The Hemodynamic Effects of Landiolol, an Ultra-Short-Acting β₁-Selective Blocker, on Endotracheal Intubation in Patients With and Without Hypertension

Abstract

BACKGROUND: 

The ultra-short-acting β₁-selective blocker, landiolol, is widely used in Japan. We investigated the effects of landiolol on intubation-induced adrenergic response in 88 patients.

METHODS: 

General anesthesia was induced and maintained with target-controlled infusion of propofol at an effect–site concentration of 5 μg/mL. Muscle relaxation was obtained with 0.1 mg/kg vecuronium, and endotracheal intubation was performed 4 min after vecuronium injection. We first investigated the optimal time point for landiolol to be administered before intubation in 43 normotensive patients. Then we examined whether landiolol was as effective as fentanyl to prevent tachycardia after intubation in 45 hypertensive patients.

RESULTS: 

Landiolol at 0.1 mg/kg was most effective against intubation-induced tachycardia when infused 4 min before intubation in normotensive patients. However, 0.2 mg/kg landiolol was necessary to prevent tachycardia after intubation in hypertensive patients. Landiolol had no significant effects on arterial blood pressure or bispectral index at any dose throughout the study period. In contrast, 2 μg/kg fentanyl frequently caused hypotension just before and 5 min after intubation.

CONCLUSION: 

Low doses of landiolol can effectively prevent tachycardia after intubation without significant effects on arterial blood pressure.

In Brief

IMPLICATIONS: Landiolol, injected at low doses of 0.1 or 0.2 mg/kg 4 min before endotracheal intubation, prevents intubation-induced tachycardia with no obvious untoward effects on arterial blood pressure in normotensive and hypertensive patients.

Recently, β₁-adrenoceptor antagonists have been advocated as adjunct drugs to decrease perioperative morbidity and mortality in patients with cardiovascular disease undergoing surgery (^1–4). Ideally, β₁-antagonists should be started as early as possible before the operation and maintained during and after surgery (⁵). Nonparenteral administration of β₁-blockers is recommended. However, the parenteral route is also useful during, or shortly after, the operation. Esmolol is one of the drugs of choice in the latter situation when the patients’ hemodynamic state is unstable.

Landiolol, an ultra-short-acting β₁-selective adrenoceptor antagonist, is now being widely used in Japan (^6,7). It has a shorter plasma half-life of approximately 4 min and a higher cardioselectivity, with a potency ratio (β₁/β₂) of 255, as compared with 9 min and 33, respectively, for esmolol (^8–10). Because of its characteristics, landiolol may be superior to esmolol for the control of heart rate (HR) during and shortly after surgery. Few studies, however, have reported the use of landiolol during anesthesia (^11,12). Particularly, the appropriate timing to administer landiolol to prevent tachycardia after intubation has not been determined. Our pilot study in normotensive and hypertensive patients strongly indicated there was an optimal dose and time point for the administration of landiolol before endotracheal intubation.

In the present study, we evaluated two series of patients to investigate whether landiolol prevented the adrenergic response caused by laryngoscopy and endotracheal intubation. In the first series, we identified the optimal time point for landiolol administration in normotensive patients. From the results of the first series, we identified the optimal dose of landiolol to prevent the adrenergic response in a series of hypertensive patients.

METHODS

After we obtained IRB approval and the patients’ informed consent, 88 patients, age range 20–69 yr, undergoing elective surgery under general anesthesia were included in this study. Those patients who were taking β-blockers before the operation, or for whom β-blockers, propofol, vecuronium, and fentanyl were contraindicated, or who had a heart rhythm other than sinus rhythm, uncontrolled diabetes mellitus, or valvular heart disease were excluded from the study.

None of the patients was premedicated before the operation. In the operating room, routine intraoperative monitoring, including cuffed blood pressure measurement, electrocardiogram, pulse oxymetry and end-tidal gas concentration (S/5, GE Yokokawa Medical, Tokyo, Japan), was started. The bispectral index (BIS; A-2000, Aspect Medical Systems, Newton, MA) was also monitored continuously because β-blockers may influence the depth of anesthesia (¹³). An IV cannula was introduced in the forearm and acetated Ringer’s solution infusion was begun at a rate of 5 mL · kg⁻¹ · h⁻¹.

