Study of Attenuation of Hemodynamic Response to Laryngoscopy and Endotracheal Intubation using Intra-oral Ivabradine.

CONTEXT: Endotracheal intubation is one of the most commonly performed procedures, where rapid and dramatic hemodynamic changes which adversely affect the patient may occur during the perioperative period. Various strategies have been applied to attenuate these responses in high-risk individuals. Ivabradine is a very unique cardiotonic drug in the medical literature which reduces the heart rate without jeopardizing hemodynamics in unhealthy, compromised patients. AIMS AND
OBJECTIVE: The aim of this study is to evaluate the effect of oral ivabradine on the hemodynamics during laryngoscopy and endotracheal intubation in patients undergoing surgical procedure under general anesthesia and to note the side effects and complications. SETTINGS AND
DESIGN: This was a prospective, randomized, and double-blind controlled study. SUBJECTS AND METHODS: A total of 50 American Society of Anesthesiologists physical status I patients between 20 and 50 years age comparable in demographic variables of either sex, undergoing surgery under general anesthesia were randomized into two groups, namely, Group T and Group C of 25 each. Group T (test group) received tablet ivabradine 5 mg 1 h before intubation. Group C (control group) received placebo 1 h before intubation. The pulse rate, systolic and diastolic blood pressures, and mean arterial pressure were recorded for around 10 min and surgery was not allowed to commence. These hemodynamic variables were measured preoperatively, at intubation, after 1 min, 5 min, 8 min and 10 min postintubation. STATISTICAL ANALYSIS USED: The Chi-square test and ANOVA test using INDOSTAT software for hemodynamics were used in this study.
RESULTS: There was an increase in all parameters in the control group during and postintubation and was undisturbed in the test group as compared to base line. The increase was constant up to 3 min and got settled within 5 min in the control group.
CONCLUSION: Ivabradine had better patient compliance in terms of blunting laryngoscopic pressor.

INTRODUCTION

Endotracheal intubation is one of the most commonly performed procedures, where rapid and dramatic hemodynamic changes which adversely affect the patient may occur during the perioperative period.[1] Hypertension and tachycardia have been recognized since 1950s as commonly associated with intubation under light anesthesia. These changes are probably of little consequence in the healthy patients. In prolonged noncardiac surgery, tachycardia and hypertension are independent predictors of adverse outcome.[2] However, failure to blunt the response to intubation may have disastrous consequences in patients with hypertension, raised intracranial pressure, aneurysmal vascular disease, and diseased cerebral vasculature or with ischemic heart disease.[3] Various strategies have been applied to attenuate these responses in high-risk individuals.[4] These include topical and intravenous (i.v.) lignocaine, deep inhalational anesthesia, ganglion blockers, precurarization, narcotics (morphine, buprenorphine, fentanyl, and alfentanyl), adrenoceptor blocking drugs, vasodilators, nitroglycerine and calcium channel blockers and manipulations such as minimizing the duration of laryngoscopy to <15 s and the placement of supraglottic devices like laryngeal mask airway, etc. Ivabradine is a very unique cardiotonic drug in the medical literature which reduces the heart rate (HR) without jeopardizing hemodynamics in unhealthy, compromised patients.

The present study evaluates the effect of oral ivabradine on the hemodynamics during laryngoscopy and endotracheal intubation and also intraoperatively in patients under general anesthesia.

Aim and objectives

To evaluate the effect of oral ivabradine on the hemodynamics during laryngoscopy and endotracheal intubation in patients undergoing surgical procedures under general anesthesia

To note the side effects and complications, if any, due to the study drug.

SUBJECTS AND METHODS

The present study was conducted after receiving approval by the Institutional Ethics Committee of our hospital and written informed consent from 50 American Society of Anesthesiologists (ASA) I adult patients undergoing general anesthesia in the age group of 20–50 years. The study was a comparative prospective randomized, double-blinded, control trial.

