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Intraoperative magnesium sulphate decreases agitation and pain in patients undergoing functional endoscopic surgery: A randomised double-blind study

Elsersy, Hazem E.; Metyas, Magdy Ch.; Elfeky, Hana A.; Hassan, Ahmed A.

European Journal of Anaesthesiology: October 2017 - Volume 34 - Issue 10 - p 658–664
doi: 10.1097/EJA.0000000000000642
Pain

BACKGROUND Postoperative agitation is harmful for the patient as it may be associated with removal of catheters, nasal packs, oxygen masks and self-injury, and pose a danger to operating theatre staff.

OBJECTIVE The current study investigated the potential role of magnesium sulphate in treatment of postoperative agitation following functional endoscopic sinus surgery.

DESIGN A randomised, double-blinded, placebo-controlled trial.

SETTING ENT operating room, Menofia University Hospitals, Egypt.

PATIENTS A total of 312 adult patients (171 men and 141 women) were enrolled in the study. Eighteen patients (10 men and eight women) were excluded; data from 294 patients were analysed. Inclusion criteria were age between 20 and 60 years, American Society of Anesthesiologists’ physical status 1 or 2 scheduled for functional endoscopic sinus surgery. Exclusion criteria were hypertension, cardiac ischaemia, cerebrovascular insufficiency, neuromuscular diseases, pregnancy, prolonged treatment with calcium-channel blockers, diabetic neuropathy or a known allergy to magnesium compounds.

INTERVENTIONS Patients were allocated randomly to either the magnesium group (a magnesium infusion of 30 mg kg−1 in the first hour followed by 9 mg kg−1 h−1 until the end of the surgical procedure) or the control group (0.9% saline at the same volume and rate). Hypotensive anaesthesia was induced by nitroglycerine 5 to 20 μg kg−1 min−1. In the postanaesthetic care unit (PACU), patients were assessed for agitation and pain using the Richmond agitation-sedation scale and numerical rating scale, respectively.

PRIMARY OUTCOME The incidence and severity of agitation measured 5 min after admission to the PACU.

RESULTS Magnesium reduced postoperative agitation at time 0 (P = 0.009) and 5, 10, 15 and 30 min after PACU admission (P < 0.0001) as well as total agitation score [3 (0 to 6) versus 9 (0 to 12), P < 0.0001]. Magnesium also reduced pain [4.5 (4 to 5) versus 6 (5 to 6.25), P < 0.0001] and length of PACU stay (88 ± 23 versus 111 ± 31 min, P < 0.0001). The magnesium group consumed less pethidine in PACU compared with the control group (43 ± 15 and 59 ± 19 mg, respectively, P < 0.0001). The intraoperative end-tidal CO2 tension was comparable between groups (4.7 ± 0.7 versus 4.8 ± 1.2 kPa).

CONCLUSION Intraoperative infusion of magnesium in patients undergoing endoscopic sinus surgery reduced postoperative agitation, pethidine consumption and pain assessed in the PACU. It also decreased the length of stay in PACU compared with the control group.

TRIAL REGISTRATION The current study was registered according to WHO and ICMJE standards on 7 January 2014, under registration number PACTR 201402000737691.

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From the Faculty of Medicine, Menoufia University, Shibin El Kom, Menofia (HEE); Faculty of Medicine, Ain Shams University, Cairo (MCM); Faculty of Medicine, Menoufia University, Shibin El Kom (HAA); and Faculty of Medicine Al-Azhar University, Cairo, Egypt (AAH)

Correspondence to Hazem E. Elsersy, Lecturer of Anaesthesia, Faculty of Medicine, Menoufia University, Zaki Shabanah Street, Alzanati Tower, Shibin El Kom 32514, Menofia, Egypt Tel: +20 1091096655; e-mail: hazelsersy@hotmail.com

Published online 18 May 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.ejanaesthesiology.com).

