Preservation of the Ratio of Cerebral Blood Flow/Metabolic Rate for Oxygen during Prolonged Anesthesia with Isoflurane, Sevoflurane, and Halothane in Humans

The study protocol was approved by the Ethical Committee for Human Study of the Yamaguchi Rosai Hospital, and informed consent was obtained from each patient. Twenty-four ASA physical status 1 or 2 patients (10 males, 14 females) were randomly assigned to three groups receiving isoflurane, sevoflurane, or halothane during elective surgery. Ages of the patients ranged from 22 to 80 yr. Preoperative examinations revealed neither cardiopulmonary nor neurologic disorders in all patients. Surgical procedures included major orthopedic and abdominal surgery. Atropine sulfate (0.5 mg) was given intramuscularly 30 min before induction. Anesthesia was induced with the selected volatile anesthetic in an air-oxygen mixture adjusted to obtain FIO²of 0.35, and inspired concentration of volatile anesthetic was increased to 3–4% over 3–4 min. Tracheal intubation was facilitated with intravenous administration of 8 mg vecuronium bromide. After intubation, end-tidal concentration of the selected volatile anesthetic was adjusted to an age-appropriate level [12–15]of 0.5 MAC, then increased to 1.0 MAC before surgery and maintained at 1.5 MAC for the surgical procedure. Actual end-tidal concentrations (22–39, 40–59, 60–80 yr) for 1.0 MAC were as follows: 1.27, 1.15, 1.04 (isoflurane); 0.82, 0.75, 0.67 (halothane); and 1.96, 1.71, 1.48 (sevoflurane), respectively. Patients' lungs were mechanically ventilated to maintain normocapnia, and FIO²was kept at 0.35. The end-tidal concentrations of carbon dioxide and volatile anesthetic were continuously monitored with a calibrated infrared gas analyzer (Capnomac Ultima, Datex, Helsinki, Finland). Apart from vecuronium, no other drugs were administered during the surgical procedure except phenylephrine, to maintain cerebral perfusion pressure (CPP; see below). The nasopharyngeal temperature was monitored by a calibrated thermistor probe and kept at 36.0–37.0 degrees C using a cooling-warming water mattress. Bilateral unipolar (ear-lap as a reference electrode), frontal, and occipitotemporal electroencephalograms (EEG) were monitored and recorded continuously (Neuropack 8, Nihon Kohden, Tokyo, Japan). The electrocardiogram also was monitored. A 22-G Teflon indwelling catheter was placed in the radial artery, and an 18-G Medicut catheter was placed in the right jugular bulb for blood sampling and pressure measurement. The position of the jugular bulb catheter tip was confirmed by x-ray. The arterial and internal jugular venous pressures were measured by strain gauge transducers with the zero point at the mastoid process and were recorded on a polygraph (Lifescope 14, Nihon Kohden, Tokyo). The difference between mean arterial blood pressure and mean jugular venous pressure was defined as CPP. CPP was maintained greater than 60 mmHg with a continuous infusion of phenylephrine (0.2–0.9 micro gram *symbol* kg sup -1 *symbol* min sup -1), if necessary. Arterial and internal jugular venous blood samples were obtained every 20 min and analyzed for oxygen tension (PO²), carbon dioxide tension (PCO²), bicarbonate ion concentration, and pH with a blood gas analyzer (ABL505, Radiometer, Copenhagen, Denmark) at 37.0 degrees C. Hemoglobin oxygen saturations and hemoglobin concentrations were measured spectrophotometrically (OSM3, Radiometer). Oxygen content was calculated from the hemoglobin oxygen-carrying capacity and the amount of dissolved oxygen (estimated from PO²and oxygen solubility). CBF equivalent was calculated as the reciprocal of arterial-jugular venous oxygen content difference.

Data are expressed as mean+/-SD. Between-group comparisons of demographic data and intraoperative fluid balances were made by one-way analysis of variance (ANOVA). Gender distribution between groups was compared by chi-square analysis. Physiologic variables were compared by the two-way ANOVA for repeated measures. For the statistical analysis on CBF equivalent and internal jugular venous PO²(Pjvo²), the data were separated into two parts, the initial dose-response data (0.5, 1.0, 1.5 MAC) and the time course data at 1.5 MAC. Two-way ANOVA for repeated measures was applied on each part. Bonferroni's post hoc test was applied for between-group comparisons as indicated. Statistical significance was assumed when P < 0.05.

