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Nicardipine Is Superior to Esmolol for the Management of Postcraniotomy Emergence Hypertension: A Randomized Open-Label Study

Bebawy, John F. MD; Houston, Christopher C. MD; Kosky, Jenna L. MD; Badri, Ahmed M. MD; Hemmer, Laura B. MD; Moreland, Natalie C. MD; Carabini, Louanne M. MD; Koht, Antoun MD; Gupta, Dhanesh K. MD

doi: 10.1213/ANE.0000000000000473
Neuroscience in Anesthesiology and Perioperative Medicine: Research Report

BACKGROUND: Emergence hypertension after craniotomy is a well-documented phenomenon for which natural history is poorly understood. Most clinicians attribute this phenomenon to an acute and transient increase in catecholamine release, but other mechanisms such as neurogenic hypertension or activation of the renin-angiotensin-aldosterone system have also been proposed. In this open-label study, we compared the monotherapeutic antihypertensive efficacy of the 2 most titratable drugs used to treat postcraniotomy emergence hypertension: nicardipine and esmolol. We also investigated the effect of preoperative hypertension on postcraniotomy hypertension and the natural history of postcraniotomy hypertension in the early postoperative period.

METHODS: Fifty-two subjects were prospectively randomized to receive either nicardipine or esmolol as the sole drug for treatment of emergence hypertension at the conclusion of brain tumor resection (40 subjects finally analyzed). After a uniform anesthetic, standardized protocols of these antihypertensive medications were administered for the treatment of systolic blood pressure (SBP) >130, with the goal of maintaining SBP <140 throughout the first postoperative day. In the event of study medication “failure,” a “rescue” antihypertensive (labetalol or hydralazine) was used. The O’Brien-Fleming Spending Function was used to calculate the appropriate α value for each interim analysis of the primary outcome; univariate analysis was performed otherwise, with a 2-sided P<0.05 considered statistically significant.

RESULTS: The incidence of nicardipine failure (5%, 95% confidence interval [CI] 0.1%–24.9%) was significantly less than that of esmolol (55%, 95% CI 31.5%–76.9%) as a sole drug in controlling SBP after brain tumor resection (difference 99% CI 13.8%–75.7%, P = 0.0012). The presence of preoperative hypertension or the approach to surgery (open craniotomy versus endonasal transsphenoidal) had no significant effect on the incidence of failure of the antihypertensive regimen used. We did not observe a difference in the need for opioid therapy for postcraniotomy pain between drug groups (99% CI difference −39.2%–30.2%). Failure of the study drug predicted the need for rescue drug therapy in the initial 12 hours after discharge from the recovery room (difference success versus failure = −41.7%, 99% CI difference −72.3% to −1.8%, P = 0.0336) but not during the period 12 to 24 hours after discharge from the recovery room (difference success versus failure = −27.4%, 99% CI difference −63.8%–9.2%, P = 0.143). However, in those patients carrying a preoperative diagnosis of hypertension, the need for rescue medication was only different during the period 12 to 24 hours after discharge from the recovery room (difference normotensive versus hypertensive = −35.4%, 99% CI difference −66.9% to −0.3%, P = 0.0254).

CONCLUSIONS: Nicardipine is superior to esmolol for the treatment of postcraniotomy emergence hypertension. This type of hypertension is thought to be a transient phenomenon not solely related to sympathetic activation and catecholamine surge but also possibly encompassing other physiologic factors. For treating postcraniotomy emergence hypertension, nicardipine is a relatively effective sole drug, whereas if esmolol is used, rescue antihypertensive medications should be readily available.

Published ahead of print October 8, 2014.

From the Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Accepted for publication August 13, 2014.

Published ahead of print October 8, 2014.

Funding: Supported financially by the Melissa Fragen Faculty Development Research Award (JFB) and the Northwestern University Department of Anesthesiology.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

This report was previously presented, in part, at the MARC 2014.

Address correspondence to John F. Bebawy, MD, Department of Anesthesiology, Northwestern University Feinberg School of Medicine, 251 E. Huron St., Suite F5-704, Chicago, IL 60611. Address e-mail to j-bebawy@northwestern.edu.

