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Effects of intravenous and inhaled nebulized lignocaine on the hemodynamic response of endotracheal intubation patients: A randomized clinical trial

Background: Endotracheal intubation is one of the most common measures in the Intensive Care Unit (ICU) which plays an important role in airway management of the critically ill patients. Aims: The study aimed to evaluate the effects of lignocaine spray on hemodynamic response of endotracheal intubation patients. Settings and Design: This study is a randomized clinical trial on a study population comprising patients admitted to the ICU. Subjects and Methods: The patients were divided into three groups using a permuted block randomization. In Group 1, inhaled nebulized lignocaine 4% (75.0 mg/kg) was sprayed around the patients' epiglottis and larynx. In Group 2, intravenous (IV) lignocaine 2% (75.0/mg/kg) was injected. No lignocaine was prescribed for or administered to the control group. One and four minutes after intubation, the patients' hemodynamic and vital signs were measured. Statistical Analysis Used: Data analysis was run using Stata 13 software through repeated measure ANOVA tests. Results: Although the mean arterial blood pressure (MAP) of Group 1 (inhaled nebulized lignocaine) was smaller than that of Group 2 (IV lignocaine), there was no significant difference between the two groups. Both groups' MAPs were significantly different from that of the control group. As for the average number of pulses, a significant difference was observed between the inhaled and IV lignocaine groups; hence, the average number of pulses in Group 1 (inhalation) was lower than that of Group 2 (IV injection). Conclusion: As blood pressure is considered to be normal under 140/90 and may not entail any hemodynamic complications, it can be concluded that inhaled nebulized lignocaine can control the hemodynamic changes of intubation more effectively than IV lignocaine.

is used to induce cardiac arrhythmias, particularly ventricular arrhythmias. It is a Class Ib antiarrhythmic drug that is effective in the zero phase of the cardiac cells' action potential. It reduces the electrical conduction velocity across the myocardial conduction system. Competing with calcium to sit in nerve membrane receptors, lignocaine controls the passage of sodium beyond the cell membrane and reduces the depolarization phase's action potential. Such effects contribute to the reversible consolidation of nerve cell membranes by reducing the permeability of the membrane to sodium ions and prevent the initiation and conduction of impulses. [7] Different studies evaluate the effects of lignocaine on the hemodynamic response of intubated patients. Most of these studies, however, attempt to investigate the effect of IV lignocaine in comparison to other drugs or control groups. For instance, by comparing the effects of lignocaine and fentanyl on the hemodynamic response of tracheal intubation patients, Splinter and Cervenko [8] observe that IV lignocaine reduces the patients' systolic blood pressure (SBP) more effectively than fentanyl. It is also shown that lignocaine complications are less than those of fentanyl. Feng et al., [9] on the other hand, do not report any effect of IV lignocaine on the hemodynamic response in patients undergoing intubation and laryngoscopy, as opposed to the reported for fentanyl.
According to the existing studies, the effects of lignocaine on improving the hemodynamic response of intubation patients are yet to be fully understood, [10,11] and the use of lignocaine spray -rather than IV lignocaine -is more convenient and brings about fewer complications. [11,12] Hence, it seems quite feasible to carry out a clinical study to evaluate the effects of lignocaine spray on the hemodynamic response of intubation patients. In addition, due to the complications associated with the hemodynamic response of intubation patients, improving such responses is of great significance. The aim of the present study is to evaluate the effects of lignocaine spray on the hemodynamic response of endotracheal intubation patients admitted to Vali-Asr Hospital.

Trial design
The study is a single-blind randomized clinical trial designed in a parallel.

Participants
The participants of the trial were selected among patients admitted to the ICU showing indications of orotracheal intubation. Based on the patients' history, they were categorized under Classes I and II of the American Society of Anesthesiologists (ASA). Sampling was carried out through availability sampling, using some inclusion and exclusion criteria.
Patients admitted to the ICU comprised the target population of this study. Patients in the age group of 25-40 years admitted to the ICU of the Vali-Asr Hospital constituted the study population. The sampling technique used in the study is availability sampling.
Inclusion criteria include being 25-40-years old; being admitted to the ICU; showing indications of endotracheal intubation; not having such underlying diseases as diabetes, hypertension, cardiovascular disease, kidney and liver diseases, respiratory diseases, and recent respiratory infection; belonging to ASA Grade I and II; and filling out the informed consent form. Patients with a history of treatment with and/or allergy to lignocaine, patients with past life-threatening medical complications, and pregnant and nursing patients were excluded from the study.

