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Anesth Analg 2002;94:163-168
© 2002 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Remifentanil Provides Hemodynamic Stability and Faster Awakening Time in Transsphenoidal Surgery

Marco Gemma, MD*, Concezione Tommasino, MD*, Silvano Cozzi, MD*, Simona Narcisi, MD*, Pietro Mortini, MD{dagger}, Marco Losa, MD{dagger}, and Armando Soldarini, MD{ddagger}

Department of *Anesthesiology and Intensive Care, University of Milano; Departments of {dagger}Neurosurgery and {ddagger}Neuropsychiatric Sciences, Division of Laboratory Medicine, IRCCS San Raffaele Hospital, Milano, Italy

Address correspondence to Concezione Tommasino, MD, Department of Anesthesiology and Intensive Care, University of Milano, Anesthesia Dpt., IRCCS San Raffaele Hospital, Via Olgettina, 60, 20132 Milano, Italy. Address e-mail to tommasino.concezione{at}hsr.it


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In this prospective study, we evaluated the effects of remifentanil in ASA I–II patients undergoing transsphenoidal surgery. After the induction of anesthesia, patients were randomly allocated to the Isoflurane (n = 22, 60% nitrous oxide, isoflurane up to 2% end-tidal) or Remifentanil group (n = 21, 60% nitrous oxide, 0.5% end-tidal isoflurane, remifentanil up to 2 µg · kg-1 · min-1). If mean arterial pressure (MAP) increased >80 mm Hg during maximal dosage of isoflurane or remifentanil, labetalol was administered. At the end of anesthesia, extubation and awakening times, respiratory rate, SpO2, MAP, heart rate, and adverse effects were recorded. Hemodynamics and bleeding (minimal, mild, moderate, severe) were not different between groups. Bleeding grade increased with MAP >80 mm Hg (P < 0.001). Labetalol was administered to 20 patients in the Isoflurane group, and 10 patients in the Remifentanil group (P < 0.01). The dose of labetalol was larger in the Isoflurane group (1.0 ± 0.6 versus 0.5 ± 0.7 mg/kg, P < 0.05). Time to extubation did not differ, whereas time to follow commands was shorter in Remifentanil patients (16 ± 8 versus 10 ± 2 min, P < 0.01). No adverse effects occurred in the early postoperative period.

IMPLICATIONS: In patients undergoing transsphenoidal surgery, balanced anesthesia with remifentanil (0.22 ± 0.17 µg · kg-1 · min-1) provides faster awakening time, as compared with large-dose volatile-based anesthesia, without the risk of postoperative opioid respiratory depression.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
A major challenge during anesthesia for transsphenoidal microsurgery is control of arterial pressure and bleeding in the surgical field. The neurosurgeon, with the aid of the operative microscope, works in a narrow operative field, and even small amounts of blood complicate selective excision of the pituitary adenoma. Moreover, as the neurosurgeon approaches the sellar floor through the sphenoid sinus, the magnitude of painful stimulation can fluctuate widely, potentially leading to sudden increases in arterial pressure (1). Various approaches have been proposed to control the hypertensive response to such stimuli (1–3).

At our institution, transsphenoidal surgery is a very short procedure, and the anesthetic protocol relies on a large volatile anesthetic concentration and use of drugs, such as labetalol, to control episodes of arterial hypertension. However, early predictable recovery of consciousness is essential in this cohort of patients, because they return to the neurosurgical ward soon after the surgical procedure. Furthermore, in the postoperative period, these patients are at risk of potential airway difficulties because of nasal packing. They can breathe only through the mouth, and in the ward they do not have special respiratory monitoring. For these reasons, we administer small doses of opioids only at induction of anesthesia, to avoid postoperative respiratory depression.

The recently introduced ultra-short-acting µ-opioid receptor agonist, remifentanil hydrochloride, is a potent analgesic (4,5) and has been successfully used to control acute autonomic responses during neurosurgical procedures (6–9). Remifentanil has predictably short terminal and context-sensitive half-lives (9–12), independent of the duration of infusion (13), and is almost devoid of postanesthetic respiratory depression (11,12,14).

