Endoscopic endonasal transphenoidal surgery is a minimally invasive procedure for the treatment of pituitary adenomas and other related lesions [1–3]. The procedure is less traumatic and allows for many different variations of the approach and the ability to reach and manage the parasellar areas as well . Nevertheless, it presents short-lived but intensely painful aspects both during the nasal and sphenoidal phases of the operation (i.e. luxation of the turbinate, enlargement of the sphenoid ostium) and in the sellar phase (i.e. incision of the dura mater, ‘curettage' of the lesion). It is necessary to control blood pressure to reduce bleeding and thus to improve the neurosurgeon's view of the operative field. As endonasal endoscopic procedures end rapidly after removal of the endoscope, the anaesthesiologist has to ensure an adequate level of anaesthesia until the completion of the endoscopic manoeuvres, without prolonging recovery times at the end of surgery.
The introduction of more rapid and shorter-acting volatile anaesthetics (sevoflurane), intravenous (i.v.) anaesthetics (propofol) and opioid analgesics (remifentanil) has allowed anaesthesiologists to achieve a more consistent recovery profile that facilitates fast-tracking after general anaesthesia. The introduction of target control infusion (TCI) systems has enabled relatively accurate dosing by continuous infusion, based on the pharmacokinetic profile of propofol. There have been several studies comparing propofol with sevoflurane for induction, maintenance and recovery [5,6]. However, TCI with propofol vs. inhalational anaesthesia with sevoflurane has not yet been compared in the clinical setting of endoscopic endonasal transphenoidal surgery. The aim of this study was to examine recovery profile, surgical operative conditions and haemodynamic differences using remifentanil infusion with either propofol TCI or sevoflurane during endoscopic pituitary surgery.
With Institutional Ethics Committee approval and written informed consent, we enrolled 44 adult male and female patients in a prospective, randomized, single-blind, two-group study. All patients were ASA I, II or III and scheduled for elective pituitary surgery. Exclusion criteria were hypersensitivity to opioids, substance abuse, or a history of treatment with opioids or any psychoactive medication. After enrolment, patients were randomized by block randomization drawing lots from a closed box. In the operating room, before induction, all patients were given 5 mL kg−1 of saline solution infusion i.v. All patients were premedicated with midazolam 0.03 mg kg−1 and atropine 5 μg kg−1 15 min before induction. It is our policy to use atropine to avoid or reduce the side-effects of the remifentanil bolus, especially when associated with propofol. Patients were assigned randomly to one of two groups: Group P (propofol–remifentanil) received propofol TCI and remifentanil; Group S (sevoflurane–remifentanil) received sevoflurane and remifentanil for maintenance of anaesthesia. In Group P, induction was achieved with remifentanil 0.5 μg kg−1, injected over 60 s, and then an infusion of remifentanil was started at 0.20 μg kg−1 min−1. The patient's age and weight were entered into the TCI unit enabling target propofol concentrations to be set, and the infusion started. For induction of anaesthesia, we selected a target blood concentration (Ct) of 5 μg mL−1, and when the effect site concentration reached a value of 3 μg mL−1, we reduced the Ct to this value. During induction, the patient's lungs were ventilated with 100% oxygen. Thereafter, the propofol Ct was titrated to maintain cardiocirculatory stability and satisfactory operating conditions.
