Laryngoscopy and tracheal intubation (LTI) may cause undesirable increases in blood pressure (BP) and/or heart rate (HR) in anesthetized patients (1). Those with chronic hypertension, even if controlled, have the most exaggerated pressor responses (2,3). The magnitude of this response correlates directly with hospital admission BP (4). In patients at risk for myocardial infarction or stroke, many practitioners consider it prudent to use some form of treatment to oppose increased BP or HR with LTI. Among the recommended methods are increased depth of anesthesia with fentanyl (5–8), lidocaine to block laryngeal reflexes (9), esmolol (ESM) by bolus injection (10–18) or infusion (19–21), nitroprusside (22), and IV bolus verapamil (23), diltiazem (24), or nicardipine (NIC) (25). Nifedipine, although available for IV use in Europe, is approved only for sublingual administration in the United States.
Due to rapid redistribution, brain concentrations of IV induction drugs may be inadequate to oppose hemodynamic changes after LTI, especially with multiple laryngoscopic attempts. However, sufficient doses of IV induction drugs used to prevent circulatory changes after LTI may cause bradycardia or hypotension. Furthermore, none of the suggested methods for attenuating hemodynamic changes with LTI (5–25) is completely satisfactory. Although β-blockers oppose increased HR and arrhythmias, they may not adequately control BP. Vasodilators oppose increased BP, but do not control HR or arrhythmias. Nifedipine absorption is unpredictable after sublingual administration and may therefore cause severe hypotension (26). A more satisfactory approach might be to use smaller doses of IV drugs with complimentary actions.
NIC, a dihydropyridine calcium channel blocker similar to nifedipine, is available for IV use. Although it reduces systemic vascular resistance, it has no discernible effect on contractility or preload (27–29). However, it may cause a dose-dependent, reflex increase in HR (25). After bolus dosing (1–7 mg), the onset of peak effect is rapid (2–3 min), with effects lasting up to 25 min (30). Bolus NIC has been shown to oppose increased BP after LTI (25,31–33). ESM also has a rapid onset and short duration of action, and opposes increased HR and arrhythmias after LTI. However, it does not reliably protect against increased BP (10–18). Therefore, we tested the premise that NIC and ESM, together in reduced dosage, might be more effective than either alone to blunt increased BP and HR after LTI.
This study had institutional approval. Written, informed consent was obtained from all patients. Adults (ASA 1–3) having elective surgery under general anesthesia were randomized to open-label pretreatment with ESM (1.0 mg/kg;n = 38), NIC (30 μg/kg;n = 31), or one-half dose of each (combination [COMB];n = 33) based on estimated ideal body weight. Also, with institutional approval and informed consent, a subsequent and separate group of 35 control (CONT) patients received no pretreatment. Excluded were patients with unstable coronary artery disease or heart failure, atrial or ventricular tachyarrhythmias, 2° or 3° heart block, sinus node dysfunction, or resting BP outside the 100/50–160/110 mm Hg range.
On arrival in the preoperative holding area, IV access, five-lead surface electrocardiogram (ECG) monitoring, surface oximetry, and noninvasive BP monitoring were established. If indicated, direct arterial and/or central venous pressure monitoring were instituted prior to induction of anesthesia. Other than antibiotics, no drugs were used for premedication. The patient was brought to the operating room, where HR, BP, and ECG rhythm (Lead II) were recorded with the patient awake (baseline = T0). Rhythm codes were: sinus = 0; sinus pause, arrest, or 2° or 3° atrioventricular (AV) block lasting ≥5 s = 1; nonsinus origin supraventricular beats = 2; and any ventricular origin beats = 3. Categories 1–3 were considered arrhythmias. Next, study drug was administered, with HR and BP recorded 2 min after pretreatment (T1). For CONTs, T1 measurements were recorded just before anesthetic induction. For induction of anesthesia, thiopental (5–7 mg/kg), fentanyl (1–2 μg/kg), and succinylcholine (1.5 mg/kg) were used, with the dose used based on estimated ideal rather than actual body weight. HR and BP were recorded 1 min after anesthetic induction (T2), and at 1-min intervals thereafter up to 5 min (T3, T4, T5, and T6). Peak HR and BP from measurements at T3, T4, T5, or T6 was recorded as the peak value after LTI (TP).
