The inhaled anesthetics, halothane and sevoflurane, are widely used in pediatric patients. Halothane causes decreases of cerebrovascular resistance and results in an increase in cerebral blood flow (CBF) (1,2) and intracranial pressure (ICP) (3). These effects were dose- and age-dependent (3–5).
Sevoflurane’s effects on cerebral hemodynamics are controversial (6,7). Some authors describe an increase in CBF, but less than during halothane (8). Others have found no change in CBF (9,10), and no or minimal effects on ICP (10,11). In adults, CO2-reactivity and cerebral autoregulation seem to be preserved under sevoflurane (12,13), whereas other authors describe CBF-fluctuations as a consequence of fluctuations of systemic blood pressure and propose an abolished autoregulation (14).
The purpose of our study was to compare cerebral blood flow velocity (CBFV) in a cross-over study using both sevoflurane and halothane during one anesthesia in the same patient. Conditions were strictly standardized with a study design that eliminates individual differences and other CBFV influencing factors. Our hypothesis was that sevoflurane causes fewer changes in CBFV than halothane.
The study was approved by the local ethics committee and written, informed consent was obtained from the parents. Twenty-three patients (0.4–9.7 yr, median 1.9; 12 male and 11 female) were enrolled into the study. All were ASA physical status I or II and were admitted for elective surgery. Operation time had to be long enough to allow the use of two inhaled anesthetics and to perform CBFV measurements during steady-state of both gases. During anesthesia, all patients were paralyzed, intubated and mechanically ventilated. Exclusion criteria were preexisting neurological diseases, increased ICP or disturbed autoregulation of CBF, as well as hemodynamic instability.
A cross-over study design was used with each patient receiving both sevoflurane and halothane in a randomized sequence. Inhaled induction was performed with either sevoflurane or halothane. CBFV was measured after achieving steady-state with the induction gas in a concentration of 1.25–1.5 minimal alveolar concentration calculated according to the age of the patient (15). Steady state was defined as the difference between the inhaled and exhaled gas concentration below 0.1 vol% for a minimum of 20 min before the measurement was performed. The anesthetic was then changed. CBFV measurement was repeated after the second anesthetic achieved steady-state in an equivalent minimal alveolar concentration as during first measurement. The inspiratory and expiratory concentrations of both anesthetics were measured continuously and in parallel. The complete elimination of the induction anesthetic was defined as a concentration of the induction anesthetic less than 10% of the inhaled gas mixture, or 0.3 vol% of the absolute gas concentration. To ensure both complete elimination of the first and steady state of the second anesthetic, we used a measurement technique (Datex-Engstrom AS/3™ Compact monitor; Datex-Omega, Finland) that records the concentrations of both gases independently. The patients were divided into two groups for the analyses of the results. Group 1 received sevoflurane first followed by halothane, whereas Group 2 received halothane first followed by sevoflurane.
Premedication was provided with flunitrazepam (0.05 mg/kg). Anesthesia was performed without nitrous oxide (NO2) because NO2 can cause an increase of CBF. Patients did not receive systemic vasodilators. Ventilation variables were registered (oxygen supply [Fio2], respiratory rate, peak airway pressure, positive end-expiratory pressure). Other CBF-influencing factors such as the partial pressure of carbon dioxide (Pco2) ETco2, oxygen saturation (SO2) (measured transcutaneous oxygen saturation [tcSO2]), systolic and diastolic arterial blood pressure, heart rate (HR), hemoglobin (Hb), and rectal body temperature were registered and maintained constant. All patients received paracetamol (25–30 mg/kg) as analgesic treatment. Other medications were registered and evaluated as possibly contributing factors in influencing CBFV.
CBFV was measured in the middle cerebral artery (MCA) with transcranial pulsed Doppler ultrasonography (TCD) (Sonovit SV 75; Schiller, Ottobrunn, Germany). Repetitive measurements during both anesthetics were performed at the same location of the vessel. The measured variables were systolic velocity (Vs), mean velocity (Vmn), and diastolic velocity (Vd). The absolute values of the blood velocity depend on the angle of incidence between the blood flow and the axis of the ultrasound beam (16). Pulsatility index (PI = Vs – Vd)/Vmn) and resistance index (RI = (Vs – Vd)/Vs) can be calculated to describe the form of the curve and consequently the vessel resistance, independent of the absolute velocity values, and therefore independent of the insonation angle. Because both PI and RI behave similarly and the use of RI is more common, our evaluation focused on RI.
The number of patients enrolled into the study was determined by power analysis. All patients served as their own controls. Only the anesthetist was informed immediately before anesthesia about the application sequence, and the investigator who measured CBFV was blinded. All comparisons of values of the same patient over the course of the measurements during the two different anesthetics were analyzed with paired Student’s t-test. P < 0.05 was considered significant. Additionally, we evaluated whether changes in CBFV values were significantly affected by any variable besides the different anesthetics. We analyzed data with linear regression techniques and analyses of variance and corrected for repeated measurements.
Of the 23 pediatric patients enrolled into the study, 16 had surgery for cleft palate, 4 for urethero-cysto-neostomia (Cohen operation), 1 for epispadia, 1 for hypospadia, and 1 received a pyeloplastic after hydronephrosis. Two patients were excluded for technical difficulties during TCD, and one was excluded because of hemodynamic instability. The other 20 were treated according to the study protocol.
The results were analyzed separately for Group 1 (sevoflurane followed by halothane;n = 10 patients) and Group 2 (halothane followed by sevoflurane;n = 10 patients). In a second step, the results were analyzed independently from the application sequence of the volatile anesthetics.