A summary of demographic data is shown in Table 1. There were no significant differences among three groups of demographic data and intraoperative fluid balances. Heart rate ranged from 54 to 120 beats/min with different agents. Hemoglobin concentration was stable (8.6–14.9 g/dl), as was PaO²(66–210 mmHg) and nasopharyngeal temperature (35.9–37.4 degrees C). There were no significant differences among groups in these variables.

(Table 2) lists CPP, PaCO², and phenylephrine doses at selected times during the study. CPP in the sevoflurane group was significantly (P < 0.05) greater than those in the halothane and isoflurane groups. Nevertheless, CPP in all groups was maintained within physiologic range. The total number of patients given phenylephrine was five, six, and five in the isoflurane, halothane, and sevoflurane groups, respectively. PaCO²was unchanged for 4 h, and there were no significant differences among three groups.

(Figure 1) shows the time course of the changes of CBF equivalent and Pjvo². CBF equivalents at 0.5 MAC of isoflurane, halothane, and sevoflurane were 21+/-4, 20+/-3, and 21 +/-5 ml blood/ml oxygen, respectively. CBF equivalent and Pjvo²significantly (P < 0.01) increased in a dose-dependent manner at volatile anesthetic concentrations of 0.5, 1.0, and 1.5 MAC. At 1.5 MAC, the increase of CBF equivalent and Pjvo²with all anesthetics was maintained increased with minimal fluctuation for 3 h. The average value of the CBF equivalent during 3 h at 1.5 MAC was significantly (P < 0.01) greater in the isoflurane group (45+/-8 ml blood/ml oxygen) than in the halothane (32+/-8) and sevoflurane (31+/-8) groups. The average value of Pjvo²in the isoflurane group (55 +/-5 mmHg) was significantly (P < 0.01) greater than that in the sevoflurane group (48+/-6), but it was not significantly different from that of the halothane group (50+/-4).

Representative EEG patterns at 1 and 4 h are shown in Figure 2. At 1.5 MAC, EEG recordings showed frequent burst (sharp or spike wave, 50–100 micro V) and suppression in the isoflurane group, whereas in the halothane and sevoflurane groups, 13–15-Hz (50–100 micro V) and 9–13-Hz activities (70–100 micro V) were predominant, respectively. These EEG patterns at 1.5 MAC, examined without knowing the sequence of each recording, proved to be relatively unchanged with time during observation period.

This study demonstrated in humans that CBF equivalent* increased in a dose-dependent manner with all three volatile anesthetics examined. The elevated global CBF relative to oxygen demand was maintained during prolonged (4 h) anesthesia. The results also showed that the CBF equivalent at 1.5 MAC in the isoflurane group was significantly greater than in the halothane and sevoflurane groups.

In general, all volatile anesthetics are considered potent cerebral vasodilators and to increase CBF. It is, however, controversial whether the increase of CBF by volatile anesthetics is maintained for a prolonged period of anesthesia. Many animal studies using dogs and goats revealed that isoflurane- and halothane-induced cerebral hyperemia spontaneously decreased over time. [1–6,16]No definitive explanation has been obtained for this gradual decline of CBF. The decrease of CBF over time may be partially explained in one report [16]by the decrease of CMRO², probably related to the gradual increase in the depth of anesthesia (although the concentration of anesthetic was not measured). However, in most of the studies, CMRO²was either unchanged [1–5]or increased slightly [6]during the measurement period. Immobilization and/or mechanical ventilation has been postulated as the cause, [1]but this is not conclusive. The time-dependent changes in the status of autoregulation [6]or in the pH of cerebrospinal fluid, [4]and the involvement of alpha/beta-receptor [6]failed to reveal the mechanism.

Some reports have failed to observe the gradual decrease in CBF over time. Roald et al. reported that CBF and CMRO²remained unchanged during isoflurane anesthesia of 3–4 h in dogs using sagittal sinus outflow technique. [7]The authors speculated that the gradual decrease in CBF with time in the previous study [2]might have been caused by the changes in the blood rheology due to exposure to air combined with mechanical destruction by a roller pump. McPherson et al. reported that the CBF measured by the technique of radiolabeled microspheres was increased without decay by isoflurane for 4 h in primates, whereas CMRO²was unchanged over time. [8]Although not conclusive, the different results reported in animals may be due to the differences of species and/or the technique of CBF measurement. In McPherson et al.'s study, at the end of 4 h of isoflurane anesthesia, increased CBF was attenuated by the nitric oxide synthase inhibitor, L-NAME. [8]The authors concluded that sustained production of nitric oxide during prolonged isoflurane anesthesia in monkeys prevents the gradual decrease in CBF. Other recent studies suggested that volatile anesthetic-induced cerebral hyperemia is partially attributed to an increased production of nitric oxide in the rat, pig, and dog. [17–19]Thus, further studies are necessary to determine the contribution of nitric oxide to CBF during prolonged exposure to volatile anesthetics in different species.