Exclusion criteria comprised patients who refused to give consent for study, with the baseline HR <60 bpm, baseline systolic blood pressure <100 mm Hg and those with electrocardiography (ECG) abnormalities, with history of chest pain/palpitations/syncope, with history of any visual disturbances, with Sick sinus syndrome, already on calcium channel blockers, azole antifungals, antiretroviral drugs and macrolide antibiotics, with hepatic impairment or renal dysfunction, pregnant and breastfeeding females and patients in whom intubation is thought to be difficult (time taken to intubate >20 s).

All the patients were subjected to preoperative evaluation 1 day before surgery, including detailed history taking, physical examination, and investigations, including preoperative urine analysis, blood urea, serum creatinine, complete blood count and blood sugar, liver function tests, ECG, and X-ray chest. All patients were advised for fasting at least 8 h before surgery. The procedure of GA and our study was explained to each patient, and written informed consent was obtained from the patient and his relatives in the presence of independent witness. Patients were enrolled a day before surgery by investigators in the surgical ward. Patients were randomized into two groups with the help of computer-generated random number tables in opaque sealed envelopes prepared by an independent staff nurse.

Patients were divided into two groups of 25 each, Group T (test) and Group C (control) where Group-T received oral ivabradine, 5 mg tablet 1 h before intubation and Group-C received placebo 1 h before intubation. i.v. cannulation was done with 18G cannula after shifting the patient into the waiting area of the operation theater and was connected to a drip of Ringer's lactate solution, and all the patients were pre-oxygenated with 100% oxygen for 3 min.

The patient was connected to noninvasive blood pressure monitors, pulse oximeter probe, and electrocardiographic leads. The parameters recorded were heart rate, systolic blood pressure, diastolic blood pressure and mean arterial pressure at various intervals as detailed: Preoperatively (basal line value) just before the study drug or placebo was administered, just before premedication, just after intubation, 1 min after intubation, 3 min after intubation, 5 min after intubation, 8 min after intubation, 10 min after intubation. The premedication, induction agent, and muscle relaxant to facilitate intubation was standardized for both the groups. Premedication was carried out by injection glycopyrrolate 0.2 mg and by injection ondansetron 4 mg slowly intravenously, just before induction. The patient was induced by injection propofol (2 mg/kg body weight). Intubation was facilitated by using by succinylcholine 2 mg/kg i.v. The lungs were ventilated with 100% oxygen for 60 s. Intubation was timed at 60 min after ivabradine pre-treatment in Group-T and 60 min after placebo in Group-C. Intubation was achieved with an appropriate size oral cuffed, portex endotracheal tube with the aid of Macintosh laryngoscope blade. The time taken for intubation did not exceed 20 s (intubation that needed >20 s was excluded from the study). Surgery was not allowed to commence until the recordings were completed which was 10 min after intubation. Ten minutes after the intubation, after taking all the recordings of hemodynamic parameters, fentanyl 2 mcg/kg, and inhalational agent halothane was introduced for maintenance of anesthesia by intermittent positive pressure ventilation with nitrous oxide and oxygen the ratio of 66%: 33% using circle absorber system connected to the Boyle's machine. Injection vecuronium bromide 0.08 mg/kg top-up doses was also administered to maintain anesthesia. At the end of the surgery, neuromuscular blockade was reversed with by neostigmine (0.05 mg/kg) and by glycopyrrolate (0.04 mg/kg). All the patients were followed in the postoperative period. Any incidence of adverse effects of ivabradine was looked for in the postoperative period.

RESULTS

The data were analyzed using INDOSTAT software (INDOSTAT services, Hyderabad, India). ANOVA test was applied to all quantitative parameters, and Chi-square test was applied for all qualitative parameters. P values were calculated using MSTAT software (Michigan State University East Lansing, MI 48824, USA). Both the groups (25 patients each) were comparable in the distribution of patients regarding age, sex, weight, ASA class, and time of medication and intubation.