Interventions
The main drugs for intubation of the three groups of patients include fentanyl 2 mg/kg, midazolam 2 mg, atracurium 5.0 mg/kg, and nesdonal 5 mg/kg. After being prepared and made ready for injection, they were intravenously injected into the patients in 1 min. We waited for another minute for the maximum effect of drugs and the induction of anesthesia. Then, the orotracheal intubation was carried out. After confirmation of the orotracheal intubation and the accuracy of endotracheal tube placement, the endotracheal tube was fixed in its place.
For patients placed in Group 1, the following procedure was followed. First, their mouth was opened and 75.0 mg/kg of inhaled nebulized lignocaine 4% was sprayed around their epiglottis and larynx. Having sprayed the lignocaine, the main drugs including fentanyl 2 mg/kg, midazolam 2 mg, atracurium 5.0 mg/kg, and nesdonal 5 mg/kg were administered to the patients within 1 min. The patients' hemodynamic and vital signs were measured. About 2 min after the start of administration of anesthetic drugs, intubation was carried out. Immediately after intubation, another 75.0 mg/kg of inhaled nebulized lignocaine 4% was sprayed around the patients' epiglottis and larynx.
For patients placed in Group 2, the following procedure was followed. First, 75.0 mg/kg of IV lignocaine 2% was intravenously injected into the patients. Having injected the lignocaine, the same main drugs used for Group 1 were administered to them within 1 min. Their hemodynamic and vital signs were then measured. About 2 min after the start of anesthetic drugs prescription, intubation was carried out. Immediately after intubation, another 75.0 kg − 1 of lignocaine 2% was intravenously injected into the patients. For patients in the control group, no lignocaine was administered to patients; only the essential drugs were injected. In all three groups, both 2 and 5 min after anesthesia induction (i.e., 1 and 4 min after intubation), the patients' hemodynamic and vital signs were measured.

Outcome
Hemodynamic and vital signs include SBP, diastolic blood pressure (DBP), heart rate (HR), and mean arterial blood pressure (MAP). Using a prepared checklist, these parameters were all measured for all patients and values were recorded both "before" and (2 and 5 min) "after" anesthesia induction. SBP and DBP values were measured using noninvasive blood pressure amplifier pressure gauges, HR was measured through cardiac monitors, and arterial blood pressure was calculated using the following formula:

Sample size
For each of the three groups of 64 participants each and the total number of 192 patients, the sample size was set based on the alpha coefficient of 0.05, effect size of 10, and 80% power.

Randomization and sequence generation
Patients were randomly allocated to three groups using a balanced block randomization technique. For this, they were divided into six blocks. The subjects were allocated to the three groups with the help of an online application called "Sealed Envelope." [13] In this study, allocation concealment was ensured through the use of balanced block randomization and allocation of unique codes to each individual. Owing to random allocation, the distribution of potential confounding variables can be considered to be identical between the two groups; hence, their confounding role was controlled.

Ethical considerations
Before inclusion in the study, all patients were provided with proper explanation about the study and signed the informed consent form. The participants were free to refuse to participate and to withdraw from the study. All the research group members were required to comply with all the provisions of the Declaration of Helsinki.

Implementation
Random allocation sequence was performed by our colleague, who is a methodologist, through the Sealed Envelope website. Eligibility assessment of the patients and their allocation were conducted by the emergency resident under the supervision of the main researcher responsible for the project.

Blinding
In this study, the researcher in charge of measuring the desired outcomes in different groups and the statistical analyst were both blind to the allocation of patients to different groups.

Statistical procedure
Data analysis was run using Stata 13 (Stata Corp, College Station, TX, USA) software through ANOVA and repeated measure ANOVA statistical tests. P < 0.05 was set as the significance level.

results
In this study, 192 patients were randomly allocated to three treatment groups (64 patients/group) and analyzed. The study analysis approach was that of intention to treat. Patients' flowchart is shown in Chart 1.
The baseline data for each of the three groups are shown in Table 1. Gender distribution among the three groups is similar (P = 0.618). In all, 58 people in Group 1 (inhaled nebulized lignocaine) (90.63%), 55 people in Group 2 (IV lignocaine) (85.94%), and 58 people in the control group (90.63%) were male. As shown in Table 1, at the baseline, the confounding variables were evenly distributed among the three groups, and no significant difference was observed between them. This indicates that the randomization process had created three comparative groups. Table 1 also shows the extent to which the results of this study are generalizable. Table 2 displays the mean MAP and the number of pulses at different times for different treatment groups. Repeated measure ANOVA test showed a significant difference between the mean MAP of different treatment groups (P = 0.001). Changes in MAP mean over time were also statistically significant (P = 0.001). The interaction between time and groups, on the other hand, was statistically significant (P = 0.001). This means that changes in MAP mean over time were different among the treatment groups. The average reduction of MAP in Group 1 was faster than those in other groups. As seen in Figure 1, although the MAP of Group 1 (inhalation) was clinically smaller than that of Group 2 (IV lignocaine), there was no significant difference between the two groups (P = 0.116). There was, however, a significant difference between these two groups, as compared to the control group.
Repeated measure ANOVA test showed a significant difference between the average number of pulses in different treatment groups (P = 0.001). The average number of pulse changes over time was also statistically significant (P = 0.001). The relationship between time and groups, on the other hand,  was statistically significant (P = 0.001). This means that the average number of pulse changes over time was different among the treatment groups. The average reduction of pulses in Group 1 (inhalation) was faster than those in other groups. As it can be seen in Figure 2, there was a significant difference between the two treatment groups (P = 0.001). However, there was no significant difference between Group 2 (IV lignocaine) and the control group (P = 0.404).