Data are reported as mean ± SD. Doses of thiopental and fentanyl for the induction of anesthesia in the four test groups were compared by one-way analysis of variance (ANOVA) (34), using the SAS software package. Repeated-measures ANOVA (34) was used to compare values for HR and systolic BP (SBP), diastolic BP (DBP), or mean BP (MBP) at T1, T2, and TP to those at T0 in each test group. For each test variable, 12 comparisons were made. Therefore, to account for multiple testing, each comparison was made at the 0.004 significance level. Thus, the overall significance was approximately 0.05. Repeated-measures ANOVA was also used to compare HR and BP between test groups at T0, T1, T2, and TP. This required 24 comparisons for each test variable. Therefore, each individual comparison was performed at the 0.002 level of significance, so that the overall level was approximately 0.05.
Five patients were excluded from analysis because of missing data for Time 1: four from the ESM group and one from the COMB test group. Consequently, 132 patients from the four test groups (Table 1) were used in the analysis. Demographic characteristics, concurrent medication, and associated disease for these patients are provided in Table 1. Except for more patients with hypertension in the ESM test group, there were no significant differences among test groups (Table 1).
Anesthetic Dose, LTI, and Arrhythmias
The dose of succinylcholine (1.5 mg/kg) was the same for all patients. Mean fentanyl and thiopental doses for anesthetic induction, and the number of LTI attempts, did not differ among the test groups (Table 2). Although 6 of 132 patients had more than three LTI attempts (Table 2), this was completed by T6 in all patients. No patient had sinus pause or arrest, or AV heart block with LTI. Except for one patient with transient supraventricular tachycardia of 191 bpm after LTI in the ESM test group, transient atrial or ventricular extrasystoles (duration <1 min) were the only arrhythmias observed, with no significant difference in incidence among test groups (Table 2).
Compared with baseline (T0), peak HR (TP) was increased after LTI in all test groups (Table 3). The patient with transient supraventricular tachycardia (ESM test group) likely skewed HR upward in the ESM group, so that the peak HR was significantly increased from baseline (Table 3). Although peak HR was higher in CONT patients, it was not statistically different from values in other test groups (Table 3). HR increased after pretreatment with NIC (T1 versus T0), but was not affected by other pretreatment (Table 3). HR was increased after anesthetic induction (T2 versus T0) with both NIC and COMB, but not in the ESM or CONT test groups (Table 3). Finally, HR was lower with ESM, compared with NIC at T1 and T2 (Table 3).
Compared with baseline T0, peak SBP and DBP (TP;Table 4) were increased in all but the COMB test groups. Peak MBP (TP;Table 4) was not different from baseline (T0) in any test group. However, peak SBP, DBP, and MBP were higher with ESM, compared with COMB, and peak DBP higher with ESM vs. NIC. After pretreatment (T1 versus T0), SBP and DBP were reduced by NIC and COMB, but not ESM. Also, after pretreatment (T1 versus T0), SBP, DBP, and MBP were increased with ESM, compared with NIC. MBP after pretreatment (T1 versus T0) and anesthetic induction (T2 versus T0) did not change in any test group, including CONT. Finally, after induction of anesthesia (T2 versus T0), SBP was decreased in all but the CONT group, and DBP in the NIC and COMB groups, but not ESM or CONT groups.
In patients without pretreatment (NIC and/or ESM), peak HR and BP after LTI were increased compared with baseline. No pretreatment, including ESM alone (1.0 mg/kg) or combined (0.5 mg/kg) with NIC 15 μg/kg, was effective for blunting the peak increase in HR after LTI. Furthermore, neither ESM (1.0 mg/kg) nor NIC (30 μg/kg) were effective for blocking the peak increase in BP after LTI. As expected, however, combined ESM and NIC did blunt the peak BP increase after LTI.
The dose of ESM to prevent increased BP and HR after LTI may be somewhat higher than we tested. Helfman et al. (12) administered ESM 150 mg to their patients, who had an average weight of 80 kg. This dose of ESM was effective for blunting the maximal increase in HR and BP after LTI, and calculates to approximately 2 mg/kg (based on ideal weight) versus 0.5 or 1.0 mg/kg used for pretreatment with COMB or ESM, respectively, in patients of this study. Neither dose of ESM was effective. This might be because, in the study of Helfman et al. (12), patients received 2–6 mg of midazolam premedication; our patients did not. Otherwise, induction of anesthesia was similar in both studies. In carotid endarterectomy patients, preinfusion of ESM (approximately 4.0 mg/kg over 12 min) did blunt the increase in HR and BP after LTI (21). In two additional studies, pretreatment with 200, but not 100 mg of ESM was also effective (13,20). But, in two other studies, both the 100- and 200-mg doses were effective (22,23). In one of these studies (23), these ESM doses were equal to 1.4 ± 0.3 and 2.6 ± 0.7 mg/kg, higher than those we used.