Mean pulse rate observed in preoperative stage was 97.60 bpm (standard deviation [SD]-7.326) in control and 82.60 bpm (SD-3.279) in the test group, respectively, which increased to 103.92 bpm (SD-21.675) in control group while decreased to 80.56 bpm (SD-2.551) in test group during intubation. It was observed that this increase was constant up to 3 min in the control group (101.52 to 107.64), whereas it remains settled in the test group. After 5 min, it settled to 99.12 (SD-4.868) and came to baseline after 10 min in control group, whereas no significant fluctuations were observed in the test group [Figure 1].

Figure 1

Intraoperative mean pulse at various time intervals

Mean systolic blood pressure observed was 133.369 (SD-4.572) in control group, whereas 122.24 (SD-4.977) in the test group, which slightly increased to 140.32 (SD-3.368) in control group and 126.16 (SD-4.543) in test group during intubation. The systolic blood pressure settled to 129.8 in control group 10 min after intubation, but no significant fluctuations were observed in the test group [Figure 2].

Figure 2

Intraoperative systolic blood pressure at various time intervals

Mean diastolic blood pressure observed was 83.16 (SD-2.211) in control group and 80.48 (SD-2.468) in test group which increased to 90.12 (SD-2.505) in control group, whereas there was slightly increased 82.96 (SD-2.242) in test group during intubation. It started settling down after 1 min and came to baseline after 5 min to 83.88 (SD-1.764) in control group and 80.64 (SD-1.818) in the test group [Figure 3].

Figure 3

Intraoperative diastolic blood pressure at various time intervals

Mean arterial pressure observed was 99.96 (SD-2.653) in control group, whereas 93.84 (SD-2.375) in the test group, which increased to 106.20 (SD-1.633) in control group and very slightly increased to 93.84 (SD-2.027) in the test group, during intubation. However, it came to baseline, i.e., 99.04 (SD-2.071) after 5 min and remained stable up to 10 min in control group whereas it settled in test group after 1 min and remained stable up to 10 min [Figure 4 and Table 1].

Figure 4

Intraoperative mean blood pressure at various time intervals

Table 1

Intra-operative hemodynamic parameters at various time intervals

Time	Groups	Mean PR (SD/SEM)	Mean SBP (SD/SEM)	Mean DBP (SD/SEM)	Mean MAP (SD/SEM)
Pre-op	Control	97.60 (7.326/1.465)	133.36 (4.572/0.914)	83.16 (2.211/0.442)	99.96 (2.653/0.531)
	Test	82.60 (3.279/0.656)	122.24 (4.977/0.995)	80.48 (2.468/0.494 )	93.84 (2.375/0.475)
During intubation	Control	103.92 (21.675/4.335)	139.52 (3.368/0.674)	90.12 (2.505/0.501)	106.20 (1.633/0.327)
	Test	80.56 (2.551/0.510)	126.16 (4.543/0.909)	82.88 (2.242/0.448)	96.88 (2.027/0.405)
At 1 min.	Control	107.64 (8.460/1.692)	129.40 (21.517/4.303)	86.08 (2.842/0.568)	101.96 (2.993/0.599)
	Test	79.76 (2.350/0.470)	122.32 (3.682/0.736)	80.16 (1.818/0.364)	93.88 (1.878/0.376)
At 3 min.	Control	101.52 (6.482/1.296 )	130.24 (3.887/0.777)	85.24 (2.919/0.584 )	100.20 (2.769/0.554)
	Test	79.16 (2.267/0.453)	121.12 (2.386/0.477)	80.96 (1.306/0.261)	94.60 (1.000/0.200)
At 5 min.	Control	99.12 (4.868/0.974)	169.76 (200.083/40.017)	83.88 (1.764/0.353)	99.04 (2.071/0.414)
	Test	80.00 (1.979/0.396)	120.72 (2.227/0.445)	80.64 (1.381/0.276)	94.20 (1.08/0 0.216)
At 8 min.	Control	98.16 (4.616/0.923)	129.80 (3.317/0.663)	83.88 (1.764/0.353)	99.12 (2.108/0.422)
	Test	79.72 (1.926/0.385)	120.08 (0.702/0.140)	80.56 (1.356/0.271)	93.68 (0.988/0.198)
At 10 min.	Control	97.20 (4.082/0.816)	129.88 (3.244/0.649)	83.68 (1.973/0.395)	99.04 (1.968/0.394)
	Test	79.68 (1.930/0.386)	120.08 (0.702/0.140)	80.56 (1.356/0.271)	93.56 (1.083/0.217)

