Comparison of the effect of lignocaine instilled through the endotracheal tube and intravenous lignocaine on the extubation response in patients undergoing craniotomy with skull pins: A randomized double blind clinical trial.

BACKGROUND: A desirable combination of smooth extubation and an awake patient after neurosurgical procedures is difficult to achieve in patients with skull pins. Lignocaine instilled into endotracheal tube has been reported to suppress cough by a local mucosal anesthetizing effect. We aimed to evaluate if this effect will last till extubation, if given before pin removal.
MATERIALS AND METHODS: A total of 114 patients undergoing elective craniotomy were divided into three groups and were given 1 mg/kg of intravenous (IV), 2% lignocaine (Group 1), placebo (Group 2) and 1 mg/kg of 2% lignocaine sprayed down the endotracheal tube (Group 3) before skull pin removal. The effectiveness of each to blunt extubation response was compared. Plasma levels of lignocaine were measured 10 min after administration of the study drug and at extubation. Sedation scores were noted, immediately after extubation and 10 min later.
RESULTS: Two percent of lignocaine instilled through endotracheal route was not superior to the IV route or placebo in attenuating cough or hemodynamic response at extubation when given 20-30 min before extubation. The plasma levels of lignocaine (0.8 μg/ml) were not high enough even at the end of 10 min to have a suppressive effect on cough if given IV or intratracheally (IT). Lignocaine did not delay awakening in these groups.
CONCLUSION: IT lignocaine in the dose of 1 mg/kg does not prevent cough at extubation if given 20-30 min before extubation. If the action is by a local mucosal anesthetizing effect, it does not last for 20-30 min to cover the period from pin removal to extubation.

RCT Entities:   Population Interventions Outcomes

Introduction

Avoidance of coughing during skull pin removal and during extubation is a desired prerequisite of every neurosurgical anesthetic. Lignocaine has long been used to modulate unwanted airway and circulatory reflexes,[1] via intravenous (IV) injection[23] endotracheal cuff inflation,[45] intratracheal (IT) instillation,[67] tube lubrication,[8] and aerosolized form.[9] However, IVlignocaine is short acting.[5] It is unknown whether cough suppression from tracheal instillation of lignocaine acts by a local mucosal anesthetizing effect or by systemic absorption producing a deeper plane of general anesthesia.[1] If local, its action on airway reflexes should last longer time than an IV injection, covering the period from pin removal to extubation. So we studied the effect of IT lignocaine in a dose of 1 mg/kg given before pin removal on cough and extubation response in neurosurgical patients, and compared this with IV and placebo groups.

Materials and Methods

After obtaining approval from the Institutional Ethics Committee and Institutional Review Board, 114 neurosurgical patients were included in this study. Written informed consent was obtained from all patients, who were American Society of Anesthesiologist (ASA) grade class I or II, between 18 years and 65 years of age, and who were to undergo elective craniotomies for supratentorial tumors <5 cm, either in the supine or lateral position with pre-operative glasgow coma scaleof 15/15.

Patients were excluded from the study, if they had sore throat or active Upper Respiratory Infection (URI), history of laryngeal or tracheal pathology/surgery, history of asthma or Chronic Obstructive Pulmonary Disease (COPD), known allergy to local anesthetic, on beta blocker therapy or if vascular tumors, infratentorial tumors and tumors of size >5 cm or if post-operative ventilation was planned. The patients were randomly allocated into one of thethree groups by block randomization using computer assignment. The prepared drugs were dispensed in similar looking vials, coded by the hospital pharmacy and the nature of the drug was concealed by the pharmacy. The dose of drug was prepared as 1 mg/kg of a 2% solution Allocation of the drug was done such that the patients in

Group 1: Received IV lignocaine and IT placebo

Group 2: Received IV and IT placebo (control group)

Group 3: ReceivedIT lignocaine and IV placebo

The lignocaine used for the study was manufactured by Astra Zeneca Pharma, Bangalore India. The administration of the drug and the assessment at extubation were done by the 1st or the 2nd author in all cases. After the data collection for the entire study was completed, the code was broken and analysis was done.

Patients were pre-medicated with oral Diazepam 0.15 mg/kg an hour prior to the surgery. In the operating room, monitoring included electrocardiogram, pulse oximetry, direct intra-arterial blood pressure, nasopharyngeal temperature, capnography, inhalational agent concentration and neuromuscular monitoring. All patients had central venous cannulation via the brachial vein. Lignocaine was used for IV and arterial cannulation only, not exceeding 40 mg.