The aim of this prospective randomized study was to evaluate, in patients undergoing elective transsphenoidal surgery, the effects of remifentanil on intraoperative hemodynamics, extubation and awakening time, and postoperative ventilation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
After institutional approval and written informed consent were obtained, patients undergoing elective transsphenoidal surgery by the same neurosurgeon (PM) were considered for the study. ASA I or II physical status patients were eligible if aged 18–65 yr, had normal thyroid function, and had not undergone previous pituitary surgery. Patients with known hypertension or with diastolic blood pressure >90 and/or systolic pressure >150 mm Hg, during repeated preoperatory evaluations, were excluded.

No attempt was made to blind the anesthesiologist to the anesthetic regimen received by the patient. Neurosurgeons were blinded to the group assignment for each patient. One hour before arrival in the operating room, patients received appropriate steroid therapy and were premedicated with 0.1 mg/kg oral diazepam and 0.5 mg IM atropine.

Perioperative monitoring included electrocardiogram and heart rate (HR), invasive (radial artery) mean arterial blood pressure (MAP), peripheral oxygen saturation (SpO2), and urine output (bladder catheter). During anesthesia, ETCO2, nitrous oxide (N2O), and isoflurane were measured with an infrared analyzer.

Patients were given IV fentanyl, 1.5 µg/kg, and droperidol, 35 µg/kg, as an antiemetic drug. Anesthesia was induced with IV sodium thiopental (5 mg/kg). Muscle paralysis was induced with IV vecuronium bromide (0.1 mg/kg). After orotracheal intubation, the lungs were mechanically ventilated to maintain ETCO2 at 30–35 mm Hg. The mouth and posterior pharynx were packed with moist cotton gauze to avoid bleeding into the esophagus and glottic regions, and thus prevent postoperative vomiting of blood. A lumbar subarachnoid needle was inserted to control the degree of downward push on the tumor by injecting air or draining cerebrospinal fluid, as requested by the neurosurgeon.

To attain homogeneity between groups for the four major categories of patients undergoing transsphenoidal surgery (acromegaly, Cushing disease, nonsecreting adenoma, and prolactinoma), four randomization blocks were used, and patients were randomly assigned to either the Isoflurane or Remifentanil group. For the Isoflurane group, the anesthesiologists were asked to provide anesthesia according to our "standard" anesthetic protocol. Anesthesia was maintained with isoflurane (up to 2%, end-tidal). In the Remifentanil group, anesthesia was maintained with 0.5% isoflurane (end-tidal) and continuous IV infusion of remifentanil (up to 2 µg · kg-1 · min-1) (syringe infusion pump STC-521; Terumo, Tokyo, Japan). During surgery all patients received 60% N2O in oxygen and no muscle relaxants were used.

Ten minutes before incision, local anesthesia of the nose and upper gingiva was obtained in all patients with 2% mepivacaine and epinephrine (1:200000) (7–10 mL). During the surgery (from gingival incision to gingival suturing), the attending anesthesiologist, not involved in the study, titrated the administration of isoflurane (Isoflurane group) or remifentanil (Remifentanil group) to maintain the MAP between 60 and 80 mm Hg. MAP values >80 mm Hg were treated first with the maximal dosage of isoflurane (2% end-tidal) or remifentanil (2 µg · kg-1 · min-1), then labetalol was administered as needed. MAP values <60 mm Hg were treated with fluid administration and/or by reducing isoflurane (Isoflurane group) or remifentanil doses (Remifentanil group).

At the beginning of the gingival suture, N2O, isoflurane, and remifentanil were discontinued. The patients were then ventilated with 60% O2 in air. No naloxone was administered, and the decision to extubate was left to the attending anesthesiologist. The trachea was extubated upon resumption of spontaneous respiration and control of the airway (respiratory rate >10 breaths/min, ETCO2 <=40 mm Hg). After extubation, the patients remained in the recovery room for 1 h. MAP, HR, respiratory rate, SpO2, level of consciousness, nausea, vomiting, shivering, and cough were monitored by a nurse blinded to group assignment. Extubation time (from end of anesthesia to extubation of the trachea), and time to follow verbal commands ("open your eyes," "squeeze and release my hand" asked in a normal tone) were registered. During this period, patients were not stimulated except for requests to follow verbal commands.

