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A Comparative Study Between a Calcium Channel Blocker (Nicardipine) and a Combined α-β-Blocker (Labetalol) for the Control of Emergence Hypertension During Craniotomy for Tumor Surgery

Kross, Ronald A. MD*; Ferri, Enrico MD; Leung, Denis PhD*; Pratila, Margaret MD*; Broad, Clara MD*; Veronesi, Michele MD; Melendez, Jose A. MD*

doi: 10.1097/00000539-200010000-00024

We compared the efficacy of the combination of enalaprilat/labetalol with that of enalaprilat/nicardipine to prevent emergence postcraniotomy hypertension. A prospective, randomized open labeled clinical trial was designed to compare the incidence of breakthrough hypertension (systolic blood pressure [SBP] > 140 mm Hg) and adverse effects (hypotension, tachycardia, and bradycardia) between the two drug combinations. Secondarily, the effects of the drugs on SBP, mean blood pressure, and diastolic blood pressure were evaluated over the course of the study. Forty-two patients received enalaprilat 1.25 mg IV at dural closure followed by either multidose nicardipine 2 mg IV or labetalol 5 mg IV to maintain the SBP below 140 mm Hg. SBP was similarly controlled in both groups. There was a marginally smaller incidence of failures and adverse effects with labetalol. Blood pressure profiles were similar for both groups.

Implications When given in combination with enalaprilat, nicardipine is a good alternative to labetalol for controlling emergence hypertension after craniotomies.

*Departments of Anesthesiology and Critical Care Medicine and Biostatistics, Memorial Sloan-Kettering Cancer Center and Weil Medical College of Cornell University, New York, New York; and †Department of Anesthesiology, University of Ferrara, Ferrara, Italy

June 22, 2000.

Address correspondence to Ronald A. Kross, MD, Anesthesiology and Critical Care Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, 100021.

Strict control of blood pressure can be of paramount importance during neurosurgical procedures. Anecdotally, some authors postulate that brief periods of hypertension during neurosurgery or on emergence from anesthesia may result in postoperative bleeding and cerebral edema (1–3). It is generally preferable to avoid the occurrence of hypertension by preemptive therapy. Blood pressure control may be best achieved by combining longer-acting drugs of slow onset with faster-acting drugs of short duration. At our institution, emergence hypertension is anticipated and averted by using a combination of enalaprilat and labetalol to maintain systolic blood pressure (SBP) < 140 mm Hg.

In some patients, the use of β-adrenergic blocking drugs is contraindicated (i.e., chronic obstructive pulmonary disease, asthma) or, occasionally, ineffective (i.e., nonresponders) (4). In these settings, the use of IV calcium channel antagonists may play a role. The IV infusion of nicardipine has been used as an alternative to other antihypertensive drugs (i.e., sodium nitroprusside) for controlling acute hypertension (5). Recently, an intermittent-dose nicardipine was administered to acutely decrease arterial pressure during cardiac surgery (6). Although the use of intermittent IV calcium channel blockers for blood pressure control during aneurysm clipping has been reported (7), the efficacy of intermittent dose nicardipine for the control of emergence hypertension after craniotomy for tumor resection has not been examined.

A randomized, open-labeled clinical trial was performed to test the hypothesis that acute emergence hypertension could be equally prevented by the administration of either intermittent dose labetalol or nicardipine. Nicardipine was expected to be a satisfactory alternative to labetalol. The secondary end-points were differences in the incidence of adverse effects, the numbers of doses given, and cost analysis. In addition, the effect of these test drugs on SBP, mean (MBP) and diastolic (DBP) blood pressures, and heart rate (HR) was evaluated.

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This study was approved by the hospital’s institutional review board, and all subjects provided informed consent. Patients scheduled for elective craniotomy for brain tumor resection were preoperatively evaluated by an attending anesthesiologist. Patients with a history of either allergy to the trial drugs or asthma were excluded. To simplify randomization, patients receiving angiotensin converting enzyme inhibitors, calcium channel blockers, or β-blockers were also excluded from the study.