Propofol was administered with a syringe pump (TE-372 Terufusion syringe pump TCI/TIVA, Terumo). In Group S, induction started with remifentanil as described above and propofol 0.5 mg kg−1 followed by 10 mg every 10 s until loss of verbal contact occurred. During induction, the sevoflurane vaporizer was set to 2 vol.% and ventilation with sevoflurane in oxygen was administered as required. After loss of the eyelash reflex and verbal response, a bolus dose of cisatracurium 0.15 mg kg−1 was administered for muscular paralysis with additional bolus doses as needed. The trachea then was intubated and the lungs were mechanically ventilated to achieve an end-tidal CO2 concentration of 35 mmHg with 50% nitrous oxide in oxygen. The end-tidal sevoflurane concentration and the propofol maintenance target infusion were adjusted to maintain an adequate depth of anaesthesia, as judged by clinical signs and haemodynamic responses to surgical stimuli, and were adapted in order to maintain mild hypotension (mean arterial pressure (MAP) ranging from 60 to 75 mmHg). In both groups, signs of light anaesthesia (i.e. hypertension, somatic or autonomic responses) were treated with remifentanil infusion rate increases (0.05 μg kg−1 min–1 increments). If haemodynamic instability persisted in either group, additional pharmacologic agents (clonidine) could be administered at the investigator's discretion. In both groups bradycardia was treated with atropine 0.25 mg. Residual neuromuscular block was antagonized at the end of surgery with prostigmine 2.5 mg and atropine 0.5 mg when necessary, as confirmed by neuromuscular monitoring. At the end of surgery, defined as the time when the neurosurgeon removed the endoscope, sevoflurane/remifentanil or propofol/remifentanil were discontinued and the lungs were ventilated with 100% oxygen. The doses of remifentanil and propofol administered during maintenance were recorded. The trachea was extubated when a regular spontaneous breathing pattern had been re-established and when the swallowing reflex was present. All adverse effects associated with induction such as involuntary movements, coughing, restlessness and pain on injection were noted. Fifteen minutes before the expected end of surgery, all patients received a 100 mL infusion of NaCl 0.9% containing ketorolac 30 mg for postoperative pain relief.
Continuous monitoring including heart rate (HR), oxygen saturation and end-tidal concentrations of carbon dioxide was performed. Baseline MAP was obtained immediately before induction of anaesthesia, and then systolic (SAP), diastolic (DAP) and MAP were monitored non-invasively (DINAMAP) at 2 min time intervals. Changes in HR and MAP were recorded at predetermined times in relation to surgical manoeuvres: during middle turbinate displacement, sphenoidal sinus enlargement, the removal of lesion (curettage) and at the end of surgery. The quality of the surgical field in terms of blood loss and dryness was rated at the same predetermined times by the neurosurgeon, who was unaware of the pharmacological treatments, using a four-point scale: excellent surgical conditions = 0 points; moderate bleeding = 1; abundant bleeding with reduced view of surgical field = 2; impossible to perform surgical manoeuvres = 3. Emergence from anaesthesia was assessed by measuring the times to return of spontaneous ventilation, extubation, response to verbal command (opening eyes), time–space orientation (stating name and date of birth) and when the Aldrete score was 9 or above. An observer who was blinded to the group allocation of the patients carried out the assessments of all early recovery end-points. All patients were then moved to the post-anaesthesia care unit (PACU), where observation was continued by an investigator and a PACU nurse, neither of whom was aware of the anaesthetic regimen. The level of postoperative pain was assessed by patient questioning, using a four-point scale (0 = none; 1 = mild; 2 = moderate; 3 = severe). Ondansetron 4 mg as antiemetic agent was prophylactically administered in all patients. The incidence of nausea or vomiting on a scale 0–3 (none, mild, moderate and severe) and other adverse events were also recorded. Pain and postoperative nausea or vomiting (PONV) were assessed upon PACU arrival, and then every 15 min during the initial 2 h following PACU entry.
For each patient, variations in MAP and HR were calculated from baseline values and were considered for comparison between the groups. Intragroup and intergroup comparisons were evaluated using one-way analysis of variance for repeated measures followed by Bonferroni's test. With regard to intergroup comparisons for non-parametric data, the U-test was used. The primary end-point of this study was defined as the time taken by the patient to state his/her correct name and birth date. Applying a priori power analysis, at least 19 patients had to be enrolled in each treatment group to provide 80% power to detect a 3-min difference in recovery time (α = 0.05; β = 0.2). Assuming a potential drop-out rate of 15%, we decided to recruit 22 patients per group. Data are presented as mean and standard deviation (SD). The threshold for statistical significance was taken as P<0.05.
The groups were similar with respect to age, weight, height and ASA physical status (Table 1). Pituitary pathology, duration of surgery and anaesthetic requirements during the maintenance phase are illustrated in Table 2. There was no significant difference between the two groups with respect to mean duration of surgery and remifentanil requirements. Haemodynamic responses were similar in both groups (see Table 3): HR and MAP recorded immediately before induction of anaesthesia (baseline) were similar in both groups. Induction was associated with a significant decrease in HR and MAP (between 15% in Group S and 20% in Group P). A transient increase towards baseline values in both HR and MAP was recorded after tracheal intubation. In both groups blood arterial pressure was successfully controlled throughout the surgical procedure with statistically significant decreases in MAP at each predetermined time. Two patients in the sevoflurane group and none in the propofol group required additional clonidine to achieve haemodynamic stability.