NIC, a direct arterial dilator, has little direct effect on the sinoatrial or AV nodes (27–29). However, there may be a reflex-mediated, dose-related increase in HR after its administration (23,25), and the drug does not block increased HR after LTI (23–25,32,33,35–37). The inability of NIC to prevent increases in HR after LTI was confirmed in this study. These same earlier studies (23–25,32,33,35–37) indicate that NIC 20–30 μg/kg will blunt the maximal increase in BP after LTI. In contrast, in our study, NIC 30 μg/kg failed to show significant protection, although in no test group, including CONT, was maximal BP as great as with ESM (Table 4). Song et al. (25) have reported that as little as 1.0 mg of NIC (10–15 μg/kg for most patients of this study) provided optimal BP control for laryngoscopy and tracheal intubation. However, the reduction in maximum BP after LTI in the Song et al. (25) study may be in part attributed to midazolam 2.0 mg for premedication, and propofol 1.5 mg/kg, sufentanil 10 μg and vecuronium 0.1 mg/kg for anesthetic induction. Based on known circulatory effects, propofol, sufentanil, and vecuronium may support slower HRs than thiopental, fentanyl, and succinylcholine, in addition to more vasodilation with propofol than with thiopental.
Limitations to this study include the absence of dose ranging for NIC, ESM, or COMB, and the variable induction doses for thiopental (5–7 mg/kg) and fentanyl (1–2 μg/kg). As discussed herein, it is likely a dose for ESM ≥ 1.5 mg/kg (based on ideal body weight) would have been needed to blunt increased BP and HR in patients of the ESM test group. With regard to COMB, we can only speculate that ESM 1.0 mg/kg with NIC 30 μg/kg would be sufficient. Whereas doses of fentanyl and thiopental used for induction of anesthesia varied, the average amounts used (Table 2) did not differ among test groups. Consequently, we believe that they had little effect on the outcome. However, as noted previously, there is considerable variation in the dose of drugs used for premedication and anesthetic induction in studies of methods to blunt the increase in HR and BP after LTI. This study was open-label, which may introduce a possible source of bias. Such bias was likely reduced by use of an impartial observer who recorded the data. Furthermore, the peak increase in HR or BP may have been missed, especially in those patients with multiple attempts at LTI. However, only six patients had more than three attempts at LTI (Table 2), and these were distributed among the four test groups.
Lastly, it was not a purpose of this study to address issues such as cost, convenience, or patient outcomes. ESM is relatively inexpensive and conveniently packaged for IV bolus use. NIC is not inexpensive, and is currently packaged in 10 mL vials (2.5 mg/mL), labeled for dilution to 100 μg/mL for continuous IV infusion. A better repackaging would reduce wastage. NIC (0.5 mg/mL) is stable for up to one week when stored in glass syringes and multiple standard IV solutions: 5% dextrose and 0.45% NaCl injection; 5% dextrose and 0.9% NaCl injection; 0.45% and 0.9% NaCl injection; 5% dextrose and lactated Ringer’s injection; 5% dextrose injection; lactated Ringer’s injection; and 5% dextrose injection with KCl 40 mEq/L (38). However, it is not stable in polyvinyl chloride containers or 5% NaHCO3 injection (38). Our pharmacy supplies us with 5-mL glass syringes containing 1.0 mg/mL NIC in 0.9% NaCl. The syringes are protected from light (black plastic bag) and have a shelf-life of 48 hours. This practice helps reduce cost and increase convenience. To our knowledge, the stability of combined NIC and ESM has not been tested. Finally, neither this nor other studies have addressed the issue of patient outcomes after preemptive treatment to blunt hyperdynamic circulatory changes after LTI. However, if it can be shown that preemptive treatment prevents unanticipated hospital admission or added testing for complications (e.g., ECG changes suggestive of ischemia), then this practice does appear justified.
The authors extend their appreciation to Ms. Joyce Peck and Ning Xi, MS for invaluable technical assistance with the study.
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