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Introduction

Postoperative agitation, although short-lived, is potentially harmful to both patients and recovery room staff.1,2 An agitated patient requires four to six recovery room nurses to control exaggerated movement and has a potential for self-injury by removing intravenous catheters, tubing, oxygen masks and nasal packs. Furthermore, very agitated patients can pose an immediate danger to operating theatre staff.3 In our department, patients anaesthetised for endoscopic sinus surgery present a high incidence of agitation during emergence and in the early recovery stage, not responding to the administration of opioids. We have recorded cases of removal of nasal packs with subsequent bleeding, dislodgement of arterial and venous cannulae, and bruises and ecchymoses from restraint of severely agitated patients. For these reasons, we studied the effect of magnesium in prevention and or amelioration of postoperative agitation in patients undergoing functional endoscopic sinus surgery. We administered magnesium intraoperatively as it has a calming and relaxing effect4; it may also provide analgesia5 and enhance the hypotension required for this type of surgical procedure.6

Our hypothesis was that the central sedative effect and muscle-relaxing properties of magnesium might be beneficial in patients presenting with agitation in the early postoperative period. The aims of the current study were to investigate the effect of magnesium on agitation and postoperative pain when administered intraoperatively in patients undergoing endoscopic sinus surgery.

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Methods

The study was approved by the Menofia University ethics committee in January 2014 (Chairperson Professor Fouad Gareeb). Written informed consent was obtained from all patients enrolled in the study.

Patients of either sex aged between 20 and 60 years, American Society of Anesthesiologists’ physical status 1 or 2 and scheduled for endoscopic sinus surgery at Menofia University Hospitals were invited to participate in the study. Exclusion criteria were hypertension, cardiac ischaemia, history of transient ischaemic attacks, history of stroke and prescribed antiplatelet therapy for stroke protection, neuromuscular diseases, pregnancy, prolonged treatment with calcium-channel blockers, diabetic neuropathy or known allergy to magnesium compounds. The first patient entered the study on 2 February 2014 and the last on 4 August 2014.

Patients were assigned randomly to one of two equal parallel groups to receive intraoperative magnesium (magnesium group) or 0.9% saline solution (control group). Randomisation was undertaken using a computer-generated programme (research randomiser). An anaesthetic technician who did not participate in the study was provided with patient identification, body weight and group allocation, and prepared the colourless coded solutions in transparent syringes. The codes were kept confidential by the technician until completion of the study.

The technician prepared the magnesium solution syringes by mixing magnesium sulphate with 0.9% saline according to the body weight of each patient. We used magnesium sulphate solution (MgSO4 USP 50%, 500 mg ml−1); thus, each 2 ml of magnesium solution contained 1000 mg of magnesium. For each patient, a total dose of magnesium sulphate of 60 mg kg−1 was diluted to 20 ml. Patients in the magnesium group received an initial intravenous loading dose of 30 mg kg−1 over 1 h, followed by a continuous infusion of 9 mg kg−1 h−1 for the duration of surgery. The infusion was delivered by a syringe pump attached to a side port of a double-port infusion set. The control group received an equivalent volume of 0.9% saline.

One hour before induction of anaesthesia, all patients received atropine 0.5 mg and promethazine 25 mg intramuscularly as premedication. On arrival at the operating room, an 18-gauge cannula was inserted in a peripheral vein, and an infusion of magnesium or NaCl was initiated. A second cannula was inserted into the saphenous vein of the left lower leg and used for infusion of nitroglycerine. A 20-gauge catheter was inserted in the left radial artery and connected to a transducer for direct measurement of arterial pressure throughout the procedure.

Before induction of anaesthesia, standard monitoring [pulse oximetry (SpO2), noninvasive blood pressure (NIBP), ECG and heart rate (HR)] was implemented. Inspired and end-tidal concentrations of oxygen and sevoflurane, and end-tidal CO2 concentration, were monitored intraoperatively (Dräger Infinity Vista XL; Drägerwerk AG & Co., Lübeck 23558, Germany). Bispectral Index (BIS) was also monitored (Aspect XP, A2000; Aspect Medical Systems, Minneapolis, Minnesota, USA) to prevent awareness, a possible contributing factor to postoperative agitation.

Anaesthesia was induced with propofol 2.5 mg kg−1 and fentanyl 1 μg kg−1 followed by atracurium 0.5 mg kg−1 to facilitate tracheal intubation. Mechanical ventilation was then started, and anaesthesia was maintained with an inspired sevoflurane concentration of 2% in a N2O/O2 mixture (1/1 l min−1). The inspired concentration of sevoflurane was decreased to 1.5% after induction of hypotension. Neuromuscular block was maintained with atracurium 0.3 mg kg−1 h−1.

Nitroglycerine (5 mg ml−1, Hospira UK Ltd., Maidenhead, UK) was infused during surgery at a rate of 5 to 20 μg kg−1 min−1 with the aim of maintaining a mean arterial BP (MAP) of 55 ± 5 mmHg to reduce bleeding and improve the surgical field (see video which demonstrates monitoring of invasive arterial pressure, http://links.lww.com/EJA/A120). After the onset of hypotension, MAP and BIS values were recorded every 10 min. The medians of the readings obtained were calculated for each patient.

