Four studies have examined the cerebral effects of sevoflurane in patients during cranial or spinal surgery or during minor nonneurologic surgery [1-4]. With sevoflurane, cerebral blood flow (CBF) and/or mean middle cerebral artery flow velocity (Vmca) was unchanged or decreased, autoregulation and carbon dioxide (CO2) reactivity of CBF or Vmca was preserved, the cerebral metabolic rate for oxygen decreased, and internal jugular venous oxygen tension did not decrease to values suggestive of hypoxia. Before sevoflurane was available in the United States, isoflurane was recommended for use during intracranial neurosurgery . No studies in patients have compared sevoflurane with isoflurane during intracranial neurosurgery. Accordingly, one aim of this study was to make such a comparison. Based on previous reports of the cerebral effects of isoflurane in patients and of sevoflurane compared with isoflurane in laboratory animals, we hypothesized that the effects of sevoflurane on Vmca, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and jugular venous oxygen saturation would be similar to those of isoflurane and that neither anesthetic would cause epileptiform activity on the electroencephalogram (EEG).
In addition, plasma inorganic fluoride concentrations reportedly increase during and after sevoflurane anesthesia in patients. Mean peak plasma inorganic fluoride concentrations were reported to range from 25.0 +/- 2.2 micro M with 1 minimum alveolar anesthetic concentration (MAC) hour of sevoflurane to 57.5 +/- 4.3 micro M with 14 MAC hours of sevoflurane [6-11]. Because spinal or cranial surgery often entails numerous MAC hours of anesthesia, high concentrations of plasma inorganic fluoride might be expected with sevoflurane. Further, during intracranial neurosurgery, the use of large doses of mannitol to produce substantial diuresis may decrease plasma volume, which elevates plasma inorganic fluoride concentrations from those previously reported during prolonged anesthesia [6-11]. Accordingly, a second aim of the present study was to determine peak plasma inorganic fluoride concentrations when mannitol 0.5-0.75 g/kg was given intravenously (IV) during sevoflurane anesthesia in patients having intracranial surgery.
The protocol for this study was reviewed and approved by the Human Subjects Committee at the University of Washington and the Institutional Review Board at the University of Utah. Fourteen patients of ASA physical status I-III who were scheduled for elective intracranial neurosurgery consented in writing to participate in the study. Included were patients undergoing tumor removal, aneurysm clipping, or resection of seizure focus or arteriovenous malformation. Excluded were minors and patients with tumors of a size expected to increase intracranial elastance or who were unsuitable for medical reasons. If needed for seizure prophylaxis, perioperative administration of phenytoin was permitted. Using a nonbalanced randomization sequence, patients were randomly assigned to receive either sevoflurane or isoflurane using a rebreathing (semiclosed) system with soda lime as the CO2 absorbent.
Standard intraoperative monitors were placed. In addition, a 20-gauge catheter was inserted into a radial artery to measure systolic and diastolic blood pressure and to sample arterial blood to measure blood gas tensions, hematocrit, inorganic fluoride, and routine laboratory values (see below). Mean arterial blood pressure (MAP) was determined by electronic integration of systolic and diastolic blood pressures. Anesthesia was induced with thiopental (3-5 mg/kg) or etomidate (0.25 mg/kg). Vecuronium (0.1 mg/kg) was given for muscle relaxation, the trachea was intubated, and the lungs were mechanically ventilated to achieve an expired CO (2) partial pressure (PETCO2) of 35-40 mm Hg. Anesthesia was maintained with sufentanil (0.2-1.0 micro g [center dot] kg-1 [center dot] h-1) and nitrous oxide (50%-70%) in oxygen. Total fresh gas flow was 1.5-3.0 L/min. Realtime EEG activity was monitored using a 16-electrode (Spectrum; Cadwell, Kennewick, WA) or 5-electrode (Lifescan; Neurometrics, San Diego, CA) montage. Vmca was measured by isonating the middle cerebral artery using a 2-mHz Doppler probe (Neuroguard or Transpect TCD; Medsonics, Fremont, CA or Multi-Dop; DWL, Sipplingen, Germany). The scalp was incised, a frontoparietal burr hole was made, and a Camino fiberoptic intraparenchymal monitor (Model 110-4B, NeuroCare[trademark symbol]; Saba Medical Group, San Diego, CA) was placed to measure ICP. Intraparenchymal monitors measure ICP by determining the degree of phase shift of an externally generated laser beam reflected off a deformable membrane in the transducer tip. CPP was calculated as the difference between MAP and ICP. Estimated cerebral vascular resistance (CVRe) was calculated as the ratio of CPP (mm Hg) to Vmca (cm/s) and expressed as millimeters of mercury per centimeter per second. In 9 of the 14 patients (5 patients assigned to receive sevoflurane and 4 patients assigned to receive isoflurane), a 16-gauge catheter was inserted cephalad into an internal jugular vein and placed in the jugular bulb to measure jugular venous oxygen saturation. Cerebral values (Vmca, ICP, CPP, EEG, and jugular venous oxygen saturation) and systemic values (MAP, heart rate, arterial blood gas tensions, hematocrit, esophageal temperature, PETCO2, and expired anesthetic concentration) were recorded during this baseline condition.
