Postoperative respiratory impairment may result from various factors, including surgical factors (site of incision, postoperative pain and type of surgical procedure), anaesthetic factors (residual anaesthetics, mechanical ventilation and type of anaesthesia) and many other patient factors.1,2 Lung resections lead to the permanent loss of pulmonary function because the remaining lung cannot completely compensate for the lost lung tissue, particularly when the extent of parenchymal reduction is significant, such as after segmentectomy or lobectomy. Video-assisted thoracoscopic surgery (VATS), which avoids large thoracic incisions, enables a significant reduction of surgical trauma and postoperative pain compared with open thoracotomy3 but also may lead to a decline in the remaining lung function. Several drugs and devices can facilitate recovery from thoracic surgery and improve lung function in various clinical settings.4–6 However, no clinical trial to date has evaluated the effects of systemic administration of intraoperative magnesium sulphate (MgSO4) on pulmonary function in patients who have undergone lung resection surgery.
Intraoperative use of MgSO4 reduces the need for neuromuscular blocking drugs (NMBDs) and lessens postoperative pain and/or opioid consumption in various surgical patients.7–9 Residual neuromuscular blockade can be a primary cause of respiratory muscle weakness during the postoperative period, particularly when coupled with a reduction in lung volume, an abnormally restricted respiratory pattern due to an incompletely functioning respiratory pump muscle or direct chest trauma after thoracic surgery.10,11 The careful titration of NMBDs can help early recovery from muscle relaxation and respiratory muscle dysfunction. Better pain control and less opioid consumption also improve clinical recovery and reduce pulmonary complications.
We designed the present randomised double-blind study to evaluate the effects of MgSO4 on postoperative pulmonary function and recovery profile in patients undergoing VATS. The hypothesis was that intraoperative administration of MgSO4 contributes to dose reductions in administered NMBDs and analgesics, which improve pulmonary function [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC)] and quality of recovery 24 and 48 h following VATS.
The current study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (IRB no. B-1306-208-004, date 22 July 2013) and was registered at cris.nih.go.kr (registration number KCT0001410).
We studied 66 patients undergoing elective video-assisted thoracoscopic pulmonary resection after obtaining written informed consent. Inclusion criteria were age 25 to 75 years, thoracoscopic surgery of segmentectomy or lobectomy, tracheal extubation in the operating room and postoperative pain management using intravenous patient-controlled analgesia (PCA). Exclusion criteria were sleeve resection, pneumonectomy or wedge resection; BMI less than 15 or more than 35 kg m−2; presence of renal, hepatic or cardiovascular dysfunction; presence of neuromuscular disease; baseline FEV1 less than 30% of predicted; preoperative treatment with supplemental oxygen or tracheal intubation; ICU admission after the operation; any physical or mental illness rendering the patient unable to use the spirometry device.
Preoperatively, baseline spirometry was measured after a thorough explanation and demonstration of a portable spirometer (Microplus; Carefusion, Chatham, UK). Pulmonary function test (PFT) recordings were performed three times with the patient in an upright sitting position, and the best value was chosen. FEV1, FVC and peak expiratory flow rate (PEFR) were measured before surgery and 2, 24 and 48 h postoperatively. PFT values were also measured 12 months after surgery during regular outpatient follow-up.
A computer-generated block randomisation was performed by an independent investigator. Before induction of anaesthesia, the assignments were opened by a trained nurse who was not involved in the study. She prepared the active drug and placebo in identical syringes, and all clinicians, the patient and investigators collecting data were blind to group allocations.
Midazolam (0.03 mg kg−1) was given intravenously in the reception area for premedication. In the operating room, the patients were monitored using pulse oximetry, non-invasive arterial pressure measurement, electrocardiography, capnography and train-of-four (TOF) Watch SX (Organon Ltd., Dublin, Ireland). General anaesthesia was induced with a continuous infusion of propofol and remifentanil by target-controlled infusions using an Orchestra system (Fresenius vial, Brezins, France). After ensuring loss of consciousness, rocuronium 0.6 mg kg−1 was administered to facilitate double-lumen tube (DLT) insertion. Mask ventilation was maintained for 2 min, and intubation was performed with left-sided 35 and 37 Fr DLTs in female and male patients, respectively.