The neurosurgeon (blinded to group assignment and hemodynamic data) evaluated intraoperative bleeding as "minimal," "mild," "moderate," or "severe." Only the naso-sphenoid dissection period was considered.

To evaluate intraoperative awareness, patients were asked in the postoperative period whether they could recall any intraoperative event.

To quantify the maintenance of targeted MAP with the two different anesthetic protocols, the time (min/h) during which MAP was <60 or >80 mm Hg was calculated for each patient and indicated as low (LPt, MAP <60 mm Hg) and high (HPt, MAP >80 mm Hg) pressure time. MAP values outside the targeted range were averaged (LPmean and HPmean).

Qualitative data were analyzed with Pearson {chi}2 and Fisher’s exact test. Quantitative data, expressed as mean ± SD or SEM, were analyzed with Bonferroni adjusted Student’s t-test, and one-way analysis of variance (ANOVA) for repeated measures as appropriate. A multivariate analysis, a one-way ANOVA was performed, where the bleeding grade was taken as the grouping factor. The trend of the MAP >80 mm Hg (HPmean), as well as the mean time during which MAP was >80 mm Hg (HPt), were tested by using orthogonal polynomial contrasts. A probability <0.05 was considered statistically significant. All analyses were calculated by using SYSTAT 7 (SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Forty-three patients were randomly assigned to either the Isoflurane (n = 22) or the Remifentanil (n = 21) group. Patients were comparable with respect to demographics, clinical pathology, baseline blood pressure, and thyroid function (Table 1).


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  		Table 1. Patient Demographics
 
Surgical time was similar in both groups (Table 2). The amount of 2% mepivacaine with epinephrine used for local anesthesia was the same, 8.9 ± 1 and 8.5 ± 1 mL, respectively, in the Isoflurane and Remifentanil groups. In the Isoflurane group, anesthesia was maintained with an average isoflurane end-tidal concentration of 1.5% ± 0.3%. During the last 10 min of surgery, the end-tidal concentration of isoflurane in the patients of this group was 0.7% ± 0.2%. In the Remifentanil group, the isoflurane concentration was kept unchanged during surgery (0.5% ± 0.0%), and patients received an average remifentanil infusion rate of 0.22 ± 0.17 µg · kg-1 · min-1.


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  		Table 2. Data Collected During the Study Period
 
In both groups, the hemodynamic profile was similar (Fig. 1), and the time during which MAP was <60 mm Hg (LPt) or >80 mm Hg (HPt), as well as the mean MAP values of these periods (LPmean, HPmean), did not differ (Table 2).



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  		Figure 1. Mean arterial blood pressure in the two groups of patients, Isoflurane and Remifentanil groups, during anesthesia for transsphenoidal surgery. All data are mean ± SEM. No significant difference was found between the two groups (one-way analysis of variance for repeated measures).

 
MAP values <60 mm Hg were easily controlled by increasing fluid administration and/or by reducing isoflurane concentration or remifentanil infusion rate. There was no need for the administration of vasopressor drugs.

Twenty of 22 patients in the Isoflurane group, and 10 of 21 patients in the Remifentanil group required labetalol to control MAP >80 mm Hg (P < 0.01). The dosage of labetalol administered was significantly larger in the Isoflurane group (1.01 ± 0.64 versus 0.47 ± 0.73 mg/kg, P < 0.05) (Table 2).

Bleeding grade did not differ between the two groups, and was not influenced by the anesthetic regimen. In the multivariate analysis, there was a significant (P < 0.001) linear increase in average HPt and HPmean across the 4 ordered levels of bleeding (Fig. 2).