Nitrous oxide was then discontinued, and sevoflurane (n = 8) or isoflurane (n = 6) was added to the inspired gas mixture in stepwise fashion to achieve expired concentrations (Capnomac Ultima[trademark symbol]; Datex, Helsinki, Finland) of 0.5, 1.0, and 1.5 MAC [0.1%, 2.0%, and 3.0%, respectively, for sevoflurane , and 0.5%, 1.0%, and 1.5%, respectively, for isoflurane ]. Determination of cerebral and systemic values was repeated after 10 min at each anesthetic concentration. Expired anesthetic concentrations were recorded every 5 min before adjusting the anesthetic concentration, every 1 min during adjustments, and every 15 min thereafter until the end of surgery.
The Camino fiberoptic intraparenchymal monitor was removed, nitrous oxide (50%-70%) was reintroduced into the inspired gas mixture, and concentrations of sevoflurane or isoflurane were adjusted to those necessary to maintain adequate anesthesia with systemic blood pressure within 20% of the preoperative value during the ensuing intracranial neurosurgical operation. Mannitol 0.5-0.75 g/kg was given IV to decrease brain size before incision of the dura. One hour before completion of surgery, IV infusion of sufentanil was discontinued. Nitrous oxide and sevoflurane or isoflurane were discontinued upon completion of the head dressing after surgery. Neostigmine or edrophonium were given IV to antagonize residual neuromuscular relaxation.
The number of MAC hours of anesthetic was calculated from the expired anesthetic gas concentration by first calculating the average concentration of anesthetic gas using the trapezoid rule, then by dividing the appropriate MAC value and multiplying by the duration of anesthesia. Blood was sampled preoperatively; at 2, 4, 8, and 10 h after the start of sevoflurane or isoflurane as appropriate to the length of surgery; at the end of anesthesia; at 1, 2, 4, 6, 12, and 24 h postanesthesia; and at either 72 h postanesthesia or at the time of discharge for determination of plasma inorganic fluoride concentration. Plasma inorganic fluoride concentration was determined by ion-selective electrode. Blood and urine samples for routine laboratory analysis were obtained preoperatively and at 24 and 72 h postanesthesia.
Continuous variables were compared within and between groups using repeated measures analysis of variance. A t-test that used the mean square error from the analysis of variance was used to determine whether the within-group changes were different from zero. The Cochran-Mantel-Haenszel test was used for categorical variables with ordered categories (ASA class). A P value or test statistic of <0.05 was considered significant.
Eight patients received sevoflurane and six patients received isoflurane. The two groups were comparable with regard to sex, race, age, weight, ASA class, and preoperative physiologic values (Table 1). There was no statistical significance between the two groups with regard to duration of surgery, anesthetic MAC during surgery, duration of anesthetic exposure, MAC hours of anesthesia, or percent nitrous oxide during surgery.