Emergence hypertension after craniotomy is a well-documented phenomenon, although its natural history is poorly understood. Previous investigations demonstrated that treatment with antihypertensive drugs is required in 60% to 90% of patients after craniotomy.1,2 Most clinicians attribute this phenomenon to an acute and transient increase in catecholamine release, subsequent peripheral vasoconstriction, and reduced baroreceptor sensitivity. However, mechanisms such as neurogenic hypertension from the preceding brain manipulation or activation of the renin-angiotensin-aldosterone (RAA) system have also been proposed as contributing to the development of postcraniotomy emergence hypertension (PCEH). Furthermore, the extent to which preoperative hypertension contributes to this phenomenon, as well as the duration of this hemodynamic change, is also unclear. What is more certain is that strict control of blood pressure is very important during and after intracranial procedures. Failure to prevent hypertension places patients at increased risk of periresection bed hematoma formation, hematoma formation distant from the resection bed (in some cases requiring surgical intervention), cerebral edema, and increased intracranial pressure.3,4 These complications may arise from surgical breach of the blood–brain barrier, impaired autoregulation attributable to vasoparalysis, or a combination thereof. Given the potential morbidity associated with this common phenomenon, it is important to identify how best to manage these commonly occurring hemodynamic changes.

An ideal drug for the management of PCEH would have a rapid onset of action as well as a rapid offset, making it easily titratable to the desired target blood pressure and simple to discontinue if the offending stimulus is short lived. Nicardipine is one of the most commonly used antihypertensive drugs in neurosurgical and neurocritical care patients.5 Although it has a rapid onset of action and is easily titrated when administered as an infusion, with or without an initial loading dose, its duration of action may last 4 to 6 hours after discontinuation of prolonged infusions.6 Esmolol is a B1-receptor antagonist that has a rapid onset of action and is easily titrated as a bolus and infusion.7 Furthermore, because of its metabolism by nonspecific red blood cell esterases, its duration of action is less than 30 minutes after discontinuation of even prolonged infusions. However, esmolol results primarily in a decreased heart rate (decreased chronotropy and inotropy), which may result in a lower ceiling of the maximal blood pressure reduction achievable than with nicardipine, which is a direct arteriodilator.

The primary purpose of this investigation was to compare, in a prospective and randomized fashion, the antihypertensive efficacy of the 2 most titratable drugs used to control blood pressure after craniotomy, namely nicardipine and esmolol. Our hypothesis was that nicardipine, being a direct peripheral arteriodilator, would be more effective as a sole drug for the treatment of PCEH than esmolol, which has a direct cardiac-depressant effect. Our secondary aims were to describe in more detail the natural history of PCEH and to determine whether a preoperative diagnosis of hypertension affected this phenomenon.

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METHODS

This open-label, randomized controlled trial was approved by the Northwestern University IRB (NCT01951950). After written informed consent, we enrolled adult subjects undergoing general anesthesia for elective craniotomy for resection of supratentorial, infratentorial, or suprasellar tumors. Patients were excluded if they were non-English speaking, were undergoing emergent craniotomy, or if they had active 3-vessel coronary artery disease or left main coronary artery disease, advanced heart block, severe aortic stenosis, chronic renal failure, or a known or suspected allergy or intolerance to a study drug or its components. Subjects were prospectively randomized upon enrollment in blocks of 10 to receive either nicardipine or esmolol infusions at emergence. Patients were dropped from the study if they did not meet emergence hypertension criteria (systolic blood pressure [SBP] >130 mm Hg) or were not tracheally extubated within 45 minutes after discontinuation of the volatile anesthetic.

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Anesthetic Management and Antihypertensive Protocol

The anesthetic regimen of all subjects consisted of a balanced anesthetic with a volatile anesthetic as the primary hypnotic (0.5–1 minimum alveolar concentration desflurane or sevoflurane), remifentanil as the sole intraoperative opioid (0.05–0.2 mcg/kg/min), and propofol added at the discretion of the attending anesthesiologist (0–100 mcg/kg/min) and discontinued at the beginning of dural closure. An intraarterial catheter was placed for invasive arterial blood pressure monitoring after tracheal intubation, which was facilitated by the use of rocuronium (0.6–1.2 mg/kg). Every subject received dexamethasone 10 mg after induction of anesthesia. Euvolemia was maintained during the case per the clinical judgment of the anesthesiologist, and IV fluids and vasoactive drugs given were recorded.

