Intravenously Administered Lidocaine and Magnesium During Thyroid Surgery in Female Patients for Better Quality of Recovery After Anesthesia

Abstract

BACKGROUND: 

Although systemic lidocaine and magnesium have been widely studied as perioperative analgesic adjuvants, they have been rarely evaluated with respect to recovery quality under the same conditions. We compared the quality of recovery 40 (QoR-40) scores of female patients who received intravenous lidocaine, magnesium, and saline during thyroidectomy to investigate their effects on comprehensive recovery from anesthesia.

METHODS: 

In this prospective, double-blind trial, 135 female patients scheduled for open thyroidectomy were randomly assigned to the lidocaine group (group L), magnesium group (group M), or control group (group C). Immediately after induction, lidocaine (2 mg/kg for 15 minutes followed by 2 mg/kg/h) was administered in group L and magnesium sulfate (20 mg/kg over 15 minutes followed by 20 mg/kg/h) was administered in group M. Group C received an equivalent volume of saline. The QoR-40 survey was conducted on postoperative days 1 and 2.

RESULTS: 

The mean global QoR-40 scores on postoperative day 1 were 186.3 (standard deviation, 5.5) in group L, 184.3 (4.7) in group M, and 179.4 (17.8) in group C, and there was a significant difference only between group L and group C (mean difference, 6.9; adjusted P = .018). Among the 5 dimensions of QoR-40, emotional state, physical comfort, and pain were superior in group L compared to group C.

CONCLUSIONS: 

Lidocaine administered intravenously during anesthesia led to better quality of postoperative recovery measured by QoR-40 compared with the group C. Magnesium was found to be insufficient to induce any significant improvement with the dose used in the present study.

KEY POINTS

• Question: The effect of intraoperative lidocaine and magnesium on the quality of recovery is not known well.
• Findings: Patients who received lidocaine, not magnesium, were found to show significant differences in the global quality of recovery 40 scores on both postoperative days 1 and 2 compared with the control group.
• Meaning: Intraoperative systemic lidocaine enhanced postoperative functional recovery in female patients who underwent open thyroidectomy.

As more surgical procedures are performed in the outpatient setting and as fast discharge is preferred, facilitating patients’ return to their daily life is becoming increasingly important. Accordingly, anesthesiologists must consider possible methods to improve the speed and quality of comprehensive recovery. Well-controlled postoperative pain has traditionally been at the heart of this concept. Various efforts have been made to reduce opioid-related adverse effects and provide better pain control,¹ and systemic lidocaine or magnesium as an adjuvant to general anesthesia can be a reliable option. Both medications have analgesic properties as N-methyl-d-aspartate receptor antagonists, and previous studies have demonstrated that they can reduce opioid consumption and provide better analgesia with less concern for side effects compared with opiates.^2,3 Unlike regional analgesia, they can be easily administered intravenously, and thus, their use is not restricted to certain types of surgery.

The ultimate goal of postoperative pain control is to facilitate quick return to a functionally normal status,^4,5 and thus, reevaluation of these 2 drugs with respect to a comprehensive and patient-reported outcome is necessary. So far, both drugs have been rarely evaluated under same clinical conditions from this perspective, and therefore, whether both drugs result in improvement of recovery quality is not known. Accordingly, we aimed to evaluate the effects of systemic lidocaine and magnesium, respectively, on postoperative functional recovery by conducting the survey of quality of recovery 40 (QoR-40) in female patients undergoing thyroidectomy under anesthesia with desflurane and remifentanil.

METHODS

Subjects

This prospective, randomized, double-blind, clinical trial was approved by the institutional review board (number: 4-2013-0719) at Severance Hospital, Yonsei University Health System (Seoul, Republic of Korea), and was registered before patient enrollment at clinicaltrials.gov (NCT02018276; principal investigator: J.-R.L.; date of registration: December 23, 2013). Written informed consent was obtained from all patients participating in the trial. Female patients 20–65 years of age and American Society of Anesthesiologists physical status I or II scheduled to undergo open thyroidectomy under general anesthesia were enrolled between December 2013 and October 2014.

Patients who had been experiencing pain before surgery for any reason and those taking analgesics were excluded. Additional exclusion criteria were as follows: pregnancy or breast feeding; body mass index >30 kg/m²; significant heart, kidney, or liver disease; psychiatric or neurological disorders; and contraindications or hypersensitivity reactions to lidocaine or magnesium.