Preanesthetic medication consisted of intramuscular midazolam 70 μg/kg and glycopyrrolate 0.2 mg 1 h before surgery. Anesthesia was induced with IV sodium thiopental (5 mg/kg), fentanyl (7 μg/kg) and vecuronium (0.15 mg/kg). Patients were monitored with electrocardiography, pulse oxymetry, end-tidal CO2, noninvasive blood pressure, and intraarterial blood pressure through an indwelling catheter placed in a peripheral artery before or immediately after the induction of anesthesia. Anesthesia was maintained with isoflurane (0.5%–1.5%) in N2O/O2 (70/30) mixture and pancuronium (0.03 mg · kg−1 · h−1). Ventilation was set to maintain arterial CO2 partial pressure between 20 and 25 mm Hg. Patients received enalaprilat 1.25 mg IV after closure of the dura mater. Patients were subsequently randomized by sealed enveloped technique to receive 1-mL doses of standard preparations of either nicardipine (2 mg) or labetalol (5 mg) to maintain SBP <140 mm Hg. No minimum time period was specified between doses. Attending anesthesiologists were instructed to aggressively administer the study drugs. Isoflurane 0.20%–0.60% was maintained until closure was completed. No narcotic was administered in the operating room (OR) after incision. Patients received lidocaine 1 mg/kg IV before extubation. Neuromuscular blockade was reversed with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Patients were extubated when they could follow commands. All patients received supplemental O2 (fraction of inspired oxygen = 0.30) during transport to and stay in the postanesthesia care unit (PACU).

The HR, SBP, MBP, DBP, and O2 saturation were recorded every 5 min after dural closure and every 15 min after admission to the PACU. The total number of doses of study drug administered to the subject in the OR and in the PACU were recorded. The narcotic doses given in the PACU were tabulated. Drug failure was defined as the occurrence of SBP > 140 mm Hg and lasting >2 min at any time after the initiation of study drug therapy. Each failure was considered a single event until blood pressure was reduced below 140 mm Hg. Effectiveness was defined as 1 − (total minutes of failure/total time). Adverse effects were desaturation (decrease in O2 saturation > 5%), tachycardia (HR > 100 bpm and 20% more than HR at time of enalaprilat administration), bradycardia (decrease in HR < 60 bpm and 20% less than HR at time of enalaprilat administration), and hypotension (MBP < 60 mm Hg lasting 5 min).

χ2 tables and Fisher’s exact tests were used to examine the primary and secondary end-points. Student’s t-test was used to compare the number of doses given of each drug. To identify differences across time and within drugs, one-way analysis of variance (ANOVA) for repeated measures with post hoc contrast was performed on SBP, MBP, DBP, and HR at the time of the enalaprilat administration, before admission to the PACU (60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, and 5 min), on admission to the PACU and after admission to the PACU (15, 30, 45, and 60 min). Statistical significance was achieved when P < 0.05. Data were reported as mean ± sd.

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Forty-two patients, [15 female and 27 male], were studied between July 1995 and March 1999. The average age was 50 ± 17 yr. The indication for surgery was a primary brain tumor in 20 cases and a brain metastasis in 22 cases. There were no hypertensive patients. Demographic data are shown in Table 1. Randomization yielded 22 subjects in the labetalol group and 20 subjects in the nicardipine group. There was no difference in the analgesic requirements for morphine sulfate in the PACU between the labetalol (2 ± 2 mg) and nicardipine (2 ± 3 mg) groups. There was no difference in the time between enalaprilat administration and extubation for the labetalol (67 ± 14 min) and the nicardipine (69 ± 20 min) groups.

Table 1

Table 1

The combination of either enalaprilat/labetalol or enalaprilat/nicardipine for control of SBP was 99% and 90% effective, respectively. The incidence of treatment failures was marginally less for patients treated with labetalol than for patients treated with nicardipine (P = 0.05, Table 2). There were 234 doses of labetalol given during the study: 231 in the OR and 3 in the PACU. The labetalol group experienced two episodes of failure in the OR (2 min and 5 min) and two episodes in the PACU (5 min and 5 min). The highest SBP recorded in the labetalol group was 152 mm Hg occurring at extubation in one patient. One patient required 56 doses of labetalol to maintain SBP < 140 mm Hg. There were 99 doses of nicardipine given during the study: 87 in the OR and 10 in the PACU. There were six episodes of failure in the OR (2, 2, 5, 5, 5, and 15 min), and four episodes in the PACU (5, 15, 20, and 60 min). The most notable nicardipine failure occurred in the PACU; one patient experienced a persistent SBP between 146 and 159 mm Hg for 1 h despite seven doses of nicardipine. The highest SBP recorded in the study occurred in one patient receiving nicardipine (165 mm Hg). A significantly greater number of doses were administered to control blood pressure with labetalol (11 ± 11) than with nicardipine (5 ± 3).