ICP, MAP CPP, PaCO2, Vmca, CVRe, and jugular venous oxygen saturation did not differ between groups during baseline anesthesia with sufentanil (0.2-1.0 micro g [center dot] kg-1 [center dot] h-1) and nitrous oxide (50%-70%) in oxygen (Table 2). ICP did not differ from baseline values at 0.5, 1.0, or 1.5 MAC within either the sevoflurane or isoflurane group. Vmca decreased compared with baseline values at 0.5, 1.0, and 1.5 MAC sevoflurane or isoflurane. CPP decreased at 0.5 MAC sevoflurane and at 0.5, 1.0, and 1.5 MAC isoflurane. CVR (e) increased compared with baseline values at 1.0 and 1.5 MAC sevoflurane. The EEG was characterized by higher amplitude in the lower frequencies with sevoflurane or isoflurane compared with baseline. At 1.5 MAC, a burst suppression pattern was predominant in two of the eight patients receiving sevoflurane and one of the six patients receiving isoflurane. No instances of epileptiform EEG activity were noted in any of the patients. Jugular venous oxygen saturation remained >or=to50% intraoperatively and did not differ between groups.
Plasma inorganic fluoride concentrations did not differ between groups preoperatively. During anesthesia and for the first 72 h postanesthesia, plasma inorganic fluoride concentration was increased in both groups. The increase was significantly greater in the sevoflurane group than in the isoflurane group (Table 3). At 8 h, the plasma inorganic fluoride concentrations were 42.1 and 54.1 micro M in two patients receiving sevoflurane for >or=to8 h, and at 10 h, the concentration was 60.3 micro M in one patient receiving sevoflurane for >or=to10 h (not tabulated). Plasma creatinine at 24 h postanesthesia decreased compared with baseline in the group receiving sevoflurane but not in the group receiving isoflurane. Blood hemoglobin, hematocrit, white blood cell count, platelet count, uric acid, glucose, urea nitrogen, creatinine, albumin, total bilirubin, glutamic oxaloacetic transaminase/aspartate transaminase, glutamic pyruvic transaminase/alanine transaminase, alkaline phosphatase, total protein, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, lactate dehydrogenase, and osmolality and urine specific gravity, protein, glucose, and osmolality did not differ significantly between groups.
In agreement with our finding that Vmca decreased when MAP decreased during 0.5 MAC sevoflurane, Kurokawa et al.  reported decreased mean blood flow velocity in the cerebral artery (range 14-46 cm/s) of patients when MAP (range 61-129 mm Hg) decreased during sevoflurane anesthesia. Fujibayashi et al.  reported decreased regional CBF (measured by hydrogen clearance) when MAP decreased during 2 MAC sevoflurane in cats. Cho et al.  reported decreased Vmca during 2% sevoflurane (1.2 MAC) in oxygen compared with awake values in patients, but they reported no change from awake values with 2% sevoflurane and 60% nitrous oxide. Others reported unchanged or increased CBF with sevoflurane 0.7-2.15 MAC in patients, dogs, and rats [1,19-21]. In our study, Vmca presumably decreased because sevoflurane and isoflurane decreased the cerebral metabolic rate (see below), and CBF:metabolism coupling was preserved. Assuming cerebral metabolic depression as the primary cause for reduced Vmca, the CVRe accompanying a decrease of Vmca should be determined chiefly by CPP. In cases in which a decrease of Vmca is accompanied by decrease of CPP, no change in CVRe is required for Vmca to remain at reduced values. In cases in which decrease of Vmca is accompanied by unchanged CPP, an increase of CVRe is required for Vmca to remain at reduced values. In accord with these principles, we observed decreased CPP with unchanged CVRe at all isoflurane concentrations and at 0.5 MAC sevoflurane, and unchanged CPP with increased CVRe at 1.0 and 1.5 MAC sevoflurane. Consistent with our finding of greater CVRe with high concentrations of sevoflurane compared with isoflurane, Conzen et al.  reported less increase of CBF (i.e., greater CVR) with sevoflurane compared with isoflurane when each drug was administered to rats at concentrations that decreased MAP to either 50 mm Hg or 70 mm Hg.