First Series of Patients

Forty-three normotensive patients scheduled to undergo hip surgery were included in this series and were prospectively randomized to one of the following four groups by the envelope method. These were the control (n = 11), Land-0 (n = 10), Land-2 (n = 11), and Land-4 (n = 11) groups set according to the time point for landiolol administration. Landiolol was not administered to the control group. To the Land-0 group, 0.1 mg/kg landiolol was administered just before the trachea was intubated. To the Land-2 and Land-4 groups, 0.1 mg/kg landiolol was administered 2 and 4 min before endotracheal intubation, respectively. It has been shown that an interval of approximately 4 min between the 0.1 mg/kg vecuronium injection and endotracheal intubation is necessary for a satisfactory intubation during propofol and fentanyl anesthesia (¹⁴). Therefore, 4 min between the landiolol injection and intubation was set as the longest interval. After administration of 100% oxygen, general anesthesia was induced and maintained with propofol infused IV using a target-controlled infusion device (TE-371, Terumo, Tokyo, Japan) set at an effect–site target concentration of 5 μg/mL (¹⁵) until the end of the investigation. Manual ventilation with 100% oxygen was started, and 0.1 mg/kg vecuronium was administered IV when the patient lost consciousness. Four minutes after vecuronium was injected, the trachea was intubated by an anesthesiology resident between 10 and 30 s of laryngoscopy because hemodynamic changes after intubation depend on the length of the procedure. The inspired oxygen concentration was then reduced to 40% (Air:O₂ = 1.5:0.5 L/min), and the patient’s lungs were ventilated with a ventilator to keep the end-tidal concentration of carbon dioxide at approximately 35 mm Hg.

Second Series of Patients

Forty-five patients with mild to moderate hypertension, scheduled to undergo minor surgery, were included in this series. This study was performed in a randomized, double-blind fashion also using the envelope method. Antihypertensive drugs administered before the operation were continued until the day of surgery except for angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists. The patients were allocated to one of four groups. These were the control (n = 11), low-dose landiolol (n = 12), high-dose landiolol (n = 11), and fentanyl groups (n = 11). Because our pilot study had indicated that 0.1 mg/kg landiolol might not be sufficient to prevent tachycardia induced by endotracheal intubation in hypertensive patients, we included a 0.2 mg/kg landiolol group in this series. The control group (n = 11) received neither fentanyl nor landiolol before induction of anesthesia or endotracheal intubation. The low-dose group (n = 12) received 0.1 mg/kg landiolol before intubation but did not receive fentanyl before induction. The high-dose group (n = 11) received 0.2 mg/kg landiolol before intubation but did not receive fentanyl before induction. The fentanyl group (n = 11) received 2 μg/kg fentanyl before induction but did not receive landiolol before intubation.

After administration of 100% oxygen, 2 μg/kg fentanyl was injected in the fentanyl group, whereas the same volume of placebo (normal saline) was injected in the other three groups. One minute later, general anesthesia was induced and maintained with propofol infused IV using the target-controlled infusion device (Terumo) set at 5 μg/mL until the end of the investigation. Manual ventilation with 100% oxygen was started, and 0.1 mg/kg vecuronium was administered IV when the patient lost consciousness. Landiolol, 0.1 and 0.2 mg/kg, was injected after vecuronium in the low- and high-dose groups, respectively. Landiolol was diluted with normal saline at the concentrations of 1 or 2 mg/mL, so that the same volume was injected in each group. The same volume of placebo (normal saline) was injected after vecuronium in the control and fentanyl groups. Four minutes after landiolol was injected, the trachea was intubated by an anesthesiology resident between 10 and 30 s of laryngoscopy. The inspired oxygen concentration was then reduced to 40% (Air:O₂ = 1.5:0.5 L/min), and the lungs were ventilated with a ventilator to keep the end-tidal concentration of carbon dioxide at approximately 35 mm Hg. Patient groups were blinded not only to the anesthesia resident who performed intubation but also to an independent observer who recorded hemodynamics and other variables.