After the completion of surgery, patients were given ephedrine hydrochloride 10 mg (Martindale Pharmaceuticals, Buckinghamshire, UK) intravenously to restore the MAP to the preoperative value. At the end of surgery, the ulnar nerve was stimulated by means of a nerve stimulator (Innervator; Fisher and Paykel Electronics Ltd., Auckland, New Zealand), and the responses of the adductor pollicis were evaluated visually. When patients exhibited spontaneous breathing and a return of two visual twitch responses of the train-of-four (TOF) stimuli in three repeated consecutive series of TOF stimulation, residual neuromuscular block was reversed with neostigmine 40 μg kg−1, given intravenously with atropine 1 mg.

The infusion of magnesium or saline was terminated, and the tracheal tube was removed when tidal volume was more than 5 ml kg−1, respiratory rate more than 12 breaths min−1, the swallowing and cough reflexes were active, the BIS value was more than 70 and all TOF twitch responses were present without fade. Patients were then transferred to the postanaesthesia care unit (PACU), where paracetamol 1 g (Perfalgan; Bristol-Myers Squibb, London, UK) was given intravenously. An oxygen face mask delivered a flow rate of 5 l min−1. Thirty minutes after admission to PACU, and when agitation and pain score recordings had been completed, incremental doses of pethidine 25 mg were administered intravenously every 10 min as rescue analgesia, targeting a pain score 2 or less. Pethidine was administered after agitation and pain recordings to avoid confounders to the outcome measurement.

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Measurements and study outcomes

In PACU, SpO2, HR and arterial BP were monitored, and agitation and pain were assessed and recorded. Pethidine consumption and the length of stay in PACU were recorded. Discharge criteria from PACU were stable vital signs, pain score 2 or less, the absence of nausea and vomiting and a calm and alert patient.

Agitation was defined as purposeless motor activity, excessive motor activity and/or inconclusive sounds or aggressive behaviour of the patient in the absence of response to commands. Agitation was assessed on admission to the PACU (time 0) and 5, 10, 15 and 30 min later. Postoperative agitation was assessed in PACU by a blinded observer using the Richmond agitation-sedation scale (RASS)7: 0, alert and calm; 1, restless (anxious or apprehensive but movements not aggressive or vigorous); 2, agitated (frequent nonpurposeful movement); 3, very agitated [pulls on or removes tube(s) or catheter(s) or has aggressive behaviour towards staff] and 4, combative (overtly combative or violent, immediate danger to staff).

Total agitation was defined as the algebraic sum of agitation values observed at all measured time points for each patient. The total agitation scores ranged from 0 (no agitation) to 20 (severe persistent agitation).

Pain scores were assessed using a numerical rating scale (NRS) where 0 represents no pain and 10 is the worst imaginable pain, as rated by the patient. A blinded team member assessed pain after the last evaluation of agitation (30 min after admission to PACU). Patients who exhibited no agitation were also evaluated for pain 30 min after admission to PACU.

The primary outcome of the study was frequency of agitation 5 min after admission to PACU. Secondary outcomes were frequency of agitation at 0, 10, 15 and 30 min after arrival in the PACU, the total agitation score, pain intensity during the first 30 min, pethidine consumption in the PACU and duration of stay in PACU.

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Statistical analysis

Power analysis was based on a pilot study comparing the frequency of agitation 5 min after PACU admission as a primary determinant of sample size. Using the difference in the means between the two groups, given α probability = 0.05, power 95%, revealed that a total sample size of 210 was required (105 per group) to detect a 50% reduction in agitation. We increased the total sample size to 312 to compensate for potential exclusions and dropouts.

Descriptive statistics were used to represent patient characteristics. Continuous variables such as age, BMI and MAP were tested for normality and are presented as means or medians as appropriate; categorical data such as sex and smoking status are represented as patient numbers and percentages.

Although RASS is ordinal, we have used five defined points that can be treated as a continuous variable.8 All the measured agitation points were compared using the Mann–Whitney U test, and the P value was determined by the Monte Carlo resampling method with 10 000 simulations. Medians of pain scores were compared by Mood's test. The length of PACU stay and pethidine consumption variables were compared by two-tailed Student t test. The 95% confidence interval (CI) between means was calculated for parametric variables, and 95% CIs around the medians were estimated for nonparametric variables. A P value less than 0.05 was considered significant.