Table 2

Table 2

The nicardipine group experienced a more increased incidence of adverse effects than the labetalol group. In the nicardipine group, two patients experienced bradycardia, four patients experienced tachycardia, and three patients experienced hypotension. Both events of bradycardia occurred in the PACU and both events were self-limited; they occurred at 25 and 120 min after nicardipine dose. The slowest HR was 48 bpm. In all four patients experiencing tachycardia, the events occurred between 0 and 15 min after the nicardipine dose; in one patient, tachycardia was associated with hypotension (78/36) requiring treatment with phenylephrine. Two other patients experienced hypotension (80/36, 77/43) within 10 min of a nicardipine dose. Episodes of hypotension lasted 20, 5, and 25 min, respectively. There was no relationship between the dose of nicardipine and the extent or duration of hypotension. In the labetalol group, only two patients experienced bradycardia, both occurring within 3 min of drug administration; none required treatment. There were no episodes of desaturation in either group.

In the labetalol group, at closure of dura, the SBP, MBP, DBP, and HR were 104 ± 9 mm Hg, 75 ± 8 mm Hg, 60 ± 8 mm Hg, and 84 ± 11 bpm, respectively. The first dose of labetalol resulted in a 8 ± 10 mm Hg, 4 ± 10 mm Hg, and 5 ± 8 mm Hg decrease in SBP, MBP, and DBP, respectively. During the same period, HR decreased by 3 ± 8 bpm. ANOVA revealed a significant increase between OR and PACU values of SBP (6%), MBP (9%), and DBP (15%) (Figure 1). The labetalol group experienced a progressive decrease in HR (14%) (Figure 2). The mean cost per patient was $5.23 ± $2.0.

Figure 1

Figure 1

Figure 2

Figure 2

In the nicardipine group, at closure of dura, the SBP, MBP, and DBP were 109 ± 9 mm Hg, 76 ± 8 mm Hg, and 60 ± 8 mm Hg, respectively. The first dose of nicardipine resulted in a 6 ± 13 mm Hg, 3 ± 7 mm Hg, and 2 ± 6 mm Hg decrease in SBP, MBP, and DBP, respectively. During the same period, there was no change in HR. ANOVA revealed no difference across time for SBP and MBP. There was a significant increase in DBP (9%) and decrease in HR (11%) (Figures 1 and 2). The mean cost per patient was $23.65 ± $6.62.

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We demonstrated that, when combined with enalaprilat, nicardipine was a suitable alternative to labetalol for control of postcraniotomy emergence hypertension. IV enalaprilat, half-life 11 hours, was administered to patients at the closure of the dura mater to provide relatively long-term antihypertensive protection (8). Because of the delayed onset (maximum effect 28.1 minutes) and moderate efficacy of the drug, enalaprilat was routinely supplemented with labetalol. The control of plasma renin levels and catecholamine effect was 98% effective. The pharmacodynamics of labetalol, onset of 10–20 seconds and peak activity at 5 minutes, compared well with those of nicardipine (9). Nicardipine, maximal response < 2 minutes (6,10), displayed a 90% effectiveness in controlling blood pressure. These results are consistent with those of others who have described the usefulness of intermittent-dose nicardipine (20–30 μg/kg) to prevent the circulatory responses to tracheal intubation in hypertensive patients (11). The finding that the nicardipine group required more PACU doses was consistent with the shorter half-life of nicardipine (one versus 5–6 hours).

