After induction of anesthesia laryngoscopy and endotracheal intubation causes sympato-adrenal response which can be caused by stimulation of epi-pharynx and laryngopharynx. The major cause of stimulation is caused during laryngoscopy due to stimulation of supra-glottis region and placement of endotracheal tube (ETT) causes little additional stimulation1,2. The stimulation can cause a significant hemodynamic responses that includes hypertension, tachycardia, and increase in intracranial pressure3. Hemodynamic response to laryngoscopy and tracheal intubation is first described by Reid and Braise in 19404.
The effect of sympato-adrenal responses can result in an increased catecholamine level which results, raised in blood pressure, heart rate (HR), increased myocardial oxygen demand, and dysrhythmia. The rise in blood pressure and heart are usually variable and unpredictable. The average increase in HR is about 23 beats/min and average increase in blood pressure is 53/54 mm Hg5. This pressure response to laryngoscopy and intubation starts within 5 seconds and reaches peak level in 1–2 minutes and returns to base line within 5 minutes in patients who has no coexisting disease6. The high pressure response to laryngoscopy and endotracheal intubation increase the myocardial oxygen demand and results in supply demand imbalance. The problem is more fatal in patient with preexisting disease7,8.
Fentanyl and lidocaine are among recommended drugs for attenuation of hemodynamic response to laryngoscopy and endotracheal intubation. Fentanyl acts at opioid receptor and predominantly on µ receptors and it brings hemodynamic stability perioperatively by its action on cardiovascular system and autonomic regulatory areas. It results in decrease in sympathetic tone and increase in parasympathetic tone9. Fentanyl blunts hemodynamic response to laryngoscopy and endotracheal intubation at 2 µg/kg10.
Lidocaine acts by blocking the initiation and conduction of pain signals to brain by blocking Na+ channels and prevents the signals from reaching postsynaptic cell11. The numbers of studies done to assess the effectiveness of different techniques and combinations of drugs failed to show the ideal agent in attenuation of these hemodynamic responses to laryngoscopy and endotracheal intubation3,12. A systemic review which assess efficacy of intravenous lidocaine also recommends further studies13. Thus, main aim of this study is to compare the effects of intravenous lidocaine and fentanyl on attenuation of hemodynamic response to intubation and laryngoscopy for adults undergoing elective procedures.
The primary outcome of this study is to compare change in hemodynamic variable from base line after intubation and laryngoscopy. The secondary outcome is to compare hemodynamic variables between groups after intubation and laryngoscopy.
Study design and patients
Institutional-based double-blinded parallel randomized clinical trial was employed in Dilla University Referral Hospital, Ethiopia from September 2018 to January 2019. Ethical clearance were obtained from Institutional review board of Dilla University, College of Medicine and Health Science and the trial was registered on Pan African Clinical trial registry with an Identification number of PACTR202001700384281. The manuscript was prepared in accordance with 2010 consort guideline for clinical trial. Adult patient aged 18–65, ASA class I patient were enrolled in the study. Allergy to study to study drugs, obstetric patient, anticipated difficult airway and patient on sympatholytic and vasodilator were excluded from the study. Fifty-two patient were randomized to either intravenous fentanyl (received 2 mcg/kg) or intravenous lidocaine (received 1.5 mg/kg) 3 minutes before induction of anesthesia using a sealed envelope randomization technique by anesthetist who did not participate in the research or patient care. The trial was completed when the calculated sample size was reached.
Sample size determination and sampling
The sample size was calculated from a result of previous randomized controlled trial done in India14. Using a G-power version 126.96.36.199 and taking mean change in HR, SBP, DBP, MAP at different time and the largest sample size was taken and calculated by taking power (80%), α—0.05, effect size 0.3275, and allocation ratio 1 and adding a 10% nonresponse rate. A total sample size is 60 and 30 in each group. Sampling were made using a systematic sampling technique provided that order of schedule were used as sequencing mechanism. The consort flow chart of study participant were shown in Figure 1.
Data was analyzed using SPSS V 20. Shapiro Wilks test were used to test for distributions of data. Homogeneity of variance was assessed using the Levene test for equality of variance. Numeric data were described in terms of mean±SD for symmetric and median (interquartile range) for asymmetric data. Between groups comparison of vital sign was made using independent t test for symmetric data and Mann-Whitney U test were used for asymmetric data. Paired t test was used for within group comparison for symmetric data and Wilcoxon sign rank test was used for asymmetric data. Frequency and percentage were used to describe categorical variable and statistical difference between groups were tested using χ2 or Fisher exact test.
Data collection and anesthesia protocol
After obtaining a written informed consent data were collected from patient charts by chart review and directly from patients using direct observations and interview. Sociodemographic data, preoperative diagnosis, medication history, ASA physical status, and others perioperative variables were collected with trained data collectors. All patients were assessed 1 day before operation. The patients were kept NPO for 8 hours. All patients were premeditated by diazepam 5 mg at night before operation. Paracetamol 500 mg at mid night (6 o’clock) and 500 mg morning (12 o’clock) will be given as part of multimodal analgesia.