Data Collection

Systolic blood pressure (SBP) was measured noninvasively before induction, 1 and 2 min after the start of propofol infusion, just before endotracheal intubation, and 1, 2, and 5 min after endotracheal intubation. HR, Spo₂, BIS, and the estimated effect–site concentration of propofol were monitored continuously and recorded simultaneously with the cuffed blood pressure measurements. The maximum value of HR after endotracheal intubation was also recorded in each patient.

Ephedrine 4 mg was administered for hypotension (SBP < 80 mm Hg for >60 s) and atropine 0.3 mg for bradycardia (HR < 40 bpm) as escape medications. For hypertension (SBP > 200 mm Hg, or an increase of >30% above baseline values, for >60 s) or tachycardia (HR > 130 bpm), the effect–site concentration of propofol was increased in increments of 0.5 μg/mL.

Data Analysis

Data were expressed as the mean value ± sd. Statistical analyses were performed with repeated measures analysis of variance or χ² test when appropriate, and a P value <0.05 was considered significant. When a significant difference was obtained using ANOVA, post hoc analysis was performed with Bonferroni test using KaleidaGraph ver.3.6.

RESULTS

Although 88 patients participated in this study, eight were excluded from the data collection because laryngoscopy time exceeded 30 s. As a result, data from 80 patients (10 patients in each group) were analyzed. No escape medications or interventions were required for any patient during the study period. The dose of propofol administered to each patient was between 2.5 and 3 mg/kg by intubation and around 4 mg/kg by the end of the investigation.

In the first series, there were no significant differences in age, height, or weight among the four groups (Table 1). Figure 1 shows SBP and HR changes during the study period. SBP decreased significantly in all groups just before intubation and returned to the baseline level within 2 min after endotracheal intubation. There were no significant differences in SBP among the four groups at any point of measurement. HR did not change significantly within each group or among the groups before intubation. HR increased significantly in all groups except the Land-4 group after the patients were intubated, and the peak HR was observed within a minute of intubation. The maximum and 1-min values of HR after intubation in the Land-4 group were significantly lower (P < 0.05) than those in the other three groups. BIS and the estimated effect–site concentration of propofol did not differ significantly among the four groups throughout the study period (Fig. 2). This study indicated that an interval of >2 min between the infusion of landiolol and endotracheal intubation was necessary to prevent tachycardia after intubation.

Table 1: Characteristics of the First Series of Patients

Figure 1.: Changes in systolic blood pressure (SBP) (A) and heart rate (HR) (B) in normotensive patients. Compared with the respective baseline value, SBP decreased significantly just before intubation in all groups. Then, it increased significantly after endotracheal intubation but returned to the baseline value within 2 min of intubation. No significant differences were observed in SBP among the four groups throughout the study period. HR did not change from the respective baseline value in the four groups before intubation. It reached the maximum value within 1 min of intubation in all groups. Significant differences were obtained between the Land-4 and the other three groups. Data are presented as the mean value ± sd. *P < 0.05 versus the Control group; †P < 0.05 versus the respective baseline value.

Figure 2.: Changes in bispectral index (BIS) (A) and the effect–site concentration of propofol (B) in normotensive patients. No significant differences were observed among the four groups regarding these two variables.

From the results obtained in the first series of patients, we determined that landiolol should be administered 4 min before endotracheal intubation in hypertensive patients. Again, there were no significant differences in age, height, or weight among the four groups in the second series of patients (Table 2). Antihypertensive drugs administered before the operation are shown in Table 2. Figure 3 illustrates changes in SBP and HR during the study period in the second series of patients. SBP decreased significantly after propofol infusion but returned to the preinfusion level after endotracheal intubation. Significant differences were observed between the fentanyl group and the other three groups; 2 μg/kg of fentanyl, in combination with propofol at the effect–site concentration of 5 μg/mL, frequently induced hypotension (>30% decrease from the baseline) just before (the number of hypotensive patients 4, 10, 4, and 6 for the control, fentanyl, low-dose landiolol, and high-dose landiolol groups, respectively; not significant by χ² test) and 5 min after intubation (the number of hypotensive patients 2, 8, 3, and 3 for the control, fentanyl, low-dose landiolol, and high-dose landiolol groups, respectively; not significant by χ² test).