The emergence period was defined as beginning after the Mayfield head holder pins were removed. During this time, the remifentanil infusion was continued at 0.03 to 0.1 mcg/kg/min until immediately after extubation. Infusion of the study drug (nicardipine or esmolol) was initiated when the SBP was >130 mm Hg, with the goal of maintaining SBP <140 mm Hg. Although there is no clear definition of PCEH, our institutional practice is to maintain SBP <140 mm Hg for all craniotomies for tumor postoperatively; therefore, for the purposes of this study, we defined PCEH as an SBP >140 mm Hg and as a short-lived phenomenon (<24 hours). Nicardipine subjects received a 15 mcg/kg initial loading dose of nicardipine, and the infusion was initiated at 5 mg/h. Nicardipine infusions were increased no more frequently than every 5 minutes, if needed, with each increase in the infusion rate by 5 mg/h accompanied by a 15 mcg/kg initial loading dose. The maximum infusion rate of nicardipine was 15 mg/h. During the 4 minutes between allowed increases in the nicardipine infusion, the anesthesiologist could administer a 15 mcg/kg bolus every minute for SBP >140 mm Hg. If SBP was not maintained at <140 mm Hg 5 minutes after achieving the 15 mg/h infusion rate of nicardipine, medication “failure” was declared and “rescue” labetalol or hydralazine was administered at the discretion of the anesthesiologist. The infusion was titrated down if SBP decreased to <90 mm Hg.

Esmolol subjects received a 0.5 mg/kg initial loading dose of esmolol, and the infusion was initiated at 50 mcg/kg/min. Esmolol infusions were not increased more frequently than every 5 minutes, if needed, with each increase in the infusion rate by 50 mcg/kg/min accompanied by a 0.5 mg/kg initial loading dose. The maximum infusion rate of esmolol was 200 mcg/kg/min. During the 4 minutes between allowed increases in the esmolol infusion, the anesthesiologist could administer a 0.5 mg/kg bolus every minute for SBP >140 mm Hg. If SBP was not maintained <140 mm Hg 5 minutes after achieving the 200 mcg/kg/min infusion rate of esmolol, medication failure was declared and rescue labetalol or hydralazine was administered at the discretion of the anesthesiologist. The infusion was titrated down if SBP decreased to <90 mm Hg.

Blood pressure and heart rate variables were recorded continuously from the time of initiation of nicardipine or esmolol infusion through the first hour in the postanesthesia care unit (PACU). All infusion doses, rescue antihypertensives, and opioids (given only for a Visual Analog Scale pain score >4) required during the first 24 hours postoperatively were recorded. All doses were based on actual body weight.

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Statistical Methods

The primary outcome was the incidence of failure to treat PCEH (SBP >140 mm Hg) after 5 minutes of receiving the maximum infusion dose of nicardipine (15 mg/h) or esmolol (200 mcg/kg/min). On the basis of an approximately 30% failure rate of nicardipine8 versus an 8% failure rate of esmolol,2 60 patients per group would provide 84% power to detect a difference of 22% in the incidence of drug failure between groups, using a 2-sided Fisher exact test with a significance of 0.05. An a priori interim analysis was planned when 30 patients (15 per drug group) had completed the study to determine the true failure rate of each patient cohort given our specific anesthetic protocol, with a 2-sided P < 0.001 considered significant.9

At the planned interim analysis, the failure rate of nicardipine was 5% versus a 40% failure rate of esmolol (P = 0.0104). Because this analysis did not meet stopping criteria, the trial was continued. The recalculated sample size of 24 patients in each group would provide 80% power to detect a difference of 35% in the incidence of drug failure using a 2-sided Fisher exact test with a significance of 0.049, whereas 30 patients in each group would provide 89% power to detect a difference of 35%.

With the subsequent 10 patients, it was noted that all 5 patients who received esmolol met failure criteria, whereas none of the nicardipine patients failed. Because of the concern for futility of esmolol therapy with the possibility of exposing additional patients to undue hypertension, we performed a second unplanned interim analysis that met the stopping criteria (P < 0.01) that was revised because of the reevaluated risk versus benefit of exposure to ineffective therapy and unnecessary hypertension.

Univariate analysis was performed using StatsDirect statistical software (version 2.6.5; StatsDirect, Ltd.; Cheshire, UK). All of the data were tested for normality using the Shapiro-Wilk W test (all P > 0.12). Normally distributed data are presented as mean ± SD, and these data were compared between groups using an unpaired t test. Categorical data are presented as number (percent, 95% confidence interval [CI] calculated using the Clopper-Pearson method)10 and compared using Fisher exact test or χ2 test. An approximate 99% CI for differences between proportions was calculated using the iterative method of Miettinen and Nurminen, assuming 2 independent proportions.11 A 2-sided P < 0.05 was considered statistically significant, except as noted above for the primary outcome, where the O’Brien-Fleming Spending Function was used to calculate the appropriate α value for each interim analysis.