The nicardipine-treated group experienced a higher incidence of hypotension and tachycardia than the labetalol group; oxygen desaturation, a consequence of augmentation of pulmonary shunting, was not observed (12). Although nicardipine causes reflex tachycardia when administered to awake patients (10), the nicardipine group did not experience consistent increases in HR after drug administration. Reflex tachycardia was observed in only 2 of 20 patients. In addition, the increased HR observed during emergence and extubation, when most of the doses were given, was probably caused by unopposed increased catecholamines. Cheung et al. (6), who studied the hemodynamic effects of nicardipine during cardiac surgery, suggested that general anesthesia may attenuate the reflex adrenergic response to vasodilation. In our study, most doses of nicardipine were administered in the presence of 0.5% isoflurane in N2O/O2. In addition, the enalaprilat effect, an increase in the stroke volume and a reduction of the HR, peaks after 30 min and may become the dominant influence on vital signs after extubation. In contrast, labetalol consistently decreased HR as a result of its effect on β-adrenal receptors in the sinus node.

Previous studies had demonstrated that nicardipine has a high efficacy in rapidly decreasing blood pressure with a minimal occurrence of side effects when administered as a continuous infusion (5). Nicardipine (2 mg) bolus results in hypotension (SBP < 85 mm Hg) in 6 of 10 patients after cardiac operations (12). In this series, we observed an incidence of hypotension of 4 of 20 patients. The smaller incidence of hypotension was probably the result of the difference in test conditions. In most cases, hypotension was self-limited; in one case, it was easily treated with phenylephrine. In contrast, there were no episodes of hypotension in the labetalol group. Oxygen desaturation, a consequence of augmentation of pulmonary shunting, was not observed (12).

Investigators postulate that hypertension increases the tendency to bleed at the operative site by disrupting the hemostatic plugs, blocking autoregulation, and thus allowing the blood volume to increase as the blood pressure increases. This causes vasogenic edema favoring the leakage of fluid through a blood-brain barrier damaged by surgical intervention. Labetalol may be the ideal antihypertensive for patients undergoing craniotomy because it does not influence cerebral blood flow or cerebral blood flow autoregulation (13,14). In contrast, nicardipine causes a dose-dependent cerebral vasodilation and inhibition of autoregulation. The occurrence of hypotension during nicardipine infusion results in decreases in regional cerebral blood flow (15). The significance of these findings and their relationship to surgical outcome have not been studied.

When comparing our results to those of other authors, we noticed a reduced blood pressure effect after either nicardipine or labetalol. Vincent et al. (12) showed a decrease of 3.9 mm Hg/mg nicardipine after 15 minutes in patients experiencing postoperative hypertension after vascular surgery. Abe et al. (16) demonstrated a larger reduction in MBP with 15 mm Hg/mg nicardipine in patients experiencing hypertension during aneurysmal clipping. In our study, the nicardipine group experienced an average decrease in MBP of 1.2 mm Hg/mg nicardipine. Orlowski et al. (9) reported a 20% reduction in mean arterial pressure with an average decrease of 0.71 mm Hg/mg labetalol after 15 minutes. Huey et al. (17), in a study on the treatment of hypertensive crisis, described an average reduction in SBP of 0.48 mm Hg/mg labetalol. Our series showed a 3.4% decrease in MBP, which corresponds to 0.09 mm Hg/mg labetalol. The variability in potency between studies may be explained by differences in anesthetic level at the time of drug administration. We studied patients during emergence, whereas other investigators studied patients under stable anesthetic or awake conditions. Based on the number of total doses needed to control BP, nicardipine (2 mg) appeared to be twice as potent as labetalol (5 mg). However, because the anesthesiologist administering the drug was not blinded, this finding may have been caused by a lack of familiarity with nicardipine.

The factors involved in emergence hypertension after craniotomy are likely different from those common to other surgical procedures. Pain does not appear to be an important factor in the development of postoperative hypertension. Although scalp infiltration with bupivacaine and epinephrine at end of craniotomy relieved postoperative pain, it did not have an influence on hemodynamics in the PACU (18). Interference with central autoregulation may provide an explanation for the high incidence of postoperative hypertension after craniotomy (19). Alterations of central autoregulation may result in a positive feedback loop, which induces an increase in blood pressure. Hypertensive patients may have a higher incidence of postoperative hypertension because of an increased sensitivity to this phenomenon (20). This study fails to address this critically important population. Further study is required to evaluate nicardipine-effected cerebral vasodilation in hypertensive patients.

Despite some important pharmacologic differences, nicardipine is an effective alternative to labetalol in controlling emergence hypertension after craniotomy. Although a higher incidence of side effects was noted, nicardipine provided acceptable control of blood pressure in most patients.

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