Effect of ketamine combined with lidocaine in pediatric anesthesia

Abstract Background We conducted a randomized clinical trial to determine whether adjunctive lidocaine diminishes the incidence of adverse effects in pediatric patients sedated with ketamine. Methods This case‐control study involved 586 consecutive pediatric patients necessitating anesthesia. Then systolic blood pressure, heart rate, respiratory rate, and blood oxygen saturation were observed. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen (BUN), and creatinine (Cr) levels were tested. General dose of ketamine, the time of onset and duration of anesthesia and postoperative recovery, anesthesia effect, and adverse reaction were subsequently compared. High‐performance liquid chromatography was employed to detect ketamine concentration at different time points after administration, and the postoperative cognition function was further evaluated. Results Intra‐ and post‐operation, the rising degree of ALT, AST, BUN, and Cr in patients treated with ketamine was higher than those in patients treated with the ketamine‐lidocaine complex. General dose of ketamine, the time of onset and duration of anesthesia, postoperative recovery time, and the incidence rate of adverse reaction in patients treated with ketamine‐lidocaine complex were lower, but the concentration of ketamine was higher compared to the patients treated with ketamine. In patients treated with the ketamine‐lidocaine complex, elimination half‐life of ketamine was prolonged, the area under curve was increased, and the plasma clearance rate was decreased relative to those with ketamine alone. Conclusions Ketamine combined with lidocaine may be beneficial in shortening the onset of anesthesia, promoting postoperative awake, prolonging elimination half‐life, increasing area under curve, and decreasing plasma clearance rate and incidence of adverse reactions.


| INTRODUC TI ON
Adequate pain control plays an important role in patients undergoing operation and painful procedures, which is particularly essential for pediatric patients undergoing operation. During operation process, inadequate pain control may lead to incomplete procedure and adverse complications. 1 To facilitate a higher success rate, a majority of procedures are performed under anesthetic effect, especially for uncooperative circumstances among children. 2,3 Therefore, administering an appropriate degree of anesthesia to cope with the procedural demands remains a challenge for the anesthesiologist. Recently, administering a combination of two or more agents has become a readily adopted solution to meet the procedural requirements. 4 Ketamine is acknowledged among the oldest hypnotic agents for anesthesia due to its analgesic properties and minimal suppressive effects on respiration. 5 Based on its effective bronchodilating respiratory properties and stable hemodynamics, ketamine use has been reported in patients with brain injury, resulting in increased clinical use. 6 Moreover, the administration of ketamine as an anesthetic has branched for extraperitoneal procedures, cardiac catheterization, orthopedics, and skin grafting, as well as otolaryngology and optical procedures. 7 Lidocaine, firstly synthesized by the Swedish chemist Lofgren, has been used extensively, such as for pain management, clinical anesthesia, nervous system diseases, arrhythmia, treatment of respiratory diseases, and gastrointestinal diseases. 8 The administration of a high concentration of lidocaine led to the illustration of adverse reactions such as skeletal muscle twitching, slurred speech, and drowsiness. 9 As an amide local anesthetic, the analgesic, prokinetic, and antiarrhythmic properties of lidocaine are evident upon systemic administration in humans. 10  Hence, we hypothesized that a combination of lidocaine and ketamine would produce a clinically relevant decrease in the adverse effects in pediatric patients.

| Ethics statement
The present study was conducted under the approval of the medical ethics committee of the Guizhou Provincial People's Hospital and Guizhou University People's Hospital. The participants and patient guardians included in the current study signed written informed consents.

| Study subjects
The study recruited children (n = 586) who were operated upon in

| Anesthesia methods
All pediatric patients were fasted for 6 hours and prohibited to

| Observation of indices
Changes of systolic blood pressure (SBP), heart rate (HR), respiratory rate (RR) and blood oxygen saturation (SpO 2 ) pre-anesthesia, intra-and post-operation were observed using a multifunctional

| Anesthetic effect criteria
Through the course of the operation, no body movement was judged as excellent anesthetic effect; body movement having no influence on the operative procedure and no need for further anesthetic administration was assessed as good anesthetic effect; strong body movement interfering with the operation so as to increase the anesthetic dose was regarded as poor anesthetic effect.

| Drug concentration monitoring and measurement
With drug induced pre-anesthesia as a baseline, venous blood was collected for the patients prior to drug administration. Next, repeated venous blood collection was conducted for the pediatric patients after administration at 5, 15, 30, 60, 120, 240, and 480 minutes, respectively. The venous blood was allowed to stand for 30 minutes, and then centrifuged at 1610 g for 10 minutes, after which the serum was collected. High-performance liquid chromatography (HPLC; Spectra-Physics Analytical) was used to measure the ratio of ketamine/internal standard peak height, in which the detection wavelength was set at 215 nm, the injection volume was 60 μL at 1 mL/min, and the mobile phase was the mixture of acetonitrile, methanol, and monometallic sodium orthophosphate at a ratio of 32:51: 16. Standard curve Y = 1.0862X − 0.0072 was employed to calculate the value with ketamine/internal standard peak height ratio as Y-axis and ketamine concentration as X-axis; and the correlation coefficient "r" was .9995; the lowest limit of detection was 10 ng/L; and the recovery rates were 96% (0.5 g/ mL, n = 2) and 92.3% (0.2 g/mL, n = 2). According to the changes of ketamine concentration, two groups of compartment models were fitted to two-compartment model (Model 7) with the Winnolin software, and pharmacokinetic parameters were detected using a computer, and further assessed by the combination with Akaike information criterion.