Following tracheal intubation, patients received either MgSO4 or 0.9% saline. In the Mg group, MgSO4 50 mg kg−1 was administered intravenously over 10 min, followed by a continuous infusion of 15 mg kg−1 h−1 during the operation. In the control group, the same volumes of 0.9% saline were administered. Mean arterial pressure (MAP) and heart rate (HR) were maintained within 20% of baseline. The effect-site concentration of propofol was set to ensure a bispectral index (BIS) (A-2000 BIS monitor; Aspect Medical Systems Inc., Natick, Massachusetts, USA) between 40 and 60. The target concentration of remifentanil was tuned so that haemodynamic measurements were within the recommended range. Hypotension (≥20% decrease in MAP or MAP <60 mmHg) was treated with either phenylephrine (30 to 100 μg) or ephedrine (5 to 20 mg) at the discretion of the anaesthesiologists. If bradycardia (HR < 45 beat min−1) occurred for longer than 5 min, the patient was treated with atropine 0.5 mg. Controlled ventilation was regulated to ensure an end-tidal CO2 of 4.1 to 5.6 kPa and a PaO2 greater than 12.0 kPa. The TOF response was checked at the wrist every 5 min, and patients received supplementary doses of rocuronium 0.15 mg kg−1 to maintain muscle relaxation whenever the TOF count was at least 2.
The correct position of the DLT was confirmed using fibreoptic bronchoscopy before and after lateral decubitus positioning. During one-lung ventilation, the lungs were ventilated with a tidal volume of 6 ml kg−1 and positive end-expiratory pressure (PEEP) of 4 to 10 cmH2O for protective ventilation. In all patients, PEEP was initially applied at 4 cmH2O but discontinued if peak inspiratory pressure exceeded 30 mmHg. FIO2 was initially set at 0.6, and in cases of desaturation, it was increased up to 1.0. The respiratory rate was set at 10 to 20 breaths min−1 to maintain PaCO2 at 4.6 to 5.3 kPa, and frequent recruitment manoeuvres were used. After completion of surgery, MgSO4 or saline was discontinued, both lumens of the DLT were suctioned and two-lung ventilation was resumed. Reventilation of the previously unventilated lung was performed while clamping the dependent lung lumen of the DLT and using an extension manoeuvre. Approximately 30 min before the anticipated end of surgery, intravenous PCA was given to provide acute postoperative pain relief. Fentanyl 900 to 1500 μg was used in intravenous PCA pumps (total volume of 100 ml, basal infusion of 1 ml h−1, a patient-controlled bolus of 1 ml and a lockout interval of 15 min). Neither opioid nor nonopioid analgesics were injected before commencing the PCA pump.
After the return of the third twitch of the TOF response, glycopyrrolate 0.01 mg kg−1 and neostigmine 0.03 mg kg−1 were administered to reverse residual neuromuscular blockade. After extubation of the trachea, the patients were transferred to the postanaesthesia care unit (PACU). Upon arrival, they were re-evaluated regarding the TOF ratio and Aldrete scoring system. The Aldrete score includes five categories: consciousness, respiration, colour, circulation and activity; a score of zero to two is given for each category. The patients received supplementary oxygen through a face mask at a flow rate of 5 l min−1.
At the end of the procedure, the total amount of rocuronium used was recorded. Pain intensity was assessed using a numerical rating scale (NRS) from 0 (no pain at all) to 10 (the worst possible pain) by a blinded investigator at 2, 24 and 48 h after surgery. The postoperative consumption of PCA solution was recorded at each time period, and rescue analgesics (morphine 5 mg intravenously) were administered if necessary in the recovery room and in the wards. Intravenous NSAIDs were also given at the discretion of the anaesthesiologists and thoracic surgeons.