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  		Figure 2. Relationship between bleeding grade, mean arterial blood pressure (MAP) >80 mm Hg (HPmean, P < 0.001) during surgery, and time (min/h) during which MAP was >80 mm Hg (HPt, P = 0.01) (one-way analysis of variance and orthogonal polynomial contrasts). HPmean and HPt values from both groups were pooled. Values are mean ± SD.

 
Time to extubation did not differ between groups. Time to follow verbal commands was significantly shorter (P < 0.01) in patients receiving remifentanil (Table 2).

In the recovery room, HR, MAP, and respiratory rate were similar, SpO2 was always >=97%, and no patient exhibited clinically significant nausea, vomiting, shivering, cough, or reduction in the level of consciousness. No patient reported explicit awareness of intraoperative events.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study we used a continuous infusion of remifentanil to supplement N2O-isoflurane anesthesia during transsphenoidal pituitary surgery, with the goal of preventing hemodynamic changes secondary to surgical stimulation, and to avoid postoperative opioid side effects, such as respiratory depression. Our results show that balanced anesthesia with small-dose isoflurane and remifentanil provides good control of acute intraoperative autonomic blood pressure responses, and allows faster awakening time, as compared with inhaled anesthesia alone, without risk of postopioid respiratory depression.

A major concern is whether the anesthetic regimens used in the present study provide comparable depths of anesthesia. In the Isoflurane group, the mean end-tidal isoflurane concentration during surgery was 1.5% ± 0.3%. This concentration, combined with 60% N2O, and considering the age of the patients, should provide a minimum alveolar anesthetic concentration (MAC) of approximately 1.5 (15). In surgical patients, Lang et al. (16) have demonstrated that remifentanil decreases the MAC of isoflurane, like other potent µ-opioid receptor agonists (17,18). At isoflurane concentrations of 0.4%–0.5%, remifentanil concentrations of 4–8 ng/mL (infusion rate 0.15–0.30 µg · kg-1 · min-1) likely provide adequate anesthesia (16). In our Remifentanil group, anesthesia was maintained with an end-tidal concentration of 0.5% ± 0.0% isoflurane, a mean remifentanil dose of 0.22 ± 0.17 µg · kg-1 · min-1, and 60% N2O. Therefore, the anesthesia regimen used in the Remifentanil group should have provided a MAC level similar to that of the Isoflurane group. Anesthesia depth was not evaluated with an electroencephalogram or other monitoring device. However, from the clinical point of view, the depth of anesthesia was similar in both groups. A study on depth of anesthesia, during balanced anesthesia with 0.5 MAC isoflurane, and 0.25 µg · kg-1 · min-1 remifentanil, has reported no changes in electrophysiologic variables in response to nociceptive stimuli (19).

Perioperative hemodynamic values were not different between groups. The targeted MAP range was similarly maintained with both anesthetic protocols, although the amount of labetalol needed to control blood pressure was significantly less in patients receiving remifentanil. This result is likely because of the potent analgesic effect of remifentanil (4,5), which has been used successfully to control acute autonomic responses during neurosurgical procedures (6–9). During transsphenoidal surgery, increases in blood pressure occur suddenly (1–3). It is possible that a larger isoflurane concentration in the Isoflurane group would reduce the requirements of labetalol, because larger isoflurane concentrations can provide better analgesia (20). However, previous human and animal studies have demonstrated that isoflurane did not prevent cardiovascular responses to painful stimuli at clinical concentrations (1 or 2 MAC) when given as a sole drug (21,22). Furthermore, we did not use larger concentrations of isoflurane because of the risk of hemodynamic instability (23). In the past, we have noticed that when MAP >80 mm Hg is controlled with isoflurane concentrations larger than 2% (maximal-allowed end-tidal concentration in the present study), hypotension can occur and the blood pressure reduction can last longer than required. We use labetalol to control the increase in blood pressure because of its rapid onset and short duration of action.

A weakness of the study design was the use of an open-label protocol from the anesthesiologist’s perspective. Because it was impossible to blind the attending anesthesiologist, it is conceivable that in the Remifentanil group MAP values larger than 80 mm Hg were treated more often with labetalol than with a large dose of remifentanil. By study protocol, it was possible to administer remifentanil up to 2 µg · kg-1 · min-1; however, the largest dose was always used for very short periods of time, and the remifentanil dosage used was 0.22 ± 0.17 µg · kg-1 · min-1. It is likely that a larger mean dosage of remifentanil could have further reduced the labetalol requirements in the Remifentanil group.