Our finding of unchanged ICP during 0.5, 1.0, and 1.5 MAC sevoflurane is consistent with previous studies by Takahashi et al. [16,17], who reported no significant change of ICP at 0.5, 1.0, and 1.5 MAC sevoflurane in dogs compared with baseline ICP values obtained during anesthesia with pentobarbital 30 mg/kg and nitrous oxide 60% in oxygen. Others reported statistically significant but clinically unimportant increases of 2-4 mm Hg or a potentially clinically relevant increase of 12 mm Hg relative to comparison groups in rabbits, dogs, and cats [16,18-20]. Unchanged ICP despite decreased Vmca suggests that either cerebral blood volume did not decrease concomitantly with Vmca or that cerebral blood volume did decrease but that decrease was offset by an increase of cerebrospinal fluid volume or an increase of intracranial elastance. A divergence between cerebral blood volume and CBF was previously reported with isoflurane, propofol, and pentobarbital in rats . Our finding of unchanged CPP at 1.0 and 1.5 MAC sevoflurane is consistent with a previous study by Crawford et al. , who reported no change of MAP at 1.0 MAC sevoflurane compared with awake control values in rats. In other studies, sevoflurane 0.7-2.15 MAC decreased MAP in patients, dogs, rats, and cats [14,15,17,19,23,24].
Our EEG findings are similar to those of Osawa et al. , who reported that the cortical EEG progressed from high-amplitude slow waves to a burst suppression pattern as the concentration of sevoflurane was increased from 2% [close to 1.0 MAC based on the pilot study of Osawa et al. ] to 5% in cats. Scheller et al.  reported increased amplitude in the lower frequencies with 0.5 MAC sevoflurane and a burst suppression pattern with 1.0 MAC sevoflurane in rabbits. Scheller et al.  also reported increased amplitude in the lower frequencies with 0.5 and 1.5 MAC sevoflurane and a burst suppression pattern with 2.15 MAC sevoflurane in dogs. In our study, the change of jugular venous oxygen saturation values from baseline during administration of sevoflurane or isoflurane was not different between groups, which indicates no major difference between the two anesthetics on the ratio of CBF to cerebral metabolism. With both anesthetics, the trend for increasing jugular venous oxygen saturation with increasing anesthetic concentration is consistent with a dose-related decrease of cerebral metabolism.
In the present study, mean plasma inorganic fluoride concentration was 39.0 +/- 12.9 micro M after sevoflurane anesthesia. The mean MAC hours of sevoflurane were 3.2 +/- 2.0 h. This value for the mean plasma inorganic fluoride concentration is consistent with the range (21.8 +/- 9.3 micro M [mean +/- SD] to 36.2 +/- 3.9 micro M [mean +/- SE]) reported for 2.9 +/- 0.8 to 3.7 +/- 0.1 MAC hours of sevoflurane in patients [6-11]. The mean plasma inorganic fluoride concentration for 3.2 MAC hours of sevoflurane in our study, in which mannitol 0.5-0.75 g/kg was given, was similar to that found for 2.9-3.7 MAC hours of sevoflurane in previous studies, in which mannitol was not given, which suggests that the use of mannitol during intracranial surgery does not significantly alter mean plasma inorganic fluoride concentration.
In summary, in neurosurgical patients receiving sufentanil, the cerebral effects of sevoflurane are, for the most part, similar to those of isoflurane. Sevoflurane 0.5, 1.0, and 1.5 MAC decreased Vmca and tended to increase jugular venous oxygen saturation, consistent with decreased cerebral metabolism. Appropriately, decreased Vmca was accompanied by decreased CPP and unchanged CVRe at 0.5 MAC, and by unchanged CPP and increased CVRe at 1.0 and 1.5 MAC. Unchanged ICP despite decreased Vmca suggests that either cerebral blood volume did not decrease concomitantly with Vmca or that cerebral blood volume did decrease, but that decrease was offset by an increase of cerebrospinal fluid volume or an increase of intracranial elastance. The EEG was characterized by higher amplitude in the lower frequencies, and no epileptiform EEG activity was observed. The use of mannitol in the present group of neurosurgical patients did not substantially alter mean peak plasma inorganic fluoride concentrations compared with those previously reported for a similar duration of exposure to sevoflurane in patients not receiving mannitol.
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