Q: Could there have been bias in the selection of the study subjects? How likely might selection bias affect the data?

--> when I read the article, it doesn't sound like there is a bias in the selection of study subject. am I wrong?

Q: Could there have been bias in the collection of information? How likely might observation bias affect the data? - study says that the limitation of the current study is the usage of a fixed dose of epidural magnesium due to the absence of scientific evidence regarding body-weight-based dosage of epidural magnesium. In addition, cough VAS score was not measured because of patients' incompliance. Cough increases pain in post-thoracotomy patients and may affect the result of VAS score in these patients

I am wondering this can be the answer or not.

Effect of Adding Magnesium Sulphate to Epidural Bupivacaine and Morphine on Post-Thoracotomy Pain Management: A Randomized, Double-Blind, Clinical Trial

Abstract

Post-thoracotomy pain is very severe and may cause pulmonary complications. Thoracic epidural analgesia can greatly decrease the pain experience and its consequences. However, finding new methods to decrease the amount of administered opioids is an important issue of research. We aimed to evaluate the effect of adding epidural magnesium sulphate to bupivacaine and morphine on pain control and the amount of opioid consumption after thoracotomy. Eighty patients undergoing thoracotomy at a tertiary cardiothoracic referral centre were enrolled in a randomized, double-blind trial. Patients were randomly allocated to two groups. Bupivacaine (12.5 mg) and morphine (2 mg) were administered epidurally to all patients at the end of operation. Patients in the magnesium (Mg) group received epidural magnesium sulphate (50 mg), and patients in the control (C) group received normal saline as an adjuvant. Visual analogue scale (VAS) score and the amount of morphine consumption were measured during 24 hr post-operation. Thirty-nine patients in the Mg group and 41 patients in the C group completed the study. Patients in the Mg group had significantly less VAS score at recovery time (p< 0.05), 2 hr (p< 0.01) and 4 hr (p< 0.05) after surgery. The patient-controlled analgesia pump was started earlier in the C group than in the Mg group (p< 0.05). The amount of morphine needed in the Mg group was significantly lower than in the C group (5.64 1.69 mg/24 hrversus8.44 3.98 mg/24 hr;p< 0.001). Pruritus was seen in the C group (9.7%) and absent in the Mg group (p< 0.05). Co-administration of magnesium sulphate with bupivacaine and morphine for thoracic epidural analgesia after thoracotomy leads to a reduction in post-operative pain score and the need for opioid administration.

Patients undergoing thoracotomy experience one of the most severe acute post-operative pains1. Considerable tissue damage caused by incision, constant respiratory movement of chest, and repetitive coughing are severe stimuli for post-thoracotomy pain2,3. Inadequate pain management could result in diaphragmatic dysfunction, deep inspiration failure and consequently decreased functional residual capacity, ineffective cough, atelectasis, hypoxia and pneumonia4. Therefore, optimal post-thoracotomy pain management is required to secure adequate ventilation, coughing and reduction in post-operative respiratory complications5.

A variety of pain management methods such as thoracic epidural analgesia, paravertebral blocks, intercostal nerve blockade, systemic analgesia, cryoanalgesia, intrathecal administration of opioids and transcutaneous electrical nerve stimulation have been applied for post-thoracotomy pain relief6-10. Epidural analgesia is a common and acceptable technique in which administration of two or more medications increases analgesic effects and decreases adverse effects5,6. Morphine and bupivacaine, as the most common opioid and local anaesthetic medications, are usually administered epidurally for this purpose11,12.

The usage of magnesium for its antinociceptive effect is on the rise in anaesthesiology. This effect is explained by two main mechanisms: regulation of calcium entry into cell and antagonizing the N-methyl-D-aspartate (NMDA) receptors13. According to a meta-analysis of randomized controlled trials in different surgical procedures, systemic administration of perioperative magnesium as an analgesic adjunct lowers post-operative pain and consequently analgesic requirements14. Recently, a few studies on post-thoracotomy pain management (with limited number of patients) also showed positive effect of epidural magnesium on the pain reduction and lesser need for opioid administration15-17. However, the efficacy and safety of epidural magnesium is still a controversial issue. We designed this study to evaluate the effect of epidural magnesium sulphate as an adjuvant to bupivacaine and morphine on the severity of post-thoracotomy pain, amount of opioid consumption and occurrence of side effects.

Materials and Methods

This double-blind, parallel-group study was carried out at the anaesthesiology department of Masih Daneshvari Hospital. The Institutional Review Board of National Research Institute of Tuberculosis and Lung Diseases (NRITLD) approved the study. The study registration number is NCT03343548.

Patient selection and blinding

Patients aged 16-65 years undergoing thoracotomy were recruited from December 2016 until November 2017. Patients with known hypersensitivity to magnesium sulphate, renal failure, hepatic dysfunction, severe obesity, psychotic or neurologic diseases, currently taking opioid or calcium channel blockers, and AV block degree II or III were excluded from the study. At any stages, patients' refusal to participate in the trial was also considered as exclusion criteria. Before thoracotomy, patients were instructed about visual analogue scale (VAS) and use of patient-controlled epidural analgesia (PCEA) device. An anaesthesiologist performed all epidural infusion and PCEA set-up. All assessments were performed by an observer blinded to the groups' allocation.