| Maze and decoding test
In the experiment, the pediatric patients were treated with maze and decoding test before and after the operation for evaluating cognition function. At first, a demonstration on a sample paper with a pencil was given to patients as an illustration; next, the patients were facilitated to depict the maze path on the test paper, followed by calculation of the correct numbers of the maze in quantitative time, which served as the value of maze. The patients underwent observation of a set of simple graphs and symbols (each graph had its symbol) and were asked to draw the corresponding symbol in response to the given graph. Right answer was credited as one score to the patient. The correct numbers of graphic matching by pediatric patients within 2 minutes were defined as the decoding value.

| Statistical analysis
All statistical data analyses were conducted using the SPSS 20.0 software (IBM Corp.). The measurement data were expressed as mean ± standard deviations. Initially, normal distribution and homogeneity of variance were tested for all the data. If data conformed to normal distribution and homogeneity of variance, comparison between groups was analyzed by unpaired t test, data in different group were analyzed by one-way analysis of variance (ANOVA), and pairwise comparisons were conducted using Tukey's post hoc test. The data with skew distribution or unequal variances were compared by the rank sum test. Categorical data were measured using a Chi-square test, and rank data were compared with rank sum test. A value of P < .05 indicated statistical significance.
As for one-way ANOVA, the power observed was determined to be 80.53%, and for repeated measurement ANOVA, the power was determined to be 90.75%. This was based on the effect value of 0.8165 obtained by calculating the concentration of ketamine in serum at 5 minutes (peak value) and 240 minutes after administration. Power calculation was analyzed using the G* Power Software.

| Baseline characteristics of patients
The observation group was comprised of 170 pediatric patients with hernia repair, 71 with cleft lip and palate repair, and 52 with appendectomy; 237 males and 56 females, aged between 1 and 12 years (mean age of 6.91 ± 2.23 years) and weighing 8.

| Pediatric patients receiving intravenous injections of ketamine/lidocaine combination show stable vital signs during operation
As shown in Table 2

Note:
The statistical values of the data obeying the normal distribution between the observation group and the control group were >0.05.
*Compared with pre-anesthesia, P < .05. and Cr in the control group was higher than those in the observation group without any statistical differences (all P > .05) ( Table 3).

| Ketamine/lidocaine combination reduces recovery agitation in pediatric patients
As shown in Table 4, a general dose of ketamine in the observation group was lower than that in the control group; the time of onset and duration of anesthesia, and postoperative recovery time were shorter in the observation group compared with the control group (all P < .05).

| Ketamine/lidocaine combination reduces the incidence of adverse reactions
As shown in Table 5, the excellent rate of anesthesia in the observation group was higher than the rate in the control group (P < .05). The incidence rate of various adverse reactions like nausea and vomiting, suctioning, shiver, dysphoria, and lethargy of anesthesia was lower in the observation group compared with the control group, with a lower number of overall adverse reactions in the observation group than the control group (all P < .05).  Table 6, compared with the control group, the elimination half-life of ketamine in the observation group was prolonged, the AUC was increased, and the plasma clearance rate was decreased (all P < .05).

| Ketamine/lidocaine combination favors postoperative cognition function
The scores of maze and decoding test among the observation and control groups are shown in Table 7, which exhibited no significant differences between the two groups before administration (both P > .05). In the observation group, the scores of maze and decoding TA B L E 3 ALT, AST, BUN, and Cr levels when ketamine is administered alone or with lidocaine at pre-anesthesia, intra-operation, and post-operation test post-operation were lower than that during pre-anesthesia, with no significant differences (both P > .05); however, those in the control group were decreased compared with the same pre-anesthesia (both P < .05). The scores in the observation group were higher than the scores observed in the control group (both P < .05).

| D ISCUSS I ON
Surgical care of all patients relies on proper anesthesia. 15 Anesthetic exposure may work as a specific marker of ascended risk, 16 irrespective of risk association with patient characteristics. 2 Principally in young children, the administration of general anesthesia should be performed if it emerges as a necessity and the general anesthesia duration should be as shorter as well. 16 With an effort to improve the current anesthetic practice, this study was performed to explore the efficacy and safety of ketamine use combined with lidocaine on pediatric anesthesia.
Ketamine has been extensively used in the emergency department for various emergencies including conscious sedation and rapid sequence induction. 17 Ketamine inhibits morphine metabolism to increase the duration of analgesia, thereby exercising its intrinsic anti-inflammatory effects. 18 In our study, the findings exhibited the combination of ketamine and lidocaine to be more effective and safer for pediatric anesthesia, which was evidenced by more stable vital signs (reduced SBP, HR, and RR) of pediatric patients in response to the combination treatment with ketamine and lidocaine than ketamine treatment alone. It has been suggested that IV lidocaine could po- can make the hemodynamics more stable during operation. 11,33,34 Additionally, the incidence rate of adverse reactions after anesthesia in the observation group was lower than the rate in the con- thus preventing a wide array of side effects. 37 Besides, decreased general anesthesia can induce adverse laryngeal effects after operation, such as hoarseness and vocal cord injuries. 38 After intravenous injection, lidocaine could not only reduce the adverse effects such as the increase of BP, HR, and myocardial oxygen consumption caused by the increase of catecholamine level induced by ketamine, but also diminish the increase of intracranial pressure and brain oxygen consumption induced by ketamine, thus effectively protect the brain tissue. 11,33,34 In conclusion, the gathered evidence in our study provided information supporting the use of the combination of ketamine and lidocaine contributed to more stable vital signs, shorter onset and recovery time, prolonged elimination half-life, increased area under curve, decreased plasma clearance rate, and less general dosage and adverse reactions. In this study, however, only two kinds of regimens were administered: ketamine and ketamine combined with lidocaine.
Further studies are warranted in the future to determine the efficacy of multiple anesthetic agents such as morphine or fentanyl in comparison.

ACK N OWLED G M ENT
We would like to acknowledge the helpful comments on this paper received from our reviewers.