Human studies of this subject are limited because repeated measurement of CBF for prolonged periods is not easy in the operating theater. Madsen et al. [9]reported no significant differences of CBF and CMRO²between 1 and 2 h after induction of isoflurane anesthesia in patients with small cerebral tumors. In patients with intracranial mass lesions, Ornstein [10]found no demonstrable decrease in CBF between two times of measurements (3 and 6 h after induction) in desflurane or isoflurane anesthesia (1.25 MAC) using intravenous¹³³Xenon methods during hypocapnia (PaCO²25 mmHg). These results suggest that CBF does not change over time during anesthesia in humans. However, the measurements were made only twice. A recent transcranial Doppler study in children showed that pulsatility and blood flow velocity in the middle cerebral artery measured every 15 min remained stable with 90–150 min of isoflurane exposure, [11]suggesting no decay in CBF over time indirectly. The constant CBF equivalent was observed in the current study for prolonged periods of anesthesia at 1.5 MAC. Although CBF and CMRO²were not measured in this study, EEG pattern was relatively unchanged during the 3 h of anesthesia at 1.5 MAC, and it is unlikely that CMRO²had changed markedly over time. Hence, our results suggest that the increase of CBF is maintained during prolonged volatile (isoflurane, halothane, and sevoflurane) anesthesia in humans.

Because our measurements of CBF equivalent were taken while surgery has been ongoing, one may have to consider the possibility of contribution of nociceptive stimulation to the results. It is possible that the decrease of CBF over time observed in many animal studies was due to the gradual decrease of nociceptive stimulation after surgical preparation. However, in goats whose surgical preparations have been completed 10 days before the experiment, the increase in CBF caused by 1% halothane returned to the preanesthetic level over 150 min of anesthesia. [6]In primates, CBF was increased gradually during 4 h of isoflurane anesthesia, the measurements having been started 15 min after the completion of surgical preparation. [8]Furthermore, in the above-mentioned clinical studies, [9–11]CBF (and blood flow velocity) was unchanged during 1.5–6 h of anesthesia, while surgical nociceptive stimulation was of minor importance. From these results, it is unlikely that the lack of CBF decay over time in clinical studies, including the current one, is due to the nociceptive stimulation.

The current results also showed that, at 1.5 MAC, isoflurane possesses greater capability to maintain global CBF relative to CMRO²than does halothane or sevoflurane. CPP in the sevoflurane group was higher than in the isoflurane or halothane groups at 1.5 MAC. However, CPP in all groups was maintained within physiologic range, and there were no significant changes over time. Provided that autoregulation is attenuated at 1.5 MAC, the values of CBF equivalent in the sevoflurane group might have been a bit exaggerated, and hence, the difference of CBF equivalent between isoflurane and sevoflurane groups might have been underestimated. Therefore, the conclusion is not affected.

Because we did not directly measure CBF or CMRO², we are unable to conclude whether our results that isoflurane possesses greater capability to maintain global CBF relative to CMRO²than halothane or sevoflurane are due to greater vasodilating capability and/or greater metabolic depressive effects. In isoflurane anesthesia, many studies reported that the increase in CBF, if present at all, is smaller, whereas the decrease in CMRO²is greater than the changes observed with halothane. [20]This partly coincides with the experimental results reported by Hansen et al., [21]that isoflurane possesses greater cerebral vasodilating capability relative to CMRO²than halothane. Although Smith reported that CBF equivalent was a function of anesthetic depth (MAC) regardless of volatile anesthetics, [22]we postulate that CBF equivalent depends on MAC as well as on volatile anesthetics used.

In summary, the current study demonstrates that global CBF relative to oxygen demand is markedly increased and maintained during prolonged inhalation of volatile anesthetics in humans. It is impossible to determine whether these data indicate a stable CBF or whether CBF and CMRO²are changing in parallel during the observation period. The unchanging EEG pattern suggests that the former possibility is more likely and that the increase in CBF produced by volatile anesthetics is maintained over time without decay, which has been reported in several animal studies. The current results also suggest that isoflurane possesses greater capability to maintain global CBF relative to CMRO²than does halothane or sevoflurane.

*The CBF equivalent in normal, awake humans is 15+/-3 ml blood/ml oxygen (mean+/-SD) in our department (Sari A, Maekawa T, Tohjo M, Okuda Y, Takeshita H: Effects of althesin on cerebral blood flow and oxygen consumption in man. Br J Anaesth 1976; 48:545–50).