If complications occurred postoperatively prior to discharge from hospital, they were recorded. Postoperative pneumonia was diagnosed on the basis of clinical suspicion after daily physical examination and regular chest radiograph. In addition, postoperative PFT values and chronic postsurgical pain assessment after 1 year were collected by reviewing the electronic medical records.
The primary outcome variable was FEV1 48 h postoperatively. The minimum sample size was estimated as 30 patients per group, which would offer an 80% chance of detecting a 20% relative increase in FEV1 from a presumed postoperative FEV1 of 1.96 (0.23) l. Allowing for a 10% loss due to dropout, the study population consisted of 66 patients.
Data are shown as absolute values, mean (SD) or number (%) and are grouped on an intention-to-treat basis. The independent t test, Mann–Whitney U test, Pearson's χ2 test or Fisher's exact test were used as appropriate. P values less than 0.05 were considered statistically significant.
Sixty-six patients were enrolled into the study, and four patients in the Mg group were excluded from analysis (Fig. 1). Table 1 presents the patient demographics and baseline characteristics. The two groups showed similar preoperative values for FEV1, FVC, FEV1/FVC ratio and PEFR. All preoperative values of PFTs were within the normal ranges and decreased significantly after surgery in both groups.
Regarding the primary outcome measures, postoperative values of FEV1 at 24 (1.7 ± 0.6 vs. 1.3 ± 0.5 l, P = 0.033) and 48 h (1.7 ± 0.6 vs. 1.4 ± 0.5 l, P = 0.021), and FVC at 24 (2.0 ± 0.8 vs. 1.6 ± 0.6 l, P = 0.038) and 48 h (2.2 ± 0.8 vs. 1.7 ± 0.7 l, P = 0.008, Table 2) were significantly greater in the Mg group than in the control group. PEFR and the FEV1/FVC ratio did not differ between the groups at any time point. At 2 h postoperatively, PFT values were similar in the two groups (Table 2).
Patients in the Mg group required less rocuronium than those in the control group (64.2 ± 19.9 vs. 74.9 ± 20.3 mg, respectively; P = 0.041). Less consumption of postoperative PCA was also observed at 24 and 48 h postoperatively in the Mg group (P = 0.042 and 0.023, respectively) (Table 3), although the pain scores and rescue analgesics were comparable in the two groups (Tables 3 and 4). The TOF ratio on arrival in the PACU was greater than 0.9 in both groups (0.91 ± 0.04 vs. 0.93 ± 0.03, respectively). There were also no differences in the use of phenylephrine, ephedrine or atropine. There was no incidence of electrocardiographic changes, bradycardia, respiratory depression, delayed ankle jerk reflex or delayed discharge from PACU in any of our patients. The Aldrete score was similar in both groups (9.9 ± 0.4 vs. 9.9 ± 0.2).
Before discharge, five patients in the control group were diagnosed with postoperative pneumonia. Postoperative air leaks were reported in three patients in the Mg group, and in two patients in the control group, and pleural effusion was reported in one patient in each group (Table 5).
PFTs were compared between the two groups 1 year postoperatively. At this point, we excluded patients who were unable to perform PFTs adequately or who had undergone additional pulmonary surgery within the year. Data from 24 patients in the Mg group and 25 patients in the control group were analysed, and there were no differences between the groups for FEV1 (2.3 ± 0.4 vs. 2.2 ± 0.6 l), FVC (3.2 ± 0.8 vs. 3.1 ± 0.9 l) or PEFR (data not presented). No chronic postsurgical pain was detected at 1 year.
The current randomised, placebo-controlled, double-blind study demonstrated that MgSO4 improves postoperative pulmonary function and analgesia and reduces the need for NMBDs in patients who underwent VATS. These results are consistent with previous investigations, including our own,7,9,12–15 and no complications associated with the use of MgSO4 were evident. Pulmonary function immediately after thoracic surgery was maximally reduced in both groups (FVC 48 and 46% of the preoperative values); thereafter, lung function steadily improved and was better preserved in patients who received MgSO4 than in the control group.