Table 2: Characteristics of the Second Series of Patients

Figure 3.: Changes in systolic blood pressure (SBP) (A) and heart rate (HR) (B) in hypertensive patients. Compared with the normotensive patients, similar changes were observed in the hypertensive patients. However, low-dose (0.1 mg/kg) landiolol did not prevent tachycardia in this series. In contrast, high-dose (0.2 mg/kg) landiolol completely abolished intubation-induced increases in HR. Although fentanyl also decreased HR after intubation, it frequently induced hypotension just before and after intubation. Data are presented as the mean value ± sd. *P < 0.05 versus the Control group; †P < 0.05 versus the respective baseline value.

Compared with the baseline value, significant increases in HR occurred in the control group until 1 min after intubation. High-dose landiolol prevented intubation-induced tachycardia without affecting the HR before intubation. In contrast, neither low-dose landiolol nor fentanyl attenuated the maximum increase in HR. As a result, no significant difference was observed between the low-dose landiolol or fentanyl group and the control group. Fentanyl decreased HR as compared with the control group both before and after endotracheal intubation but the decrease was not statistically significant. Again, BIS and the estimated effect–site concentration of propofol did not differ significantly among the four groups throughout the study period (Fig. 4).

Figure 4.: Changes in bispectral index (BIS) (A) and the effect–site concentration of propofol (B) in hypertensive patients. No significant differences were observed among the four groups regarding these two variables.

DISCUSSION

The main findings of the present study were as follows: Landiolol 0.1 and 0.2 mg/kg had no influence on SBP and HR before endotracheal intubation. Although landiolol is a rapid onset drug, a 4-min interval from its administration to endotracheal intubation was necessary to prevent intubation-induced tachycardia. In hypertensive patients, landiolol 0.2 mg/kg was necessary to suppress tachycardia after intubation, whereas at 0.1 mg/kg it was effective in normotensive patients. Moreover, while fentanyl prevented tachycardia induced by endotracheal intubation, it frequently caused hypotension (>30% decrease from baseline) before and after the procedure.

This is the first study that emphasizes the timing for landiolol injection to inhibit sympathetic responses induced by endotracheal intubation. In addition, no studies have examined the hemodynamic effects of landiolol during anesthesia induction and intubation in hypertensive patients. The present study showed that landiolol effectively suppressed HR changes after intubation in hypertensive patients, although a larger dose was necessary than that used in normotensive patients.

There have been several reports concerning the effects of landiolol on tachycardia induced by endotracheal intubation. Kitamura et al. (¹¹) reported that 0.1 mg/kg landiolol was not enough to suppress tachycardia or the rate-pressure product after intubation under thiamylal anesthesia. They advocated landiolol at 0.25 or 0.5 mg/kg to prevent tachycardia after intubation. In contrast, Yamazaki et al. (¹²) reported that 0.1 mg/kg landiolol could attenuate intubation-associated tachycardia under propofol and sevoflurane anesthesia. Those two groups, however, did not investigate the timing of landiolol administration before intubation. In our study, a 2-min interval from the administration of landiolol to endotracheal intubation may not have been long enough for landiolol to prevent tachycardia elicited by intense stimuli, as might be induced by endotracheal intubation. From the present study, the timing for drug administration before intubation is an important factor in examining the effect of landiolol, although the anesthesia technique may also have influenced the effect of landiolol. Because the present study did not address the relationship between anesthesia technique and landiolol, further studies are required to determine whether specific anesthetic management influences the effects of the drug.

Excessive bradycardia and hypotension is a concern if a β-blocking drug is administered very early before intubation when the sympathetic nervous tone is low. However, neither low- nor high-dose landiolol influenced SBP or HR before endotracheal intubation, whereas at both doses landiolol effectively prevented tachycardia after intubation. This result is consistent with those of a previous report (¹²). It is generally accepted that β-blockers have a modest effect on HR when tonic stimulation of β-receptors is low (¹⁶). This was the case before endotracheal intubation when anesthesia was deep enough and no stimulus was given to the patients. In contrast, β-blockers attenuate tachycardia when sympathetic nervous system activity is increased, as was seen after endotracheal intubation in the present study. Therefore, landiolol infusion should be provided as early as 4 min before endotracheal intubation to patients who would most likely benefit from it.