On the morning of surgery patient were randomized to either of the 2 groups by using a sealed envelope technique. On arrival to operation theater NIBP, pulse oximetry, and ECG were attached. The average of 3 times measurement of blood pressure and HR within 5 minutes were taken as base line vital sign. Blinding was made by drawing the 2 drugs on different syringe of equal volume and were diluted using an equal volume of normal saline. Then either fentanyl 2 mcg/kg or 2% lidocaine 1.5 mg/kg was given 3 minutes before laryngoscopy and intubation for attenuation of pressor response.
Anesthesia protocol was similarly applied for both groups’ preoxygenation for 5 minutes, thiopentone 5 mg/kg and suxamethonium 2 mg/kg for induction. Laryngoscopy and intubation was performed after 3 minute of induction by using ETT 6 and 6.5 cm for women and 7 and 7.5 for men. Anesthesia was maintained with halothane 1%–2%. The primary outcome variable were HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) recorded at 1st, 3rd, 5th, and 10th minutes after intubation. The grouping was concealed from the care giver who performed intubation and also from patients who participated in the study. Only the data collector who recorded hemodynamic variable at the study time was aware of the grouping. There were no any reported adverse outcomes during the perioperative time of the study.
Immediately after the patient arrived in postanesthesia care unit, diclofenac 1 mg/kg was given as part of multimodal analgesia. Postoperative pain was assessed using numeric rating scale and it was recorded. Postoperative pain was managed depending on its severity and according to the protocol.
Intubation was performed 2 minutes after Suxamethonium. Immediately after endotracheal intubation, hemodynamic parameters were measured at 1, 3, and 5 minutes postintubation and recorded. After confirming the position of ETT, anesthesia was maintained using oxygen with volatile anesthetic agent with halothane 2% and the surgery was started after 10 minute.
An intubation attempts that take >30 seconds.
It is defined as an increase in hemodynamic parameter (HR, SBP, DBP) by 20% and above from base line.
A time from insertion of laryngoscopy into mouth up to removal.
Demographic and clinical characteristics of the patients
Fifty-two patients were enrolled in the analysis based on whether they received prophylactic intravenous lidocaine or fentanyl for attenuation of hemodynamic response to laryngoscopy and intubation. There is no statistically significant difference between 2 groups regarding to sociodemographic and preoperative characteristics. The preoperative hemodynamic variables which were taken on the night before surgery is also comparable between 2 groups with statistically no significance difference for HR, DBP, SBP, and MAP (Table 1).
Table 1 -
Demographic and clinical characteristics of the study participants between groups.
| Male (%)
| Female (%)
| ASA I (%)
| ASA II (%)
| OPV I (%)
| OPV II (%)
|Laryngoscopy grade (A/B)
| Grade A (%)
| Grade B (%)
|Preoperative HR (bpm)*
|Preoperative SBP (mm Hg)*
|Preoperative DBP (mm Hg)*
|Preoperative MAP (mm Hg)*
BMI indicates body mass index; DBP, diastolic blood pressure; HR, heart rate; MAP, means arterial pressure; SBP, systolic blood pressure.
Comparison of base line hemodynamic parameters between fentanyl and lidocaine group
The base line hemodynamic variables were also comparable with no statistically significant difference between treatment groups (Table 2).
Table 2 -
Comparison of base line hemodynamic parameters between groups.
|Base Line Hemodynamic Parameter
|Base line HR (bpm)
|Base line SBP (mm Hg)
|Base line DBP (mm Hg)
|Base line MAP (mm Hg)
DBP indicates diastolic blood pressure; HR, heart rate; MAP, means arterial pressure; SBP, systolic blood pressure.
Comparison of change in HR from base line between groups
The mean change in HR at first minute were lower in fentanyl group (17.56±10.287 mm Hg) compared with lidocaine (29.26±15.022 mm Hg) with t(50)=3.27, P-value=0.002, effect size coherence d=1.145. At 3rd, 5th, and 10th minute after intubation there is no statistically significant difference in HR from base line with P-value >0.05 (Fig. 2).
Comparison of change in SBP from base line between fentanyl and lidocaine
The mean change in SBP at first minute from base line was higher in lidocaine group (31.53±17.244 mm Hg) compared with fentanyl (17.53±13.046 mm Hg) with t(50)=3.301, P-value=0.002, effect size Cohen d=1.145. At 3rd, 5th, and 10th minute after intubation there is no statistically significant difference in SBP from base line with P-value >0.05 (Fig. 3).
Comparison of change in DBP after intubation from base line
The mean change in DBP from base line were lower in fentanyl group compared with lidocaine with a mean difference of 11.93 mm Hg, t(50)=3.321, P=0.002. There is no statistically significant difference in DBP from base line after intubation at 3rd, 5th, and 10th minutes with (P-value >0.05) (Fig. 4).
Comparison of change in mean arterial blood pressure from base line
The mean change in mean arterial blood pressure at first minute from base line were lower in fentanyl group (15.10±11.225 mm Hg) compared with lidocaine (27.71±14.504 mm Hg) with t(50)=3.507, P=0.001, effect size Cohen d=1.211. There is no statistically difference in MAP from base line after intubation at 3rd, 5th, and 10th minutes with P-value >0.05 (Fig. 5).