Intervention

On the morning of the surgery, patients were randomly allocated to one of the 3 groups with a 1:1:1 ratio: the lidocaine group (group L, n = 45), magnesium group (group M, n = 45), or control group (group C, n = 45) using a random number sequence downloaded from the Internet website (http://www.random.org). The assignments were placed in a sealed envelope, and the randomization was not blocked or stratified. One particular researcher (J.-R.L) prepared the study drugs and labeled them as “study drug” for double blind purposes. Immediately after intubation, lidocaine was administered at 2 mg/kg for 15 minutes, followed by 2 mg/kg/h infusions in group L. In group M, magnesium sulfate 20 mg/kg over 15 minutes and 20 mg/kg/h was administered. We administered lidocaine and magnesium based on doses used in previous studies.^6,7 The lidocaine and magnesium diluents were mixed to concentrations of 5 and 50 mg/mL, respectively. This was to ensure that all drugs were infused at a rate of 0.4 mL/kg for 15 minutes followed by 0.4 mL/kg/h thereafter. The saline administered to the patients in group C was infused at the same rate. The study drug was discontinued just before transfer to the postanesthetic care unit (PACU).

Anesthetic Management

The subjects did not receive any premedication. On arrival at the operating room, routine monitoring of electrocardiography and pulse oximetry was started, and noninvasive blood pressure measurements were performed every 5 minutes. Anesthesia was induced by a bolus administration of propofol (1–2 mg/kg) and remifentanil (1–2 μg/kg). Rocuronium (0.6 mg/kg) was injected only once to facilitate tracheal intubation, which was performed using a 6.5-mm (internal diameter) tracheal tube, and the cuff pressure was adjusted to 20–25 cm H₂O with a manometer. Mechanical ventilation was maintained with a tidal volume of 8 mL/kg, and ventilatory frequency was adjusted to maintain an end-tidal carbon dioxide concentration of 35–40 mm Hg with an air/oxygen mixture (fraction of inspired oxygen, 0.5). Midesophageal temperature was maintained at 36°C–37°C. Anesthesia was conducted with 4%–7% desflurane with adjuvant intravenous infusion of remifentanil (0.05–0.1 μg/kg/min) to maintain the bispectral index within a range of 40–60 and the mean arterial pressure within 20% of preinduction values.

About 30 minutes before the end of surgery, 2 g of propacetamol was administered over 10 minutes, and 0.3 mg of ramosetron was injected 15 minutes before the end of surgery. All anesthetics were discontinued at surgery completion, and 1 mg of neostigmine with 0.2 mg of glycopyrrolate was administered to reverse possible residual neuromuscular blocking. The tracheal tube was removed when the patients regained their consciousness and were able to breathe spontaneously. The patients were then transferred to the PACU.

In the PACU, severity of pain was measured with an 11-point numeric rating scale (NRS, 0–10) at regular time intervals. Fentanyl (50 μg) was administered if a patient complained of pain of NRS >3. The patients were discharged from the PACU and moved to the ward after at least a 30-minute stay and when the Aldrete score was ≥9.⁸

Outcomes Assessment

The primary end point of the present study was the global QoR-40 score on postoperative day 1 (POD1). One particular researcher (M.H.K) who was unaware of the group assignments visited each patient to administer the QoR-40 survey on the day before surgery, on POD1, and on postoperative day 2 (POD2), between 6 and 8 pm. The QoR-40 is composed of 40 questions (items) categorized as 5 quality of recovery dimensions including physical comfort (12 items), emotional state (9 items), physical independence (5 items), psychological support (7 items), and pain (7 items). Each item is graded on a 5-point Likert scale, and the total sum of scores ranges from 40 (extremely poor quality of recovery) to 200 (excellent quality of recovery). The QoR-40 survey has been widely used and validated for patients undergoing a variety of surgical procedures.^9–11 The scoring system was explained in detail to all subjects. The survey was completed by the patients in person in the presence of a researcher and was reviewed to ensure that all questions were answered.

Among the vital signs recorded during the anesthetic period, heart rate, peripheral oxygen saturation, and mean arterial pressure at 3 measured time points (before induction [T1], the moment of response to the verbal command [T2], and the moment of extubation [T3]) were chosen for analysis. The average intraoperative end-tidal desflurane concentration and total remifentanil consumption divided by patient’s weight and anesthetic time were also analyzed and compared. The response time (from discontinuation of desflurane to restoration of consciousness) and extubation time (from discontinuation of desflurane to extubation) were also recorded.

During the stay in the PACU, the NRS pain scale and sedation scores (5-point scale) at the time of arrival to and discharge from the PACU were analyzed.¹² The 5-point sedation scale was as follows: 1, patient perfectly conscious; 2, patient felt a little drowsy; 3, patient seemed to be sleeping but immediately reacted to verbal stimulation; 4, patient seemed to be sleeping but slowly reacted to verbal stimulation; and 5, patient seemed to be sleeping and did not react to verbal stimulation but did react to a stimulus such as shaking or pain. Other symptoms and any drugs administered in the PACU as well as the duration of stay in the PACU were recorded.