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RESULTS

We enrolled 52 patients, of whom 40 completed the study (Fig. 1). There were no differences between drug groups in major demographics, including the presence of a preoperative hypertension diagnosis, the outpatient antihypertensive therapy used, or the type of surgical procedure being performed (Table 1). There was a 5% (95% CI 0.1%–24.9%) incidence of failure in the nicardipine group and 55% (95% CI 31.5%–76.9%) incidence of failure in the esmolol group (difference 99% CI 13.8%–75.7%, P = 0.0012, Table 1). The preoperative diagnosis of hypertension did not predict failure of the respective study drug (P = 0.7723, Table 2). Patients who had a transsphenoidal resection of a suprasellar tumor did not have a different failure rate (44.4%, 95% CI 13.7%–78.8%) to their assigned drug than patients who underwent open craniotomy (25.8%, 95% CI 11.9% to 44.6%) (difference transsphenoidal versus open craniotomy 18.6%, 99% CI difference −21.4% to 59.3%, P = 0.4989).

Figure 1

Figure 1

Table 1

Table 1

Table 2

Table 2

Although we did not keep patients for a predetermined time in the operating room before moving to the recovery room, only 1 patient (2.5%, 95% CI 0.06%–13.2%) was in the operating room at the time of assigned study drug failure compared with 11 patients who failed on their study drug in the recovery room (27.5%, 95% CI 14.6%–43.9%) (difference in operating room failure versus recovery room failure −25%, 99% CI difference −46%- 5.4%, P = 0.0017). All of the study drug infusions were successfully weaned off in the recovery room, in some cases, because of the necessity for a rescue drug resulting from study drug failure. During the initial 12 hours and from 12 to 24 hours after discharge from the recovery room, there was no difference between the drug groups in the need for rescue medication (Table 3). Rescue medication was required in the initial 12 hours after discharge from the recovery room in 15 (37.5%, 95% CI 22.7%–54.2%) patients. Patients who failed one of the study drugs in the operating room or recovery room were more likely to require rescue medication during this initial 12-hour period on the ward (difference in success versus failure of study drug −41.7%, 99% CI −72.3% to −1.8%, P = 0.0336, Table 4). Rescue medication was required during the period from 12 to 24 hours after discharge from the recovery room in 9 (22.5%, 95% CI 10.8%–38.5%) of the patients. Failure of the study drug did not predict these patients (Table 4). A preoperative diagnosis of hypertension did not predict failure of monotherapy of the assigned study drug or the need for rescue medication during the initial 12 hours after discharge from the recovery room (Table 5). However, a preoperative diagnosis of hypertension did result in an increased need for rescue therapy during the period from 12 to 24 hours after discharge from the recovery room (difference normotensive versus hypertensive −35.4%, 99% CI difference −66.9% to −0.3%, P = 0.0254).

Table 3

Table 3

Table 4

Table 4

Table 5

Table 5

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DISCUSSION

Our data demonstrate that nicardipine is superior to esmolol as monotherapy for the treatment of PCEH. These data also demonstrate that PCEH is a transient phenomenon, although 37.5% of these patients required additional therapy during the initial 12 hours after discharge from the recovery room. Failure of monotherapy predicted the need for subsequent antihypertensive rescue medication during this initial period on the ward, but not usually during the 12- to 24-hour period. However, those patients with preoperative hypertension required additional antihypertensive medications within 24 hours because presumably, their underlying essential hypertension required treatment.