Anesthesia was administered using a standard protocol in all patients. Induction of anesthesia was using Propofol 2 mg/kg without lignocaine through the central venous cannula, Fentanyl 1-2μg/kg, along with oxygen/air/isoflurane at one Minimum Alveolar Concentration (MAC), and muscle relaxation was achieved with vecuronium 0.15 mg/kg. At the time of pin insertion, propofol was given at a dose of 1 mg/kg to attenuate the haemodynamic response to pinning. The scalp was infiltrated using saline and adrenaline at 5μg/ml avoiding lignocaine. Fentanyl was given upto 5μg/kg intra operatively in increments of 1 μg/kg, the last dose given at dural closure. Vecuronium infusion was started at a dose of 60 μg/kg/min before skin incision titrated to two twitches on the neuromuscular monitor, and stopped at the start of skin sutures. Paracetamol was given intravenously at a dose of 20 mg/kg early in the course of surgery. Forced-air warming was used to maintain a central body temperature around 36°.

Isoflurane was given at one MAC using an agent analyzer. At dural closure, isoflurane was discontinued and sevoflurane introduced to maintain oneMAC. Gas flows were increased temporarily to wash out isoflurane and build up sevoflurane concentration; this was continued until removal of pins. The study drug was given at the time of wound dressing both via the endotracheal tube and intravenously using a dose of 1 mg/kg. After stopping sevoflurane, gas flows were increased to 6 l/min.

After the removal of pins and pharyngeal suctioning, residual muscle paralysis was reversed using neostigmine (0.05 mg/kg) and glycopyrrolate (0.02 mg/kg). Extubation was planned at eye opening to command; when purposeful movements were observed; or if the patient coughed, provided regular respiration was established. During this time the patient was not disturbed, other than by repeated verbal request (“open your eyes”). All other kinds of stimulation were strictly avoided at emergence.

The tolerance to endotracheal tube at this time was noted by the number of coughs and smoothness of extubation, graded as follows as suggested by Venkatesan and Korula.[5]

Grade 1: No cough or mild cough only during removal of endotracheal tube

Grade 2: Coughing while breathing regularly

Grade 3: Coughing before regular breathing is established

Coughing and hemodynamic parameters at the time of extubation and the total time taken for extubation were noted in all cases, starting from the time sevoflurane was discontinued. Blood pressure and heart rate readings were recorded, at baseline, before giving the study drug and every min for a period of 5 min after extubation.

The level of sedation of the patient was noted, both immediately after extubation and 10 min later. The following sedation score, as described by Berkenbosch and Tobias,[10] was used.

0- Patient awake

1- Mild (occasionally drowsy)

2- Moderate (frequently drowsy)

3- Severe (difficult to arouse)

Blood samples were taken to check the plasma levels of lignocaine, 10 min after the drug administration and at the time of extubation. Blood was centrifuged and the separated plasma stored at -80°C, following which plasma levels of lignocaine were assessed using high performance liquid chromatography assay.

Statistical analysis

All statistical analyses were performed using Statistical Package for Social Sciences for Windows 11.0. The sample size was based on a study done by Daelim Jee and SoYoung Park[1] where three groups of patients were assessed similarly, and the means and standard deviation of number of coughs in the three groups were 10.2 ± 6.0, 4.5 ± 3.7, 7.8 ± 4.6. With an alpha error of 5% and power of 80%, the sample size for each group was calculated to be 38. Therefore, the total sample size was 114. The sample size was determined assuming that the anticipated analysis will be done using analysis of variance (ANOVA).

The data was presented using descriptive statistics such as mean and standard deviation for continuous variables and frequency and percentage for categorical variables. Associations between categorical variables were assessed using Chi-square tests with Yates continuity correction. Comparison of continuous outcomes among groups was performed by ANOVA. Continuous outcomes that are not normally distributed or ordered observations were analyzed using Kruskal-Wallis test. A P value <0.05 was considered statistically significant.

Results

The study was conducted in 114 patients between March 2008 and September 2008.

Table 1 shows the patient characteristics. There was no significant difference between the three groups with respect to age, weight or gender.

Table 1

Patient characteristics (mean±standard deviation)

The duration of surgery and the time intervals from various events such as the last dose of fentanyl, stopping of isoflurane, stopping of vecuronium infusion and administration of the study drug to extubation were all comparable in the three groups, as shown in Table 2. There was no significant difference in the total time taken for extubation in the three groups. The administration of lignocaine intravenously or intratracheally did not delay awakening.

Table 2

Comparison of surgery time and mean time intervals between last dose of each anesthetic drug and extubation

Table 3 shows the number of coughs and the grading of cough at the time of extubation. There was no statistically significant difference in the grade or number of coughs at extubation, in the three groups (P value of 0.13 for grade of cough).

Table 3

Comparison of number of coughs and grading between groups

There were no significant differences in the mean blood pressure or heart rate measured at various points in time before and after extubation between the 3 groups. Heart rate and mean arterial pressure increased very slightly after extubation, reaching peak values in the first or 2nd min in all groups, but declined thereafter.

Lignocaine did not significantly attenuate the cardiovascular responses to extubation in both groups as shown in Figures 1 and 2.

