Lidocaine combined with magnesium sulfate preserved hemodynamic stability during general anesthesia without prolonging neuromuscular blockade: a randomized, double-blind, controlled trial

Background Lidocaine and magnesium sulfate have become increasingly utilized in general anesthesia. The present study evaluated the effects of these drugs, isolated or combined, on hemodynamic parameters as well as on the cisatracurium-induced neuromuscular blockade (NMB). Methods At a university hospital, 64 patients, ASA physical status I and II, undergoing elective surgery with similar pain stimuli were randomly assigned to four groups. Patients received a bolus of lidocaine and magnesium sulfate before the tracheal intubation and a continuous infusion during the operation as follows: 3 mg.kg− 1 and 3 mg.kg− 1.h− 1 (lidocaine - L group), 40 mg.kg− 1 and 20 mg.kg− 1.h− 1 (magnesium - M group), equal doses of both drugs (magnesium plus lidocaine - ML group), and an equivalent volume of isotonic solution (control - C group). Hemodynamic parameters and neuromuscular blockade features were continuously monitored until spontaneous recovery of the train of four (TOF) ratio (TOFR > 0.9). Results The magnesium sulfate significantly prolonged all NMB recovery features, without changing the speed of onset of cisatracurium. The addition of lidocaine to Magnesium Sulfate did not influence the cisatracurium neuromuscular blockade. A similar finding was observed when this drug was used alone, with a significantly smaller fluctuation of mean arterial pressure (MAP) and heart rate (HR) measures during anesthesia induction and maintenance. Interestingly, the percentage of patients who achieved a TOFR of 90% without reaching T1–95% was higher in the M and ML groups. Than in the C and L groups. There were no adverse events reported in this study. Conclusion Intravenous lidocaine plays a significant role in the hemodynamic stability of patients under general anesthesia without exerting any additional impact on the NMB, even combined with magnesium sulfate. Aside from prolonging all NMB recovery characteristics without altering the onset speed, magnesium sulfate enhances the TOF recovery rate without T1 recovery. Our findings may aid clinical decisions involving the use of these drugs by encouraging their association in multimodal anesthesia or other therapeutic purposes. Trial registration NCT02483611 (registration date: 06-29-2015). Supplementary Information The online version contains supplementary material available at 10.1186/s12871-021-01311-y.


Introduction
The aim of this project is to evaluate in a single-center randomized clinical trial (RCT) whether the use of additional lidocaine could influence the NMB enhancement. Thus, this study's primary endpoint is the time at which spontaneous recovery of a train-of-four (TOF) ratio of 90% will be achieved (complete duration). The secondary endpoints are other NMB characteristics (onset time, duration 25, duration 95) and hemodynamic parameters.
This statistical analysis plan (SAP) will give more detailed descriptions of the endpoints in the study and the corresponding analyses.

Study design
Sixty-four patients [American Society of Anesthesiologists (ASA) physical status I to II, aged 18 to 60 years] who will be scheduled for surgery (estimated surgical time greater than 90 min, with similar pain stimulus and no need for a continuous neuromuscular block during the surgical procedure) will be recruited. The exclusion criteria are patients with diseases or on medications known to interfere with neuromuscular transmission, hepatic or renal dysfunction, electrolyte abnormalities that can potentiate blockade, an allergy to the drugs used in the study, a body mass index <18 or >29 kg.m-2, and those who are expected to have difficulties during mask ventilation or intubation, pregnant or breastfeeding.
The patients will be randomly and equally allocated into four groups (figure 1). The Computer-generated randomization will be stratified by gender to pursue equal distribution of intervention and control group for both male and female subjects, and the allocation concealed with sequentially numbered, sealed, opaque envelopes. The envelope's seal will be broken before the induction of general anesthesia by trained study personnel not involved in the data collection. Throughout the perioperative period, care providers, patients, and research team members will be blinded to the group assignments. Having chosen a significance level of 5% and a power of 80%, we applied Satterthwaite's approximation (Stat Med 2001, 20 (7):1089-1095). The result revealed N=14 patients per group, and we decided to randomized 16 patients in each group to allow for drop-outs.

Aims and objectives
To investigate the effects of lidocaine associated with magnesium sulfate on the neuromuscular blockade promoted by cisatracurium and evaluate its possible hemodynamic repercussions.

Outcomes
This section will present the outcomes investigated to answer the study aims and objectives. The analyses are described in section 6-Analyses.

Primary outcome
Complete duration (T4/T1=90%): elapsed time for the TOF (T4/T1) recovery response to 90% of the original value after infusion of cisatracurium. This outcome measure will be presented in minutes.

Secondary outcomes
Other pharmacodynamic measures: 1. Latency (Onset time 5): elapsed time to reduce the response of T1 to 5% of the initial contraction force after the infusion of cisatracurium.

Mean Arterial Pressure (MAP) and Heart Rate (HR) during the Induction Period
These measures will be obtained at the following time points: (1) when the patient arrived in the operating room, (2) immediately before induction, (3) immediately before infusion of the solutions, (4) immediately after infusion of the drugs, (5) immediately before tracheal intubation, and (6) one minute after the tracheal intubation.

Mean Arterial Pressure (MAP) and Heart Rate (HR) during the Maintenance Period
These measures will be obtained every 15 min until complete neuromuscular recovery.

Adverse events
Any adverse events will be documented.

Populations
All randomized study subjects. This will be seen as the primary population for the analysis.

Subgroups
Not applicable

Analyses
All outcomes will be presented using descriptive statistics, normally distributed data by the mean and standard deviation (SD), and skewed distributions by the median and interquartile range (IQR). The Shapiro-Wilk test will be used to assess normality. The pharmacodynamic variables, clinical and demographic characteristics will be compared between the groups via the Kruskal-Wallis test, followed by Dunn's multiple comparison test or one-way ANOVA followed by the Tukey multiple comparison test, or the chi-square test, where appropriate. The area under the curve (AUC) will compare the study groups' hemodynamic responses. A p-value <0.05 will be considered statistically significant for all outcome variables. GraphPrisma version 8.3 will be used for all statistical analyses.
The subsections below will describe analyses in addition to the descriptive statistics. 7 6.1 Primary outcome The primary analysis will compare intervention groups on their mean change in NMB. The difference in time course to TOF=90% will be the dependent variable. Study subjects will be considered as random effects and treatment groups as fixed effects. The estimated difference in mean change from baseline and the corresponding 95 % confidence interval (CI) will be presented.

Secondary outcomes
Other characteristics of NMB and Hemodynamic changes will be analyzed using the same method as for the primary outcome, including usage of the baseline value for the actual factor as a covariate.

Missing data
Not applicable.