There have been no reports on the hemodynamic effects of landiolol in hypertensive patients. In this report, landiolol at 0.2 mg/kg prevented tachycardia induced by endotracheal intubation. However, the reason landiolol 0.1 mg/kg attenuated tachycardia in normotensive patients but not in hypertensive patients remains to be clarified. Several investigators have reported that sympathetic activity is increased in many hypertensive patients compared with normotensive subjects (^17,18). It is quite feasible, therefore, that β-adrenergic receptors are downregulated in hypertensives under this situation (¹⁹). Consequently, landiolol might be less effective in hypertensive, compared with normotensive, patients.

Fentanyl is frequently administered during induction of anesthesia to prevent an increase of arterial blood pressure and tachycardia after intubation (²⁰). Fentanyl at 2 μg/kg, in combination with propofol at a 5 μg/mL effect–site concentration, effectively suppressed adrenergic response induced by endotracheal intubation. However, Figure 3, when examined in detail, shows that fentanyl might have shifted the control SBP and HR curves downward. As a result, fentanyl significantly decreased SBP just before and 5 min after intubation in hypertensive patients. One possible explanation for the decreases in SBP and HR is that fentanyl not only attenuates sympathetic activity, but also stimulates vagal activity (²¹). A combined infusion of fentanyl and propofol may have deleterious effects on hemodynamics (²²). Furthermore, the plasma half-life of fentanyl is 219 min (²³), i.e., much longer than that of landiolol. In routine clinical practice, therefore, it must be emphasized that the effect–site concentration of propofol should be diminished soon after endotracheal intubation when fentanyl is concomitantly used. Opioids with a shorter half-life such as remifentanil would also reduce the frequency of this adverse effect.

Some β-adrenoceptor blockers are quite lipid-soluble and may easily cross the blood–brain barrier, causing mental depression as a side effect (¹⁶). Oda et al. (¹³) reported that β-blockers, such as esmolol and landiolol, could lower increases in BIS and HR elicited by endotracheal intubation. In that report, anesthesia was induced and maintained with one minimum alveolar concentration (MAC) of sevoflurane. Although the mean BIS value was <40 just before endotracheal intubation, it increased to 54 ± 10 after intubation in the control group, indicating that the level of anesthesia with one MAC sevoflurane was not deep enough for intubation. In that situation, esmolol and landiolol could attenuate an increase in BIS. Furthermore, they administered a larger dose of landiolol than that used in this study; a 0.125 mg/kg bolus dose was followed by a 0.04 mg · kg⁻¹ · min⁻¹ infusion for 7 min. These differences may account for the diverse effects of landiolol on BIS, because we observed neither an increase in BIS after endotracheal intubation in the control group nor a difference in BIS between the control and landiolol groups.

This study has several limitations. First, no double-blind study was performed in the first series. Therefore, some bias may have influenced the results. The dose of propofol varied from patient to patient in the range of 2.5 and 3 mg/kg by intubation in the present study. This difference is unlikely to have influenced the results, because the estimated effect–site concentration of propofol and the BIS value did not differ among the groups. In addition, Billard et al. (²⁰) reported that hemodynamic changes after induction with propofol were not modified when the propofol dose was increased from 2 to 3.5 mg/kg. In the second series of this study, the inclusion criterion was mild to moderate hypertensives (diastolic blood pressure <110 mm Hg) who were taking antihypertensive drug(s) at the time of the investigation. There must be a wide variation among the patients. However, there was a significant difference between the high-dose landiolol and control groups, despite the small sample size. This strongly indicates that landiolol inhibits the sympathetic response after endotracheal intubation in hypertensive patients.

In conclusion, landiolol at a dose of 0.1 mg/kg prevented tachycardia induced by endotracheal intubation when the drug was administered 4 min before intubation in normotensive patients. On the other hand, a 0.2 mg/kg dose of landiolol was required to prevent tachycardia after intubation in hypertensive patients. Within these doses, landiolol has no untoward effects on arterial blood pressure before or after intubation.