SBP=Systolic blood pressure, DBP=Diastolic blood pressure, MAP=Mean arterial pressure, PR=Pulse rate, SD=Standard deviation, SEM=Standard error of the mean

DISCUSSION

Reid and Brace in 1940, first reported cardiac and hemodynamic changes during laryngoscopy and endotracheal intubation with conventionally used anesthetic techniques. These sympathetic reflex effects in anesthetized patients include rise in systolic and diastolic blood pressure, mean arterial pressure and pulse rate and they usually peak 30–45 s after laryngoscope. These transient changes may cause life-threatening complication in patients with cardiovascular and cerebral diseases. To attenuate the sympathetic response to laryngoscopy and endotracheal intubation, various measures have been carried out like topical anesthesia of the larynx and pharynx along with superior laryngeal block, intratracheal lidocaine spray, deeper planes of inhalational anesthesia, i.v. lidocaine, alfa-blockers, beta-blockers, combined alfa- and beta-blockers, intranasal, oral, i.v. use of sodium nitroprusside, nitroglycerine, nifidepine, and narcotics. Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who cannot take beta-blockers. It is also indicated in combination with beta-blockers in patients inadequately controlled by beta-blocker alone and whose HR exceeds 60 bpm. Apart from angina, it is also being used off-label in the treatment of inappropriate sinus tachycardia.[5] However, it is quite different from a beta blocker. The drug can be used not only in hypertensive patients but also in normotensive patients. It has no significant negative inotropic effect like a beta-blocker and can be even used in patients with bronchial asthma where beta-blockers are contraindicated. It does not alter the metabolism in diabetic patients and in this aspect ivabradine scores significantly over a beta-blocker in all compromised patients.

Ivabradine reduces the HR without producing a precipitous fall in blood pressure; hence, it is useful in patients with angina pectoris, coronary artery disease (CAD), cardiac failure, obstructive cardiomyopathies and in all conditions where the myocardial oxygen supply is endangered, and myocardial oxygen demand is increased. By not allowing the HR to increase, ivabradine conserves the oxygen reserves of the myocardium and reduces the myocardium oxygen demand.[6] Hence in every aspect, ivabradine is an ideal drug to be used during general anesthesia procedures in view of its multiple benefits on the myocardium. Ivabradine was approved by the European Medicines Agency in 2005 and by the United States Food and Drug Administration in 2005.[7] Increased HR is a common problem of sympathetic hyperactivity and cardiovascular disorders. Ivabradine acts on If (funny channels), which is highly expressed in the sinoatrial node [Figure 5]. Ivabradine acts by reducing the HR through specific inhibition of the funny channel, a mechanism different from that of beta-blockers and calcium channel blockers, two commonly prescribed anti-anginal drugs. IF is a mixed Na-K inward current activated by hyperpolarization and modulated by the autonomic nervous system. High-HR is risk factor in congestive heart failure (CHF). Selective lowering of HRs with ivabradine improves cardiovascular outcomes. It is clinical indications include symptomatic management of chronic stable angina with HR >60–70 bpm,[8] CHF,[9] inappropriate sinus tachycardia,[10] and postural orthostatic tachycardia syndrome. IF is also present in the AV node and His-Purkinje system, and can influence physiologic and pathophysiologic automaticity in the heart.[11] Given the prominent role in pace-making, IF-channels are valuable targets for drugs designed to pharmacologically control heart rate.[11] Molecules able to bind and to block IF-channels can be used as pharmacological options for HR reduction with little or no adverse cardiovascular side effects. Indeed, the selective F-channel inhibitor ivabradine is today commercially available as an option for the treatment of chronic stable angina (CSA) heart failure and inappropriate sinus tachycardia.[12] Initial oral doses of 2.5 mg twice a day are commonly used. A maximum of 7.5 mg daily is also acceptable. However, in several randomized controlled trials, ivabradine was administered 5–10 mg twice daily.[13] Ivabradine is a drug used in several cardiovascular disorders, CSA. Reductions of HR with ivabradine could be used to reduce the incidence of CAD outcomes in a subgroup of patients who have HR >70 bpm.[14] Some common side effects associated with the use of ivabradine are luminous phenomena or phosphonea characterized by sensations of enhanced brightness in a fully maintained visual field. This is thought to be due to block of IH in the retina, a current very similar to the cardiac IF. These symptoms are mild, transient, fully reversible, and bradycardia which is proportional to the resting HR, but extreme sinus bradycardia is uncommon. It occurs in 2% and 5% of patients taking doses of 7.5 and 10 mg, respectively (compared to 4.3% in atenolol). Other less frequent adverse events reported in the literature are first-degree AV block/premature ventricular contractions/dizziness/blurred vision/headaches/muscle cramps/eosinophila/hyperuricemia. Oral ivabradine was used in the present study to attenuate the hemodynamic changes to laryngoscopy and endotracheal intubation and the same were compared with a placebo group. Monitoring of blood pressure, mean arterial pressure and pulse rate response to laryngoscopy and intubation was studied in both the groups who received the same anesthetic technique.