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Results

The number of patients enrolled and excluded for not meeting the inclusion criteria is shown in the flow diagram of the study (Fig. 1).

Fig. 1

Fig. 1

Patients’ characteristics were similar in the two groups (Table 1). Both the initial nitroglycerine dose to achieve the targeted MAP and total dose of nitroglycerine were lower in the magnesium group.

Table 1

Table 1

Magnesium treatment reduced the incidence of postoperative agitation to 59% (87 agitated and 59 non-agitated) compared with 74% (110 agitated and 38 non-agitated) in the control group (P < 0.0001). Inter-group comparisons showed significantly decreased agitation in the magnesium group at all measured time points (Tables 2 and 3). Total agitation calculated by summing the agitation scores at several time points was also less in the magnesium-treated group [3 (0 to 6) versus 9 (0 to 12), P < 0.0001].

Table 2

Table 2

Table 3

Table 3

Patients treated with magnesium experienced less pain than those in the control group [4.5 (4 to 5) and 6 (5 to 6.25), respectively, CI around the median 4.8 to 5.25, P < 0.0001]. In non-agitated patients (n = 98, 59 in the magnesium group and 39 in the control group), magnesium also reduced pain [4 (4 to 5) versus 6 (4.5 to 6), P < 0.0001, respectively]. The CIs around the medians were 3.6 to 4.3 for magnesium and 5.6 to 6.3 in the control group.

Total pethidine consumption in the PACU was significantly lower in the magnesium group than in the control group (43 ± 15 versus 59 ± 19 mg, respectively, P < 0.0001, 95% CI of the difference between the means 12 to 20 mg) (Table 1).

The length of stay in PACU was significantly shorter in the magnesium group (88 ± 23 versus 111 ± 31 min in the control group, 95% CI of the difference between the means 17.1 to 29.6, P < 0.0001) (Table 1). We did not observe hypoventilation or residual curarisation due to magnesium therapy after reversal of the neuromuscular block.

The median, interquartile range (IQR) total dose of magnesium prepared by the anaesthesia technician was 5.3 (4.8 to 5.6) g in a 20-ml syringe. The total dose of magnesium given to the patients in the magnesium group was 3.5 (3.2 to 3.7) g.

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Discussion

Our results show that in patients undergoing endoscopic sinus surgery, intraoperative administration of magnesium decreases the incidence and severity of postoperative agitation, ameliorates postoperative pain and shortens stay in the PACU.

Many inter-related postoperative events may provoke agitation, including postoperative pain9 and hypoxaemia,10 which are major confounders that may cause or result from agitation. An agitated patient can remove his oxygen mask or injure himself, resulting in more hypoxaemia and pain. In our study, none of the patients had a reduction in SpO2, excluding hypoxaemia as a confounding factor for agitation.

Although pain may be the cause of agitation,11 it cannot be considered the only cause of postoperative agitation for several reasons. Magnesium itself has antinociceptive properties. In a meta-analysis including more than 1200 patients, perioperative magnesium administration was associated with decreased postoperative morphine consumption and pain intensity at rest and on movement.5 In the current study, magnesium reduced pain in non-agitated patients, indicating that the mechanism of reduction of pain is independent of the reduction of agitation. In addition, 45% of the non-agitated patients displayed pain scores of 5 or more. Weldon et al. 12 reported that emergence agitation can occur even after adequate pain treatment or after procedures that are not associated with pain.

Postoperative agitation is a well documented phenomenon in children recovering from sevoflurane anaesthesia.9 However, adult agitation has been recorded mainly in geriatric patients.13 In paediatric patients, Apan et al. 14 failed to demonstrate a beneficial effect of magnesium sulphate on agitation after adenotonsillectomy. In contrast, Abdullatif et al. 15 showed a beneficial effect of magnesium in reducing sevoflurane agitation after the same surgical procedure. The different results between the two reports may be due to methodological issues; the former used a magnesium infusion before the end of surgery, whereas the latter used a magnesium bolus at the start and an infusion throughout surgery. This highlights the impact of dosing and timing of magnesium administration on outcome.