Although MgSO4 has been extensively investigated as an adjuvant for anaesthesia and analgesia, this is the first study to describe the benefits of magnesium on postoperative pulmonary function. Pulmonary lobectomy leads to a reduction to approximately 45 to 65% of the preoperative value in FEV1 and FVC at 24 h postoperatively, and pulmonary function recovers gradually for up to 6 days.16 Following an initial decrease, FEV1 and FVC consistently increased during the late postoperative period (at 24 and 48 h) in both groups; the use of magnesium was beneficial to the recovery of pulmonary function. Pulmonary dysfunction after lung resection surgery results from effects such as the loss of parenchymal volume, reduced ventilatory muscle activity (including the loss of diaphragmatic tone), physical sequelae on the chest wall caused by surgery and decreased lung compliance.1,17 Pulmonary complications occur much more often in patients who undergo surgery at sites closer to the diaphragm (the thorax and upper abdomen). Thoracic pain causes breathing in a slow, monotonous and shallow pattern, leading to regional hypoventilation. Systemic opioids are the commonest choice for postoperative analgesia. More recently, however, adjuvant analgesics to opioids, such as MgSO4, have been studied and have been shown to decrease the required dose and consequent undesirable effects of opioids.
The intraoperative use of magnesium reduces postoperative analgesic consumption and pain scores 24 and 48 h after surgery,9 and the postoperative use of magnesium reduces opioid consumption after thoracotomy.14,18 In the current study, PCA consumption was significantly lower in the Mg group than in the control group, and the time points of distinction between the groups exactly coincided with those of enhanced lung function.
Although we did not measure magnesium concentrations in this study, in a previous study in which we used the same dose regimen of MgSO4, the serum concentrations of Mg2+ were 0.8 to 1.06 (0.07), 1.60 (0.13), 0.95 (0.05) and 1.11 (0.08) mmol l−1 preoperatively and 1, 24 and 72 h postoperatively, respectively.12 Patients in the Mg group had significantly higher concentrations of Mg2+ during infusion than the control group, but previous studies have reported that Mg2+ levels decrease to comparable levels several hours after discontinuation7,12; none of those studies reported clinical signs of magnesium toxicity. During this period, magnesium seems to relieve pain as an N-methyl-D-aspartate (NMDA) receptor antagonist. Activation of this receptor not only increases the generation of noxious stimuli but also decreases nerve cell sensitivity to opioid receptor agonists.19 Therefore, added to this preventive function of central sensitisation, when administered together with an opioid, magnesium may avoid tolerance to opioid analgesia.19 In other words, NMDA antagonists could lead to lower amounts of opioid being needed to obtain the same degree of analgesia, and with less untoward side effects even after the termination of magnesium administration.
The TOF ratio on arrival at the PACU was higher than 0.9 in both groups, suggesting that no significant residual muscle relaxation remained. No hypoxaemia or critical respiratory events were reported, and the Aldrete scores were not different between the groups. The BIS value at the time of extubation was greater than 85, and the sedation levels in the PACU were comparable between the groups. These results dispel the worries over the potentiation and prolongation effects of Mg on NMBDs.20,21 In terms of neuromuscular blockade, magnesium potentiates NMBDs mainly by decreasing calcium-mediated release of acetylcholine from the presynaptic nerve terminal.22 As rocuronium is a competitive antagonist of acetylcholine, magnesium-induced acetylcholine reduction has the possibility of increasing the neuromuscular potency of rocuronium compared with that without magnesium at the same depth of anaesthesia.23 When magnesium is used as a pretreatment before NMBDs, it accelerates the onset of the NMBD for tracheal intubation, and the duration and intensity of neuromuscular block can be prolonged.24 However, when top-up doses of NMBDs are added under strict monitoring of neuromuscular transmission, as in the current study, the use of MgSO4 does not prolong the emergence from anaesthesia,9,25 but rather acts as an NMBD-sparing agent to help shorten the overall recovery time of the respiratory muscles.