Throughout the study period, we meticulously monitored and recorded any symptoms or signs of possible adverse effects of lidocaine or magnesium, such as electrocardiography changes during anesthesia, prolonged neuromuscular paralysis, delayed awakening after anesthesia, prolonged sedation in the PACU, metallic taste, abrupt change of consciousness, or seizure-like movement in the PACU.

Statistical Analysis and Sample Size

All continuous variables are presented as mean (standard deviation) or median (range), and nominal factors are presented as number (proportion, %). All tests were 2-tailed and were conducted at a 5% level of significance. After performing Kolmogorov–Smirnov tests to determine normal distribution, intergroup comparisons of continuous variables among 3 groups were conducted using 1-way analysis of variance or Kruskal-Wallis tests. Nominal variables were compared using χ² and Fisher exact tests. If there were significant differences among the 3 groups, post hoc multiple comparisons were performed. All P values after post hoc multiple comparisons were corrected by Bonferroni method and were expressed as “adjusted P.” SPSS software version 23.0 (IBM Corp, Armonk, NY) was used for all statistical tests, and P < .05 was considered statistically significant.

According to previously reported values of the mean and range of the QoR-40 scores in patients after anesthesia and surgery, an average difference in the global QoR-40 score of 10 or more was considered clinically relevant improvement in recovery quality.¹³ On this basis, we assumed that the global QoR-40 in the group L or M on POD1 would be 10 points higher than in the group C. The estimated sample size was 37 patients per group with a standard deviation of 13 and a power of 90% at an α level of .05. In addition, this sample size per group is required to detect a 10-point difference after Bonferroni correction with 80% power. The final study sample size was set at 45 patients per group (135 in total), allowing for a 20% drop-out rate.

RESULTS

Among 136 patients scheduled to undergo open thyroidectomy, 135 patients who provided consent were enrolled. Among them, 10 patients were excluded because the surgical plan was changed, and 7 patients refused to follow-up with the QoR-40 survey after surgery. The final analysis consisted of 118 patients (group L, n = 40; group M, n = 41; group C, n = 37) whose characteristics are shown in Table 1. There were no clinically important differences at baseline data.

Table 1.: Patients’ Characteristics

The distribution of pre- and postoperative global QoR-40 scores and subscores of each dimension are shown in Figure. The differences in QoR-40 scores between groups are presented in Table 2. Only group L was found to show significant differences in the global QoR-40 scores on both POD1 and POD2 compared with group C. The scores of group M did not meet statistical significance compared with either group C or group L.

Table 2.: Differences of QoR-40 Scores Between Groups

Figure.: The global QoR-40 scores and the subscores of 5 dimensions. Data are presented as mean (SEM). *Adjusted P < .05 different from the group C on POD1 and POD2; **adjusted P < .05 different from the group C on POD1; and ***adjusted P < .05 different from the other groups on POD2. Group C indicates control group; group L, lidocaine group; group M, magnesium group; POD1, postoperative day 1; POD2, postoperative day 2; QoR-40, quality of recovery 40; SEM, standard error of mean.

The characteristics of change in global QoR-40 scores on POD1 compared with the preoperative score were remarkable (Table 3). The patients in group L (−0.63, adjusted P < .001) and group M (−1.49, adjusted P < .001) showed a significantly lesser decline in QoR-40 score compared to the group C on POD1 (−7.68).

Table 3.: Characteristics of the Change in Global QoR-40 Scores Before and After Surgery

The other perioperative parameters are described in Table 4. The intraoperative average end-tidal desflurane concentration was significantly lower in groups L and M compared with group C (adjusted P < .001). Group L had the lowest remifentanil consumption compared to group M (adjusted P = .017) and group C (adjusted P < .001). The response and extubation times were slightly prolonged in group L compared with groups M and C.

Table 4.: Perioperative Parameters

The recovery profiles in PACU are shown in Table 5. Though the patients in groups L and M were more deeply sedated at the moment of arrival at the PACU, consciousness levels were comparable among the groups at PACU discharge. Pain intensity during the PACU stay was significantly lower in groups L and M compared to group C (both adjusted P < .001). However, these differences did not result in more analgesics consumption in the group C nor prolonged PACU stay in the treatment groups.

Table 5.: Postoperative Recovery Profiles in PACU

No symptoms or signs of lidocaine or magnesium toxicity were observed in any of the participants.

DISCUSSION

We evaluated and compared the effects of intravenously administered lidocaine and magnesium during surgery on postoperative functional recovery by means of the QoR-40 survey. Our results demonstrate that the differences in QoR-40 scores between patients who received systemic lidocaine and saline were above the minimal clinically important difference at both POD1 and POD2. The difference in QoR-40 scores between group M and group C did not meet statistical significance nor minimal clinically important difference.