The result of our study reveals that the mean change in hemodynamic variables from base line is lower in fentanyl group compared with lidocaine group in the first minute after intubation. The study also showed that there is no statistically significant difference at 3rd, 5th, and 10th minutes after intubation. The pressure response to laryngoscopy and intubation is maximum at first minute after intubation and lasts 5–10 minutes and a variety of anesthetics agent and anesthetic adjuvants have undergone many prospective study and clinical trials in relation to study attenuation of pressor responses to laryngoscopy intubation15.
The mean change in HR from base line in lidocaine group is higher at first minute compared with fentanyl with mean difference of 11.69 beats/min, P=0.002. This finding is in line with the study by Gurulingappa and colleagues which compares hemodynamic attenuation to laryngoscopy and intubation between lidocaine and fentanyl showing statistically significant difference in raise in HR is higher in lidocaine group compared with fentanyl group with mean difference of 2 beats/min, P=0.04. the later shows small mean difference with our result16. The possible explanation for this may be fentanyl brings hemodynamic stability during perioperative period by its action on cardiovascular and autonomic regulatory areas. It decreases sympathetic tone and increases parasympathetic tone17.
Also our study result was comparable with study done by Mohite et al18 that compare fentanyl and lidocaine on attenuation of hemodynamic response to laryngoscopy and intubation and their result showed lower HR at first minute after intubation in fentanyl group (82.40±1.66 bpm) compared with lidocaine group (89±2.33 bpm) with (P<0.001)19.
Our study was in contrary with study done in India which was randomized, double-blind study on 120 patients that compare, the effects of fentanyl, lidocaine, and esmolol on hemodynamic and spectral index when used before laryngoscopy and intubation to prevent stress responses stated that there were no significant different between fentanyl (109.80±11.78 bpm) and lidocaine (103.63±13.813 bpm) in producing hemodynamic stability at first minute after intubation when compared with each other (P=0.305). The possible difference from our study may be the difference in the drug used for induction, they used Etomidate for induction and it has cardiovascular stability. But in our study, we used thiopentone for induction of anesthesia14.
Our study demonstrated that the mean raise in SBP in first minute after intubation is higher in lidocaine group (31.53±17.24) compared with fentanyl group (17.53±13.04). The mean difference from base line is 14 mm Hg. The mean rise in DBP at first minute is also lower in fentanyl group (13.88±11.57) compare with lidocaine group (25.81±14.18) with mean difference of 11.93 mm Hg. The result of our study also shows that fentanyl lowers the mean raise in MAP from base line by 12.61 mm Hg compared with lidocaine in first minute after intubation.
The result of our study shows the mean rise in HR, SBP, DBP, and MAP in 3rd, 5th, and 10th minutes did not differ from base line between treatment groups with P-value >0.005 at each time. And the result of this study is in line with the study done by Siddiqui and Kiran20 found intravenous lidocaine is less effective to attenuate the pressor responses at 5 minute after intubation and at the end of 5 minutes, the HR was still higher in lidocaine group (P<0.05)21.
In contrary to our study, the randomized control trial study done in Turkey stated that there were significant different in SBP and DBP at third minute after intubation between fentanyl and lidocaine group (P<0.05) the discrepancy might be due to high dose of fentanyl (4 mcg/kg) that was used in their study rather than 2 mcg/kg that we had used in our study16.
Conclusion and recommendation
In conclusion prophylactic administration of fentanyl l.2 µg/kg 3 minute before induction is better in attenuation of hemodynamic response to laryngoscopy and intubation at first minute after intubation when compared with lidocaine 1.5 mg/kg given 3 minute before intubation. In 3rd, 5th, and 10th minute after intubation from base line fentanyl and lidocaine has no statistically significant difference with (P-value >0.05).
Based on our finding we recommend that fentanyl is better in attenuating hemodynamic response to laryngoscopy and intubation in first minute after intubation where as both fentanyl and lidocaine are comparable in preventing the rise in hemodynamic variable at 3rd, 5th, and 10th minute after intubation.
Limitation of the study
Noninvasive monitoring was used for measurement of hemodynamic variables.
Ethical approval was secured from Dilla.
University College of Health Sciences and Medicine institutional review board. Participation in the study was voluntary and based on each patient’s ability to give informed consent.
Sources of funding
The project was funded by Dilla University.
D.N.D., Z.A.F., S.M.K., and E.E.G.: contribute to study conception, collected data, and performed statistical analysis. E.E.G.: contributed for study conception and prepared manuscript. N.A., S.A.W., B.J.A., S.H.A., S.M.A., and T.R.D.: performed statistical analysis. All the authors read the manuscript and approved the final submission.
Conflict of interest disclosure
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identification number (UIN)
Retrospectively registered on Pan African Clinical Trial Registry with the identification number of PACTR202001700384281.
Zemedu Aweke, Derartu Neme.
The authors want to acknowledge Dilla University who funded and supported the authors in the development of this research paper.
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