dIscussIon
According to the findings of this study, there is a significant difference between the MAP means of the three treatment groups. Although the Group 1 (inhalation) MAP was smaller than that of Group 2 (IV lignocaine), there was no significant difference between the two groups. There was, however, a significant difference between these two groups and the control group. In addition, MAP mean changes over time were also significant. The interaction between time and groups was also statistically significant, which means MAP mean changes over time were different among the treatment groups. Moreover, the average reduction of MAP in Group 1 (inhalation) was faster than those in other groups.
Splinter and Cervenko [8] show that fentanyl increases SBP, diastolic pressure, average arterial blood pressure, and HR. However, as illustrated in this study, lignocaine leads to a significant reduction in arterial blood pressure. The results of the study also show that the incidence of drug complications in the group receiving lignocaine is significantly lower than that of the group treated with fentanyl. Nevertheless, the results of our study indicate that administration of lignocaine through inhalation leads to a decrease in MAP and HR of the patients even more rapidly than IV injection. Venus et al. [12] report that mean blood pressure and HR after intubation in the inhaled nebulized lignocaine group was significantly less than that of their control group of patients who received normal saline spray. In addition, the number of premature ventricular contraction in their case group was significantly less than that in their control group. The findings of our study are in line with those of Venus et al.; the MAP and HR after intubation were significantly lower in the inhaled nebulized lignocaine group than the control group.
Ugur et al. [14] divided patients into four groups, all of them were under the administration of routine induction of anesthesia. Group 1, the control group, received 5 ml of dextrose 5%; Group 2 received 5.1 mg/kg Esmolol; Group 3 received 1 mg/kg fentanyl; and Group 4 received 1.5 mg/kg lignocaine. In this study, HR and MAP were measured before intubation, upon intubation, and 1, 3, 5, 7, and 10 min after intubation. The results indicate that -in comparison to the control group -HR in the esmolol 5.1 mg/kg group decreased significantly immediately after intubation and 1 min afterward. In Group 3 (administered 1 mg/kg fentanyl), arterial blood pressure increased immediately after intubation. The amount of increase, however, was lower than those of other groups. Overall, the results show that administering esmolol 2 min before intubation can effectively prevent tachycardia.
Lee and Park studied the effect of lignocaine spray on the hemodynamic changes of intubation in 60 patients. They report that MAP (2.5 and 5 min after intubation) and HR (2.5 min after intubation) were significantly higher in the control group than in the case group. [11] However, in our study, the interaction between time and groups was significant. The process of change was also significantly different among the groups; MAP in the two groups (inhaled vs. IV lignocaine) was lower than that in the control group at different times. As for the HR, however, no significant differences were observed between the control group and the IV lignocaine group. Moreover, the mean HR at time 2 as compared to time 1 was not significantly different between the IV lignocaine group and the control group.
Feng et al. did an elective surgery to evaluate the effect of esmolol, IV lignocaine, and fentanyl on patients' hemodynamic response during laryngoscopy and endotracheal intubation.
Their results indicate that, among all drugs, only esmolol may have a protective effect against the increase of HR and SBP, and lignocaine has no effect on hemodynamic response. [9] However, their study findings contradict the findings of our study. In the study done by Feng et al., 80 patients were treated in four groups; while in our study, sample size was larger (192 patients in three groups); the present study is more powerful in determining the meaningful and significant differences. However, it is recommended that further studies with larger sample sizes be carried out in this regard.
A study by Hancı et al. on 80 patients in the age group of 18-60 years, divided into four groups, indicated that using esmolol 0.5 mg/kg before intubation can be a protective factor against tachycardia and arterial blood hypertension during endotracheal intubation and laryngoscopy. [7] Since this study was conducted on emergency department patients, one of its limitations is that the department was almost always busy. The other limitation of our study is its eligibility assessment of the patients and their allocation as well as problems in taking informed consent due to the special conditions of emergency departments. The main strengths of the present study include the appropriate sample size of patients as compared to similar studies and no loss in follow-up with the patients. Since some of the results of this study contradict the findings of our study, it is recommended that further studies with larger sample sizes should be conducted in different population groups.

conclusIon
Although the MAP of Group 1 (inhalation) was smaller than that of Group 2 (IV lignocaine), there was no significant difference between the two groups. There was, however, a significant difference between these two groups and the control group. As for the average number of pulses, a significant difference was observed between the two treatment  groups (inhaled vs. IV lignocaine); the average number of pulses in the Group 1 (inhalation) was lower than that of the Group 2 (IV lignocaine). As long as blood pressure is considered to be normal under 140/90 and is deemed unlikely to bring about any hemodynamic or cardiovascular complications, it can be concluded that inhaled nebulized lignocaine can control the hemodynamic changes of intubation better than IV lignocaine.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.