Figure 1

Blood pressure at different points in time

Figure 2

Heart rate at different points in time

There were a large number of patients with high sedation score at extubation. The sedation scores immediately after extubation and 10 min later were not significantly different between groups as shown in Table 4.

Table 4

Sedation score immediately and 10 min after extubation

Table 5 shows the mean and maximum plasma level of lignocaine at 10 min after the drug was given and at extubation. The level was similar in the IV and IT groups and was negligible in the placebo group. The maximum levels measured in the groups are also shown. No adverse event was observed due to the intervention in the groups.

Table 5

Mean and maximum plasma levels of lignocaine in mcg/ml

Discussion

Our study showed that 2% lignocaine in a dose of 1 mg/kg instilled into the endotracheal tube does not prevent cough or hemodynamic response at emergence if given 20-30 min prior to extubation. Emergence from neurosurgical anesthesia in patients on skull pins has two noxious stimuli - pin removal and extubation. The time period between the two is variable, depending on the position of the patient during surgery and the anesthetic agents used. IV lignocaine is widely used to prevent hemodynamic and airway reflexes during extubation but the duration of action is short.[5] Jee and Park[1] found that lignocaine instilled through the endotracheal tube IT suppressed cough if given approximately 5 min before extubation, and found it to be superior to IV injection given 3 min before extubation. They suggested a local mucosal anesthetic effect when using this route. We tested the IT route to see whether the cough suppressive effect will cover the period from pin removal to extubation and if this will reduce the sedation that may accompany IV injection. We felt that if the action of IT Lignocaine is by a local anesthetic effect, it should have lasted till the time of extubation in our patients. We measured the serum concentration of lignocaine at 10 min after administration of the study drug and at extubation. Slower absorption would also show a delayed rise in serum concentration. In our patients the concentration in the IT and IV were similar, both at 10 min, as well as at extubation. If we had serially measured the lignocaine concentration every minute after the drug administration, we may have established the possible mechanism of IT lignocaine, but due to economic constraints we measured the concentration only twice, once after 10 min and the second at the time of extubation.

We used a dose of 1 mg/kg of lignocaine in the IT and IV group as used by Jee and Park[1] and Bidwai et al.[3] Hamaya and Dohi reported that using 1 mg/kg of lignocaine, the maximal plasma lidocaine concentration was 4.3 ± 2.5 μg/ml, 5 min after injection.[11] The mean serum concentration in our IV and IT groups were 0.84 μg/ml and 0.88 μg/ml at 10 min, and 0.63 μg/ml and 0.79 μg/ml at extubation, well below the level required to blunt extubation response. The recommended plasma lignocaine levels for attenuation of the extubation response reported are between 2.3 μg/ml[1] and 3 μg/ml.[3] Only 3 out of 75 patients who received lignocaine via IV or endotracheal route had plasma levels more than this at 10 min and at extubation. The placebo group had negligent plasma levels. They had received lignocaine infiltration for IV and intra-arterial cannulation at the beginning of anesthesia. We also looked at the sedation level in the three groups and as expected from the serum concentration, there was no delay in awakening in both IV and IT groups as compared to placebo. We chose 10 min for serum measurement based on the assumption that the anesthetic is usually discontinued at the time of pin removal and it is unlikely that extubation after a long neurosurgical procedure will take less time than this, except when using desflurane. We hoped to extubate our patients around 10 min after the drug administration but our patients were extubated only 20-25 min after administration. To keep the cost down, we gave isoflurane till dural closure and switched over to sevoflurane hoping to reduce sedation and extubation time. However, we did not find the extubation time to be different from our usual practice of using isoflurane. This was surprising to us but Eger[12] in a February 2010 editorial in Anesthesia and Analgesia suggests that recovery may not be hastened by switching to a lower soluble agent. Neumann et al.[13] found that 30 min of desflurane after 90 min of isoflurane did not hasten recovery. Our total anesthetic time was within 4 h in all the three groups and sevoflurane was used for a mean time of about 70 min.

Overall, the number of coughs or degree of cough was not high among our patients. We attribute this to the sedation in our patients. There were only a few patients who had a sedation score of one at extubation. The hemodynamic response to extubation was minimal in all the three groups, which can also be attributed to the high sedation due to the various anesthetic agents rather than lignocaine.

In conclusion, lignocaine instillation of 1 mg/kg into the endotracheal tube will not attenuate the airway and hemodynamic response during emergence from anesthesia in neurosurgical patients with a prolonged time interval between skull pin removal and extubation. This suggests a weak or short acting local anesthetic effect of lignocaine, if any. An IV administration using the same dose is unlikely to prevent cough if given 10 min before extubation. When volatile agents are continued till pin removal with an adequate dose of fentanyl, cough and hemodynamic response to extubation can be suppressed but cannot be eliminated, even with significant sedation. Further studies are needed to establish the dose, duration and mechanism of action of lignocaine instillation if it is to be recommended for neurosurgical procedures to blunt extubation response.