Postoperative agitation may occur in response to unrelated factors such as pain,9,11 medications like benzodiazipines and pethidine,16 certain surgical procedures,17 the personal characteristics of the patient, preoperative anxiety and too rapid awakening.18 No single factor can explain emergence agitation.19 The high prevalence of postoperative agitation in our study may be due to the nature of the surgery, nasal packs,20 hypotensive anaesthesia or premedication with atropine.21 All of our patients were given premedication that included intramuscular atropine 0.5 mg 1 h before anaesthesia, but the dose of 1 mg of intravenous atropine given with neostigmine to reverse residual neuromuscular block might be more likely to influence the incidence of agitation.22

Yu et al. 20 reported that 55.4% of patients were agitated after ENT surgery; Kim et al. 23 reported a 52% incidence of agitation after the same surgery. The former used premedication of atropine 0.5 mg and midazolam 0.1 mg kg−1 and neostigmine–atropine for reversal, whereas the latter used premedication of glycopyrrolate 0.1 mg and midazolam 0.04 mg kg−1, and neostigmine–glycopyrrolate for reversal. It is known that glycopyrrolate does not cross the blood–brain barrier or have any central effect but the incidence of agitation was not reduced with its use. We have reported a higher incidence of agitation, and the difference between our results and theirs could be related to methodological issues. We used hypotensive anaesthesia, whereas they used a normotensive protocol. The impact of hypotension on agitation has not yet been studied.

There is some evidence of a neuroprotective effect of magnesium.24,25 The mechanism by which magnesium reduces postoperative agitation remains to be determined. Magnesium sulphate is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with antinociceptive effects and also inhibits the entry of calcium ions into cells.26 Intravenous magnesium sulphate has been shown to suppress the increase in brain lactate concentrations and improves the electroencephalographic changes in response to cerebral ischaemia.15,27,28

It is possible that magnesium may have decreased agitation by protecting the brain from deleterious effects of prolonged hypotension and other contributing factors. Some types of surgery have been shown to be associated with hypomagnesaemia.29,30 We did not monitor magnesium blood concentration in our patients but endoscopic sinus surgery is not associated with high-volume fluid replacement and haemodilution, which accompany major surgical procedures in which hypomagnesaemia has been found.

Intraoperative awareness is a possible confounding factor for postoperative agitation but, in our study, BIS values were maintained at values consistent with an adequate depth of anaesthesia. In addition, the end-tidal CO2 tension was maintained within acceptable limits (4.7 ± 0.7 versus 4.8 ± 1.2 kPa) during hypotensive anaesthesia to minimise the risk of cerebral underperfusion.

Magnesium sulphate reduced the length of stay in the PACU and the dose of nitroglycerine necessary to achieve the targeted hypotensive point. This would encourage the routine use of magnesium in hypotensive anaesthesia as a sole agent or combined with other drugs. The results of the current study support the use of magnesium for postoperative agitation in adults.

Strengths of the current study are that the trial is a randomised, double-blinded study with adequate power to support the results regarding the primary outcome. Also, to our knowledge, magnesium has not been implemented so far to prevent or relieve agitation after endoscopic sinus surgery and to shorten the duration of stay in PACU.

Limitations of the study are the assessment of pain only once in the very early recovery period, the lack of measurements of magnesium blood concentrations before and at the end of surgery in each group and the lack of neuromuscular block monitoring intraoperatively. Magnesium interacts with neuromuscular blocking agents by reducing acetylcholine release at the motor nerve terminal. When administered preoperatively, magnesium increases the duration of neuromuscular block produced by rocuronium.31 We used atracurium, which has a different pharmacokinetic profile, and we did not encounter prolonged neuromuscular block after completion of surgery, but our findings would be more robust if neuromuscular block had been monitored intraoperatively.

In conclusion, the intraoperative administration of magnesium sulphate in patients undergoing functional endoscopic sinus surgery decreases postoperative agitation, pain intensity and pethidine consumption in the early postoperative period and the length of stay in PACU. A large multi-centre investigation is required for a dose–response and toxicity study.

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Acknowledgements relating to this article

Assistance with the study: the authors thank our anaesthesia technicians and nurses who helped very much in outcome assessment. Special thanks to the late M. Kalash, the anaesthesia technician whose role of medicinal preparation and blinding the investigators, patients and outcome assessors was vital to the success of the study. We thank Dr Yasser Abdul-Shakoor, anaesthesia specialist, for his efforts and help in this study.

Financial support and sponsorship: this study was funded by Menofia University, Menofia, Egypt.

Conflicts of interest: none.

Presentation: none.

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