The main purpose of blood pressure control was to provide a dry field for the surgeon to improve visibility and facilitate the surgical approach. To achieve these goals, attention to the surgical field might be a better monitor than the absolute MAP. For this reason, we controlled the blood pressure according to both MAP values and the neurosurgeon’s subjective assessment. Bleeding during surgery was not influenced by the anesthetic regimen, as long as blood pressure was controlled. Several studies, in a variety of procedures, have demonstrated that surgical bleeding is related mostly to blood pressure and is independent of the anesthetic technique used to control the blood pressure (24,25).

In our study, remifentanil was chosen for two reasons: to provide adequate analgesia during intense stimuli in transsphenoidal surgery, and to avoid the risk of postanesthesia respiratory depression induced by opioids. Both of these aims were achieved and we found that, as compared to our "standard" inhalational technique, balanced anesthesia with remifentanil also provided faster emergence from anesthesia. Whereas awakening from anesthesia was significantly faster in remifentanil-treated patients, time of extubation did not differ between groups, likely because patients received a similar isoflurane concentration at the end of anesthesia. The early recovery after balanced anesthesia with remifentanil has been reported by other authors (26,27). In patients undergoing craniotomy, awakening time was shorter in patients receiving remifentanil as compared with fentanyl (28) or alfentanil (9). Such early recovery characteristics might provide a safety factor in surgery that involves the upper airway (29,30). Furthermore, in elderly patients undergoing laminectomy, Bekker et al. (31) have demonstrated that remifentanil-based anesthesia provides faster recovery of cognitive function, compared with isoflurane-based anesthesia. Complete awakening and orientation immediately after the termination of surgery is highly desirable when early neurologic evaluation needs to be performed in neurosurgical patients.

The pharmacokinetics of remifentanil (4,5,11,12) ensure that recovery from its effect occurs in a predictable manner, providing rapid emergence from anesthesia, which represents one of the general requirements in neuroanesthesia. There are also other reasons to believe that remifentanil is a suitable opioid for neuroanesthesia. The effect on intracranial pressure is similar to other opioids (6,7), remifentanil allows preservation of cerebral blood flow carbon dioxide reactivity (32,33), and when compared with other opioid-based anesthetics reduces the probability of a slow emergence (9,28), and provides a more rapid respiratory recovery (30).

It has been noted that, in the recovery period, patients receiving remifentanil can require analgesic drugs to prevent hypertension caused by acute loss of analgesia (9). In our study, we did not see significant hemodynamic differences in the two groups in the early postoperative period (first 60 minutes). Although neither anesthetic protocol included long-lasting analgesic drugs, all patients received extensive local anesthesia of the surgical field. Mepivacaine with epinephrine was used, and the long-lasting analgesic effect of this drug can in part explain why, in the early postoperative period, analgesic drugs were not required. Unfortunately, the study design did not include prospective postoperative pain evaluation.

The results of the present study lead to the following conclusions: First, balanced anesthesia with remifentanil was found to provide stable and similar hemodynamics during transsphenoidal surgery when compared with inhaled anesthesia. Second, the infusion of remifentanil during an operation with varying stimuli reduces the requirements of drugs controlling increased blood pressure, without increasing the risk of postoperative opioid respiratory depression. Third, awakening time from remifentanil-based anesthesia was significantly faster than inhaled anesthesia alone.

The rapid emergence from anesthesia and the absence of postoperative respiratory depression seem to be the chief benefits from the use of balanced anesthesia with remifentanil in elective transsphenoidal surgery.


   Footnotes
 
Presented in part at the Society of Neuroanesthesia and Critical Care Meeting and at the Annual Meeting of the American Society of Anesthesiologists, San Francisco, CA, October 2000.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication August 21, 2001.




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Right arrow Neuroanesthesia
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press