As regards to the conditions of the operative field, assessed by a four-step bleeding score (0–3), no statistically significant differences between the two groups were obtained. In every case, good surgical conditions were achieved as shown in Table 4. Recovery times were considerably shorter after remifentanil–sevoflurane; tracheal extubation was performed sooner, and patients were able to state their name and date of birth sooner, permitting an earlier neurological examination and cooperation with the neurosurgeon in comparison with the remifentanil–propofol group (see Table 5). Six cases (30%) of mild and two cases (10%) of moderate postoperative nausea and vomiting (PONV) occurred in the sevoflurane group, and three cases of mild PONV in the propofol group were reported (P = 0.07). Pain scores were low with no difference between the two groups. There was no difference between the two groups with regard to the other side-effects (see Table 6). Anaesthesia and surgery were otherwise uneventful and no patient had recall of any intraoperative events when asked the next day.
Anaesthetic techniques that optimize the intraoperative surgical conditions while providing for rapid, early recovery have assumed increased importance. At our institution, we have had particular success in controlling haemodynamic parameters using intraoperative infusion of remifentanil in comparison with fentanyl for the endoscopic endonasal approach to pituitary lesions [7,8]. Propofol and sevoflurane both decrease systemic vascular resistance, which is further augmented when administered in association with remifentanil. In our patients remifentanil 0.5 μg kg−1, injected over 60 s followed by an infusion at 0.20 μg kg−1 min−1, in association with either sevoflurane or propofol, achieved mild hypotension (MAP ranging from 60 to 75 mmHg) in all cases without marked reduction in arterial pressure at induction (SAP < 80 mmHg). In previous clinical investigations, haemodynamic stability was achieved using high doses of remifentanil at induction [9,10], and the most frequent adverse event was hypotension (MAP < 60 mmHg) especially in hypertensive patients . Patients with acromegaly or Cushing's syndrome are particularly likely to have co-morbidities such as hypertension, cardiomegaly, electrocardiogram abnormalities, left ventricular hypertrophy and coronary artery disease . Our approach is to reduce the dose of remifentanil during induction, avoid a high induction dose of propofol or use propofol TCI with lower initial targets, thus reducing the risk of marked arterial hypotension, especially in those patients. The remaining period of maintenance demonstrated generally good haemodynamic stability in both groups, and MAP was efficaciously controlled throughout surgery by titrating remifentanil.
We found that patients undergoing endoscopic pituitary surgery after remifentanil–sevoflurane anaesthesia recovered more quickly than those given remifentanil–propofol. This is consistent with previous studies comparing propofol with sevoflurane . Even with the use of TCI, the interindividual variability in concentration of propofol remains relatively large, indicating a large variance of pharmacokinetics among patients. In our study larger SDs in recovery times were found in the propofol group, supporting our finding that a more predictable emergence time was possible following sevoflurane than propofol.
In the endoscopic endonasal transphenoidal approach, the neurosurgeon needs a good and clear operative field until the final phases, when the reconstruction of the pituitary fossa with dural substitutes, synthetic materials and various glues takes places. The endoscope is withdrawn from the nose and the procedure ends abruptly. Towards the end, it is reasonable to shift to the drug having the faster elimination, while reducing the concentrations of the sevoflurane or propofol. However, inspite of early postoperative recovery in patients given sevoflurane, there were no significant differences in the times when patients were ready for discharge from the recovery ward in comparison with patients given propofol. This has also been found in previous studies [13–15] and may reflect discharge criteria such as standardized times in PACU.
As there is no septal or perichondral dissection with this surgical approach, a major source of postoperative pain is avoided and smaller amounts of analgesic drugs are needed, making the short duration of remifentanil's action less of a concern. Agitation and postoperative airway obstruction, which can be a problem in patients having pituitary surgery, are also reduced by the absence of nasal packing [16–20].
The present study has shown that both sevoflurane and propofol TCI in association with remifentanil are suitable anaesthetic techniques for endoscopic pituitary surgery and achieve circulatory stability, rapid titration in relation to clinical needs, good surgical field and fast recovery. Sevoflurane–remifentanil was associated with a faster recovery and this is especially useful in these cases where the surgical procedure ends abruptly.
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