively large doses of opioid are needed and their combination with propofol can induce adverse haemodynamic events (hypotension and bradycardia).10 In our study, we chose to use fentanyl because the surgical procedures performed were not short procedures.
The factor which made the intubating scores unacceptable in our study was coughing when the tracheal tube was inserted. Coughing and limb movements during intubation have been identified as limiting factors in a number of studies.6,9 The addition of magnesium sulphate significantly decreased the occurrence of these events.
It has been demonstrated that intravenous administration of magnesium sulphate produces a significant decrease in arterial pressure secondary to a peripheral vasodilatory effect.29 Puri et al. administered magnesium sulphate 40 mg kg−1 in order to attenuate the cardiovascular response to tracheal intubation. They found that MAP and systemic vascular resistance decreased by 17 and 25%, respectively, after administration of magnesium. In our study, the decrease in MAP in the magnesium group was comparable to that in the control group. This could be explained by the infusion time of magnesium sulphate, which was longer in our study (10 vs. 1 min in the study of Puri et al.), and by the type of patients included in our study (younger and healthier).
The dose of magnesium sulphate used in our study (45 mg kg−1) was chosen because of previous trials in which magnesium was investigated as an adjuvant for perioperative analgesia.24 In our study, the blood concentration of magnesium was not measured. However, systematic review of randomised trials testing the potential analgesic properties of a variety of magnesium regimens in surgical patients (including total doses up to 16 g) did not report any serious adverse effects.24 When magnesium sulphate was administered at a dose of 50 mg kg−1, the serum concentration of magnesium increased by an average of 30 to 80%.22,30,31 No side-effects related to hypermagnesaemia were observed. Only minor symptoms of short duration, such as a feeling of heat or a burning sensation in the arm on the side of the intravenous line, have been reported by some patients.11
This study has some limitations. First, although intubation without administration of a neuromuscular blocking drug has become a part of clinical practice, this technique remains controversial. The proponents justify the practice of intubation without a neuromuscular blocking drug because of reductions in the risk of anaphylaxis and awareness, as well as residual block and its related postoperative pulmonary complications.32,33 Moreover, the use of neuromuscular blocking drugs may be controversial in some neuromuscular diseases (e.g. myasthenia gravis) and in specific surgical procedures in which intraoperative nerve identification and monitoring are required (a number of ear nose and throat and neurosurgical procedures and some thyroid surgery).34,35 The opponents of relaxant-free intubation argue that the price of omitting neuromuscular blocking agents is high: poor intubating conditions, difficult airway, laryngeal injuries and postoperative hoarseness.34,36 Our reasoning is that this technique should not be recommended to a large group of patients. Selected patients (as described above) may benefit from the use of relaxant-free intubation optimised with the addition of magnesium sulphate. It is undeniable that the use of a neuromuscular blocking drug offers the best intubating conditions.34,36 However, the effect of relaxant-sparing techniques on postoperative laryngeal symptoms remains controversial.2,9,10,37,38
Another limitation is that our study was performed in young, healthy patients scheduled for elective surgery. Our anaesthetic induction technique induced some degree of hypotension which was well tolerated in this population. Therefore, our results may not extend to emergency surgery or to elderly patients or ASA 3/4 patients in whom haemodynamic tolerance could be poor.
In conclusion, magnesium sulphate is an effective adjuvant to tracheal intubation without neuromuscular blocking drugs. Its combination with propofol and fentanyl significantly improved intubating conditions which were acceptable in 84% of the patients in the magnesium group. The dose used in this study (45 mg kg−1) did not induce any clinically important adverse haemodynamic effects. This technique could be used in ASA 1/2 patients for elective surgery when neuromuscular blocking drugs are contraindicated or should be avoided. Further studies are needed to find the most appropriate dose in older and more vulnerable ASA 3/4 patients.
The authors would like to thank the nurses of the Department of Anaesthesiology for their support.
This work was supported by the Department of Anaesthesiology of Avicenna Military Hospital. The authors have no conflicts of interest to declare.
1. Lundstrom LH, Moller AM, Rosenstock C, et al. Avoidance of neuromuscular blocking agents
may increase the risk of difficult tracheal intubation
: a cohort study of 103 812 consecutive adult patients recorded in the Danish Anaesthesia Database. Br J Anaesth
2. Mencke T, Echternach M, Kleinschmidt S, et al. Laryngeal morbidity and quality of tracheal intubation
: a randomized controlled trial. Anesthesiology
3. Savarese JJ, Caldwell JE, Lien CA, Miller RD. Pharmacology of muscle relaxants and their antagonists. In: Miller RD, editor. Anesthesia. 5th ed. Philadelphia, Pennsylvania: Churchill Livingstone Inc.; 2000. pp. 412–490.