Randomization and intervention

Before anaesthesia induction, each patient was placed in the lateral decubitus position. Then, an epidural catheter with a 0.2-m filter was located in the thoracic T6-T7 or T7-T8 region using an 18-gauge Tuohy needle. Appropriate placement of epidural catheter was confirmed by loss of cold and pinprick sensations after infusion of 3 mL lidocaine 2% with epinephrine (1:200,000).

In the operation room, general anaesthesia was induced for all patients with fentanyl 2 g/kg, midazolam 1-2 mg and sodium thiopental 5 mg/kg. Atracurium 0.6 mg/kg was used to facilitate tracheal intubation with a double-lumen endobronchial tube. Fibre-optic bronchoscopy was performed to confirm tracheal intubation accurate position. Anaesthesia was maintained with propofol and atracurium. Standard monitoring such as electrocardiography (ECG), invasive blood pressure and pulse oximeter was applied during anaesthesia.

Subsequently, patients underwent thoracotomy by posterolateral incision. A surgical team used the 3-trocar technique (212-mm- and 15-mm-diameter trocars) for all patients with the same materials. At the end of operation, patients were randomly allocated to two groups using a random number table:the magnesium (Mg) group received epidural magnesium sulphate (50 mg in 1 mL 0.9% saline) along with 12.5 mg bupivacaine and 2 mg morphine in 20 mL 0.9% saline, and the control (C) group received 1 mL 0.9% saline along with the same dose of bupivacaine and morphine. All patients were admitted to intensive care unit (ICU) after extubation. Then, PCEA device (size: 100 mL; infusion rate: 4 mL/hr; Canack Technology Co. Ltd., Vancouver, Canada) was set to deliver bupivacaine (62.5 mg/100 mL) and morphine (5 mg/100 mL) continuously. A patient-controlled injection was also programmed to deliver 0.5 mL bolus with a lockout of 15 min. between two consecutive boluses. PCEA device was started when the patients regained consciousness and had VAS score 4. Those patients complaining of pain (VAS score 4) even after performing PCEA were administered 2-5 mg intravenous rescue dose of morphine sulphate.

Outcome measures

Visual analogue scale score was measured during the first 24 hr post-operation (recovery time, 2, 4, 8, 12 and 24 hr after operation). Along with VAS, blood pressure (BP), heart rate (HR) and respiratory rate (RR) were monitored on the same occasions and recorded. Complications such as gastrointestinal bleeding or any other bleeding, respiratory distress, nausea, vomiting, pruritus, dizziness and renal functions were also checked during the first 24 hr after surgery. On day 1 post-operation, the time of initial usage of PCEA and required rescue doses of morphine sulphate were noted for each patient.

Primary outcome measures were VAS scores on post-operative evaluations. Secondary outcome measures were the time of initial usage of PCEA pump and cumulative morphine consumption during the first post-operative day.

Statistical analysis

The data were analysed by SPSS for Windows (version 22.0; SPSS, Chicago, IL, USA) software. A normal distribution of data was checked by the Kolmogorov-Smirnov test. Continuous variables were expressed as mean S.D., and categorical variables were reported as numbers (percentages). Student's unpaired t-test was used to compare normally distributed continuous variables (demographic and clinical data and morphine needed during 24 hr). Mann-WhitneyU-test was used for comparison of nonparametric data (VAS scores). Categorical variables (side effects) were compared by chi-square test or Fisher's exact test, as appropriate. Allpvalues <0.05 were considered significant.

With a two-sided type I error of 5% and study power at 80%, it was estimated that 34 patients would be needed in each group to detect a difference of 0.5 in mean VAS score between the Mg and C groups.

Results

General conditions

Eighty patients undergoing thoracotomy completed the study (39 patients in the Mg group and 41 patients in the C group), and no patient was withdrawn from the study. Patients were aged from 16 to 65 years, and 66.3% were male.

Patients in both the Mg and C groups were homogenous with reference to the age. There were no significant differences in terms of surgery type and duration of anaesthesia and surgery between the two groups (table1). Pre-operative VAS scores were less than 3 and did not differ between the two groups.

Table 1.Demographic and clinical characteristics of the participants

	Mg group	C group	pvalue
Age (year)	37.85 16.45	42.49 15.33	0.195
Sex (male)	31 (79.5%)	22 (53.7%)	0.019
Type of surgery
Lobectomy	22 (56.4%)	14 (34.1%)
Pneumonectomy	4 (10.3%)	10 (24.4%)	0.089
Decortication	13 (33.3%)	17 (41.5%)
Anaesthesia duration (min.)	230.77 53.82	248.05 81.34	0.268
Surgery duration (min.)	186.15 47.77	195.37 72.29	0.506

Post-operative pain

Patients in the Mg group showed significantly lower VAS score on post-operative evaluations compared with the C group. More precisely, VAS score in the Mg group differed significantly from the C group at recovery (3.90 1.89versus4.90 1.93;p< 0.05), 2 hr (3.41 1.12versus4.41 1.34;p< 0.01) and 4 hr (2.79 1.12versus3.68 1.39;p< 0.05) after surgery (fig.1). Patients in the Mg group disclosed significantly lower mean cumulative VAS scores throughout the first 24-hr post-thoracotomy period compared with the C group (2.59 0.84versus3.26 1.09;p< 0.01).