The NRS pain scores between the groups were not statistically different at any evaluation time point. A previous study reported that MgSO4 reduces both opioid consumption and the NRS pain score,26 and another study reported reduced postoperative analgesic consumption but not a reduced NRS score.18 Generally, perioperative MgSO4 reduces opioid consumption, and to a lesser degree, postoperative pain.7,13 In the current study, at 24 and 48 h postoperatively, the NRS scores in both groups were approximately 2 to 4, representing patients with adequate pain relief. The potential advantages of VATS include less postoperative pain, earlier mobilisation and reduced overall morbidity.3 With these benefits, walking and early activity could lead to a quick recovery and better patient cooperation at 24 and 48 h spirometry in both groups. In other words, despite the lack of a difference in the NRS, MgSO4 led to a reduced need for postoperative fentanyl and/or NMBDs, less narcotic-induced lung compromise and enhanced ventilatory function. These findings indicate that intraoperative magnesium has beneficial effects on postoperative lung function.
For a proper comparison of PCA consumption between the groups, it is recommended that basal infusions should be avoided. We set up the PCA pump by adding a basal infusion to the patient-activated dose (bolus) in the current study for the sake of patients’ comfort. No differences in the pain scores between the groups seem to have been caused by the inclusion of a basal infusion. Nonetheless, the total amount of PCA consumption (adding together the basal and bolus) differed significantly between the two groups, which suggests an analgesic-sparing effect of magnesium.27,28
In the immediate postoperative period (within 2 h after surgery), FEV1 and FVC were markedly lower than preoperative values in both groups. Although rescue analgesics were administered as needed after frequent checking of pain in the PACU, the pain scores were greater than 6 in both groups during this early period. High pain scores interfere with the function of the chest wall and diaphragm and are inevitably associated with poor PFTs. A combination of drowsiness and pain may contribute to the difficulties in blowing into the spirometer with maximal effort.
During the postoperative period before discharge, the reported types and incidence of pulmonary complications were not significantly different between the groups. Postoperative pulmonary complications occur in 5 to 10% of patients after non-cardiac thoracic surgery, and atelectasis is the pivotal cause of these complications.29,30 Atelectasis can be prevented or treated by adequate analgesia, deep breathing and early ambulation, to which Mg administration can contribute considerably. However, at long-term follow-up 1 year postoperatively, PFT values and chronic postsurgical pain were the same in both groups.
Some limitations of this study should be addressed. The magnesium concentrations were not checked, although we can expect that the ranges were within well tolerated limits because we followed the same dose regimen as in previous investigations. Second, patient compliance was not guaranteed during the measurements. PFTs are reliable only when the expiratory effort is maximal; we only asked the patients to exhale as fast and as hard as possible and to repeat the tests for quality control. Third, thoracic epidural analgesia is expected to provide a favourable milieu after thoracotomy and VATS; it may attenuate the surgical stress response, reduce opioid requirements and thus cardiopulmonary complications. However, as epidural analgesia has superior analgesic efficacy to intravenous analgesia, it might have masked the analgesia-potentiating effect of MgSO4, which was the case in previous studies.31,32 Finally, many patients who were most likely to benefit from the use of drugs and analgesic techniques to improve pulmonary function after surgery (obesity, reduced lung function perioperatively and postoperative intensive care) were excluded in this study. We expect that these patients would also benefit from the use of intraoperative magnesium because of its NMBD-sparing and analgesia-potentiating effects.
In conclusion, the results of this study suggest that intraoperative MgSO4 administration is beneficial to postoperative pulmonary function. MgSO4 alleviated FEV1 and FVC impairment and reduced intraoperative rocuronium requirements and postoperative analgesic consumption during the first 48 h after surgery without significant prolongation of recovery.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: preliminary data from this study were presented as a poster presentation at the American Society of Anesthesiologists (ASA) 2016 Annual Meeting, 22 to 26 October 2016, Chicago, USA.
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