4. Woods AW, Allam S. Tracheal intubation
without the use of neuromuscular blocking agents
. Br J Anaesth
5. Jabbour-Khoury SI, Dabbous AS, Rizk LB, et al. A combination of alfentanil-lidocaine-propofol provides better intubating conditions
than fentanyl-lidocaine-propofol in the absence of muscle relaxants. Can J Anaesth
6. Prakash S, Arora D, Prakash S, et al. A combination of fentanyl-midazolam-propofol provides better intubating conditions
than fentanyl-lignocaine-propofol in the absence of neuromuscular blocking agents
. Acta Anaesthesiol Scand
7. Klemola UM, Mennander S, Saarnivaara L. Tracheal intubation
without the use of muscle relaxants: remifentanil or alfentanil in combination with propofol. Acta Anaesthesiol Scand
8. Erhan E, Ugur G, Alper I, et al. Tracheal intubation
without muscle relaxants: remifentanil or alfentanil in combination with propofol. Eur J Anaesthesiol
9. Lieutaud T, Billard V, Khalaf H, Debaene B. Muscle relaxation and increasing doses of propofol improve intubating conditions
. Can J Anaesth
10. Combes X, Andriamifidy L, Dufresne E, et al. Comparison of two induction regimens using or not using muscle relaxant: impact on postoperative upper airway discomfort. Br J Anaesth
11. Herroeder S, Schonherr ME, De Hert SG, Hollmann MW. Magnesium: essentials for anesthesiologists. Anesthesiology
12. Dubé L, Granry JC. The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review. Can J Anaesth
13. Fawcett WJ, Haxby J, Male A. Magnesium physiology and pharmacology. Br J Anaesth
14. Mallampati S, Gatt S, Gugino LD, et al. A clinical sign to predict difficult tracheal intubation
: a prospective study. Can J Anaesth
15. Cormack RS, Lehane J. Difficult tracheal intubation
in obstetrics. Anaesthesia
16. Fuchs-Buder T, Claudius C, Skovgaard LT, et al. 8th International Neuromuscular MeetingGood clinical research practice in pharmacodynamic studies of neuromuscular blocking agents
II: the Stockholm revision. Acta Anaesthesiol Scand
17. Thompson SW, Moscicki JC, Difazio CA. The anesthetic contribution of magnesium sulphate
and ritodrine hydrochloride in rats. Anesth Analg
18. Telci L, Esen F, Akcora D, et al. Evaluation of effects of magnesium sulphate
in reducing intraoperative anaesthetic requirements. Br J Anaesth
19. Gupta K, Vohra V, Sood J. The role of magnesium as an adjuvant during general anaesthesia
20. Seyhan TO, Tugrul M, Sungur MO, et al. Effects of three different dose regimens of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery. Br J Anaesth
21. Koinig H, Wallner T, Marhofer P, et al. Magnesium sulphate
reduces intra- and postoperative analgesic requirements. Anesth Analg
22. Kara H, Sahin N, Ulusan V, Aydogdu T. Magnesium infusion reduces perioperative pain. Eur J Anaesthesiol
23. Tramer MR, Glynn CJ. An evaluation of a single dose of magnesium to supplement analgesia after ambulatory surgery: randomized controlled trial. Anesth Analg
24. Lysakowski C, Dumont L, Czarnetzki C, Tramer MR. Magnesium as an adjuvant to postoperative analgesia: a systematic review of randomized trials. Anesth Analg
25. Ghoneim MM, Long JP. The interaction between magnesium and other neuromuscular blocking agents
26. Pinard AM, Donati F, Martineau R, et al. Magnesium potentiates neuromuscular blockade with cisatracurium during cardiac surgery. Can J Anaesth
27. Czarnetzki C, Lysakowski C, Elia N, Tramer MR. Time course of rocuronium-induced neuromuscular block after pretreatment with magnesium sulphate
: a randomized study. Acta Anaesthesiol Scand
28. Hans GA, Bosenge B, Bonhomme VL, et al. Intravenous magnesium re-establishes neuromuscular block after spontaneous recovery from an intubating dose of rocuronium: a randomised controlled trial. Eur J Anaesthesiol
29. Puri GD, Marudhachalam KS, Chari P, Suri RK. The effect of magnesium sulphate
on hemodynamics and its efficacy in attenuating the response to endotracheal intubation in patients with coronary artery disease. Anesth Analg
30. Apan A, Buyukkocak U, Ozcan S, et al. Postoperative magnesium sulphate
infusion reduces analgesic requirements in spinal anaesthesia. Eur J Anaesthesiol
31. Ko SH, Lim HR, Kim DC, et al. Magnesium sulphate
does not reduce postoperative analgesic requirements. Anesthesiology
32. Mertes PM, Laxenaire MC, Alla F. Groupe d’Etudes des Reactions Anaphylactoides PeranesthesiquesAnaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000. Anesthesiology
33. Berg H, Roed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesth Scand
34. Sneyd JR, O'Sullivan E. Tracheal intubation
without neuromuscular blocking agents
: is there any point? Br J Anaesth
35. Petrun AM, Mekis D, Kamenik M. Successful use of rocuronium and sugammadex in a patient with myasthenia. Eur J Anaesthesiol
36. Donati F, Plaud B. Tracheal intubation
: optimal conditions, vocal cord damage, and allergy. Can J Anaesth
37. Baillard C, Adnet F, Borron SW, et al. Tracheal intubation
in routine practice with and without muscular relaxation: an observational study. Eur J Anaesthesiol
38. Bouvet L, Stoian A, Jacquot-Laperrière S, et al. Laryngeal injuries and intubating conditions
with or without muscular relaxation: an equivalence study. Can J Anaesth