PCEH appears to be a real and tangible phenomenon, as evidenced by the fact that only 5 of 45 (11.1%, 95% CI 3.7%–24.1%) enrolled subjects in this study failed to meet hypertensive criteria for inclusion. However, the causes of emergence hypertension after craniotomy are far from clear; it does not seem to be purely pain related or sympathetically mediated because we observed no difference in analgesic requirement between successes and failures and did confirm that a sympatholytic (i.e., esmolol) was not routinely effective in controlling this sort of hypertension (although the sympatholytic effect of esmolol is limited to B1-receptor antagonism). Postcraniotomy hypertension is likely a multifactorial phenomenon that cannot be attributed to one cause alone, but probably encompasses a spectrum of phenomena, including pain, sympathetic discharge and catecholamine release, the effects of direct brain manipulation, perturbations of the RAA system, hypothermia, or anemia. Olsen et al.12 measured plasma catecholamine levels, namely epinephrine and norepinephrine, as well as renin, aldosterone, atrial natriuretic peptide, endothelin, and cortisol levels in the perioperative period in nonhypertensive patients undergoing craniotomy. They found that the postoperative concentrations of catecholamines were significantly higher than preoperative baselines in hypertensive patients, but that only renin levels were elevated in their nonhypertensive cohort. Their conclusion was that in addition to an increased sympathetic tone, activation of the RAA system likely plays a major role in the development of postoperative hypertension after craniotomy.

Kross et al.13 point out that emergence hypertension after craniotomy is likely a different phenomenon than the hypertension seen after other surgical procedures. Pain probably plays only a limited role in this type of hypertension because postoperative scalp infiltration with local anesthetics does relieve postoperative pain but has no hemodynamic effect in the PACU.14 Cerebral autoregulation may be impaired in the vessels in or near the resection bed after craniotomy, and this may contribute to PCEH, with previously hypertensive patients being more susceptible to this effect.15

What is more clearly understood is that PCEH, and associated cerebral hyperemia, is detrimental to patients.16,17 Hypertension in this setting may disrupt areas undergoing active hemostasis in the resection bed, leading to increased postsurgical bleeding and hematoma formation, whereas disruptions in autoregulation may cause increased cerebral blood flow during systemic hypertension, leading to worsening vasogenic edema through a compromised blood–brain barrier.

Nicardipine, although superior to esmolol as a sole drug for achieving hemodynamic control after craniotomy, is associated with a dose-dependent cerebral vasodilation and inhibition of autoregulation, which can worsen hyperemia.18,19 These effects are not known to occur with the administration of esmolol or other adrenergic agonists/antagonists, which seem devoid of direct cerebral hemodynamic effects.20 However, data from stroke patients demonstrate that nicardipine can be safely used to decrease systemic blood pressure without detrimental cerebral outcomes.21,22 Altogether, these data suggested that the direct cerebral hemodynamic effects of nicardipine may not be clinically important compared with the need to effectively treat PCEH.

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Limitations

Because this was an open-label study (no investigator blinding), operator bias may have affected the choice of rescue antihypertensive medication used (observer-expectancy effect). Rescue antihypertensive medications (labetalol or hydralazine) were administered in the PACU at the discretion of the recovery room staff, and therefore, some of our observations regarding the natural history of PCEH may have been contaminated by the residual actions of those rescue medications, which could have lasted for 2 to 6 hours. Moreover, we did not characterize or quantify the types and doses of antihypertensive medications taken by patients on the morning of surgery in those patients with a hypertensive diagnosis or whether this was a factor in the occurrence of PCEH. Finally, because this study was designed to describe, to some extent, the natural history of hypertension after craniotomy as a secondary outcome, we did not assess neurologic outcomes, and therefore, we were unable to comment on the potential clinical effects of PCEH.

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CONCLUSIONS

In summary, we found that nicardipine is superior to esmolol as monotherapy in treating PCEH. Approximately 90% of the patients in this study demonstrated PCEH. This study would seem to indicate that for treating postcraniotomy emergence hypertension, nicardipine is a relatively effective sole drug, whereas if esmolol is used, rescue antihypertensive medications should be readily available. Future studies are needed to further characterize this type of hypertension and to elucidate its mechanisms, which may lead to more targeted therapies to treat this common and possibly important phenomenon.

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DISCLOSURES

Name: John F. Bebawy, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: John F. Bebawy has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Christopher C. Houston, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Christopher C. Houston has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jenna L. Kosky, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Jenna L. Kosky has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Ahmed M. Badri, MD.

Contribution: This author helped conduct the study and write the manuscript.

Attestation: Ahmed M. Badri has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Laura B. Hemmer, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Laura B. Hemmer has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Natalie C. Moreland, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Natalie C. Moreland has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Louanne M. Carabini, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Louanne M. Carabini has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Antoun Koht, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Antoun Koht has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Dhanesh K. Gupta, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Dhanesh K. Gupta has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Gregory J. Crosby, MD.

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