When the global QoR-40 was first established and verified for clinical utility, the developers supposed that a 10-point difference or more represents clinically relevant improvement in quality of recovery.¹³ Recently, Myles et al¹⁴ reported that a change of 6.3 in the global QoR-40 can signify a clinically important improvement or deterioration. In the present study, mean QoR-40 scores in group L and group M were 6.9 and 4.9 higher than in group C at POD1, and 6 and 4.3 higher at POD2. Because the differences in QoR-40 scores between patients who received systemic lidocaine and those who received saline were greater than the minimal clinically important difference, the improvement in QoR-40 scores in group L compared to group C can be considered as not only statistically but also clinically significant. In addition, the mean decline of QoR-40 scores of group C after surgery was significantly inferior compared to group L. Therefore, our results indicate that intravenous lidocaine leads to significantly better quality of recovery by preventing physiologic deterioration related to anesthesia and surgery.

Meanwhile, the clinical significance of magnesium is somewhat less clear. The difference of QoR-40 between group M and group C was not statistically significant and was inferior to minimal clinically important difference. However, the decline of QoR-40 after surgery was much less in the patients who received magnesium infusion. Therefore, the effect of systemic magnesium seems to be present but not as effective as lidocaine.

Additional statistical analysis of each dimension of QoR-40 raises the probability of risk of false positives. However, most studies of QoR-40 have accompanied analysis of each dimension of QoR-40 as evaluating which recovery component gets better or worse by treatment offers valuable information. In fact, the patients who received lidocaine had higher scores not only for the dimension of pain but also in the dimensions of emotional state and physical comfort on POD1 and POD2, and physical independence on POD2 in our study. From these findings, we can demonstrate that better recovery quality would be accompanied by other components besides well-conducted analgesia. Lidocaine is known to induce fast return of bowel function and reduce nausea/vomiting.^6,15,16 These kinds of nonanalgesic beneficial effects can contribute to better postoperative recovery, both physically and emotionally.

Our sample size calculation was based on >10 points of score difference and therefore would be not be enough to prove the possible difference between lidocaine and magnesium. However, the mean differences in QoR-40 between group L and group M were just 2 at POD1 and 1.7 at POD2, and the difference of score must be greater than minimal clinically important difference, 6.3, for clinical usefulness. Whether enrolling a larger number of patients to detect a “statistically” significant difference between groups would be worthwhile is unclear.

We administered commonly used doses of lidocaine and magnesium based on previous studies and as per our emphasis on safety over efficacy.^6,7 With regard to magnesium, reported bolus doses range widely from 30 to 50 mg/kg, and the infusion dose ranges from 6 to 25 mg/kg/h. There was no correlation between the magnesium administered over the first 24 hours postoperatively and cumulative intravenous morphine consumption at 24 hours postoperatively.⁷ Therefore, we could not anticipate that the QoR-40 score would be higher if we used a higher dose of magnesium. In addition, regarding the dimension of pain in QoR-40, both lidocaine and magnesium showed significantly higher scores than the group C, and there was no difference between lidocaine and magnesium. Consequently, lidocaine and magnesium can be accounted as almost equipotent in terms of analgesia. Therefore, as already mentioned, the less significant results of QoR-40 scores in group M might be from the differences of other prospects beside analgesia.

This study was conducted in relatively healthy females undergoing thyroid surgery. There is a sex-specific difference in QoR-40 scores; in male patients, the preoperative and POD1 QoR-40 scores were 199 and 190, respectively; in female patients, the preoperative score was 197, which dropped to 180 at POD1.¹⁷ This sex difference is bigger than the difference that we postulated between the groups in this study. In addition, we also chose to include only thyroid operations because the QoR-40 scores may vary according to the invasiveness of surgery.¹⁴ Such study conditions may limit the applicability of our findings. However, we intended to investigate the effect of lidocaine and magnesium. Hence, it was important to exclude the influence of confounding factors. Future studies are required to evaluate the efficacy of systemic lidocaine for more serious patients undergoing an invasive surgery with physiologic deterioration.

In conclusion, intraoperative systemic lidocaine enhanced postoperative functional recovery in female patients who underwent open thyroidectomy.

ACKNOWLEDGMENTS

We greatly thank the Biostatistics Collaboration Unit at Yonsei University College of Medicine for their contribution to this study.

DISCLOSURES

Name: Myoung Hwa Kim, MD, PhD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

Name: Min Soo Kim, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Name: Jae Hoon Lee, MD, PhD.

Contribution: This author helped analyze the data and write the manuscript.

Name: Sang Tae Kim, MD, PhD.

Contribution: This author helped write the manuscript.

Name: Jeong-Rim Lee, MD, PhD.

Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.