Figure 5

Action of ivabradine on sinoatrial node

Although we used glycopyrrolate injection in premedication which is a muscarinic anticholinergic agent given to block cardiac vagal inhibitory reflexes during induction of anesthesia and intubation and may cause tachycardia. However, since we used it in both the control and test group, any bias was eliminated. In the present study after premedication, hemodynamic parameters showed a slight increase in the blood pressure, mean arterial pressures, and pulse rate, when compared to the pre-anesthestic evaluation; however, the difference was not significant statistically. In the present study, after intubation, the surgeons were requested not to operate till 10 min to have proper monitoring because ivabradine has no analgesic effects and skin incision could have falsely raised hemodynamic parameters. There was no significant increase in the hemodynamic parameters during laryngoscopy and intubation in the test group as compared to the control group and the minimal rise also returned to a baseline within a minute; however, in the control group, the baseline parameters were raised and there was increase in the pulse rate, though decreased to some extent. The study results were consistent with prospective randomized, single-blinded study done by Raghuram et al.[15] where patients received oral ivabradine, 5 mg at 6 p.m. on evening before the day of surgery and 5 mg tablet 1 h before intubation. They found that there was no significant increase in the hemodynamic parameters in response to laryngoscopy and intubation in test group, when compared to the control group and the minimal raise also returned to baseline immediately within a minute. Whereas the control group, the baseline reading itself was high and the increase in the hemodynamic, especially the pulse rate though decreased to some extent, it was significantly being maintained above the normal value. They concluded that ivabradine prevents abnormal increase in HR and minimizes the extent of hypertension seen during laryngoscopy and endotracheal intubation.

To conclude, ivabradine is an extremely useful drug to prevent abnormal increase in HR seen during laryngoscopy and endotracheal intubation. It also minimizes the extent of hypertension seen during laryngoscopy and endotracheal intubation and helps in return of blood pressure to the baseline values within a short period (around 3 min after endotracheal intubation). Its proven safety in conditions such as ischemic heart disease, angina pectoris, diabetes mellitus, allergic bronchitis and asthma, obstructive cardiomyopathies enhances its claim for its routine use in all patients at risk for hypertension during laryngoscopy and endotracheal intubation. In routinely administered clinical dose as practiced in our study, there were no adverse side effects on pulse rate, blood pressure and even on the lung mechanics.

Tab Ivabradine is a cheap feasible option (Rs. 18.50 per tab) to blunt exaggerated hemodynamic response encountered during laryngoscopy and intubation.

CONCLUSION

Ivabradine had better patient compliance in terms of blunting the laryngoscopic pressor response than placebo and is a cheap substitute for the same [Figure 6].

Figure 6

Hemodynamic response attentuation by ivabradine

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.