In Group 1, the mean Vd was significantly less (P = 0.005) during sevoflurane (0.69 m/s; sd 0.29) than during halothane (0.90 m/s; sd 0.37). The same was found for Group 2; they also had a significantly less (P = 0.0002) Vd during sevoflurane (0.85 m/s, sd 0.42) than during halothane (1.11 m/s; sd 0.43) (Fig. 1). The comparison of the values of all patients, independent from the application sequence, confirmed a significantly lower Vd during sevoflurane than during halothane (P < 0.0001).
The values for Vs did not differ significantly in both groups; the mean Vs was 2.18 m/s (sd 0.38) during sevoflurane and 2.15 m/s (sd 0.36) during halothane (P = 0.32) in Group 1, compared with 2.14 m/s (sd 0.56) during sevoflurane and 2.26 m/s (sd 0.52) during halothane in Group 2.
In an evaluation of the entire study group (independent of the application sequence), we found significantly decreased (P = 0.001) values for Vmn during sevoflurane (mean 1.35 m/s, sd 0.42) than during halothane (mean 1.50 m/s sd 0.44) (Fig. 1). However, Vmn did not differ significantly in Group 1 (mean Vmn 1.32 m/s; sd 0.33 during sevoflurane and 1.38 m/s, sd 0.37, during halothane), but was significantly less (P = 0.001) in Group 2 during sevoflurane (mean 1.38 m/s, sd 0.52) than during halothane (mean 1.62 m/s, sd 0.52).
Mean values and standard deviations of all CBFV variables are presented in Table 1. The changes of RI were consistent in both groups. RI was significantly less (P < 0.001) during halothane (mean 0.59, sd 0.10 in Group 1 and mean 0.52, sd 0.11 in Group 2) than during sevoflurane (mean 0.69, sd 0.09 in Group 1 and mean 0.62, sd 0.11 in Group 2) (Fig. 1). Figure 2 shows the mean values of Vd and RI during first and second measurement for both groups. To evaluate whether the changes of Vd and RI are independent from the application sequence of the two anesthetics, we calculated the slopes of the curves for Groups 1 and 2. If the increase in one group is equivalent to the decrease in the other group, the slopes of both curves have equal values with opposite signs, and the ratio of the slopes equals −1. Comparisons of the decrease/increase of Vd and RI in both groups show similar values with opposite signs (slope ratio: slopeVd Group 1/slopeVd Group 2 = −1.20; slopeRI Group 1/slopeRI Group 2 = −1.03). This indicates that the changes of CBFV are independent of the application sequence.
Table 2 lists the mean values of all variables that could potentially influence CBFV besides the inhaled anesthetic and the results of paired Student’s t-test comparisons between values measured during sevoflurane and halothane separately for both groups (according to the application sequence). Additionally, linear regression techniques and analyses of variance, corrected for repeated measurements, were performed, revealing that no other variable besides the different anesthetics influenced the changes in CBFV-values significantly.
Our study found significantly decreased mean CBFV in the MCA during anesthesia with sevoflurane than during anesthesia with halothane. This effect was primarily attributable to a significantly increased diastolic CBFV during halothane. Therefore, the RI during halothane was significantly less than during sevoflurane and our results indicate a decreased vessel resistance with halothane. Our findings are consistent with those in animals (8) and adults (17). Although CBFV does not directly reflect the absolute CBF, the changes in MCA flow velocity are proportional to the change in CBF (18). Therefore, the observed changes may be associated with generally increased CBF during halothane. The use of a cross-over study design with all patients serving as their own controls made the results independent from individual differences (i.e., sex- and age-dependency of CBFV (19). The effects on CBFV were attributable to the anesthetic independent from the application sequence, the duration of the anesthesia, or the surgical stimulation.
There are other variables that could potentially influence cerebral circulation and therefore CBFV in the MCA and that were not controlled by the cross-over study design. The influence of CO2 partial pressure and oxygen saturation on vessel diameter and CBFV is well known. Therefore, both variables were maintained constant throughout the application of both inhaled anesthetics by adjusting mechanical ventilation. To preserve an unchanged Pco2, ventilation had to be increased during anesthesia with halothane independent of whether it was applied as the first or second anesthetic. There is no obvious reason why Pco2 would increase during halothane, and an evaluation of this finding could be interesting for a future investigation. However, this finding is not relevant for our study, because Pco2 (as a CBFV-influencing factor) was maintained constant. Oxygenation appeared unaffected by the choice of anesthetic because oxygen saturation could be maintained constant without changing inspiratory pressure or oxygen flow. HR decreased during halothane compared with sevoflurane, independent of the application sequence. This is consistent with the literature (8). However, this cannot explain the changes in CBFV because diastolic and systolic blood pressures were constant during both anesthetics. The Hb content was measured during the application of both anesthetics and remained constant in Group 1. However, in Group 2 the Hb concentration during sevoflurane decreased significantly compared with the values measured during halothane. This is not a result of a diluted Hb concentration because the IV fluid substitution (provided until the second measurement of Hb) was not larger in this group. Also, the fluids used did not generate intravascular volume. We cannot eliminate a decrease of Hb resulting from blood loss because blood losses were not monitored in detail. In Group 2, both Hb and CBFV values are less during sevoflurane than during halothane, whereas a relevant decrease in Hb would be expected to increase CBFV. Therefore, the decrease in Hb in Group 2 does not appear to be related to the changes in CBFV.
Berkowitz et al. (20) found a decrease in blood pressure and an increase in CBFV during sevoflurane and halothane to a similar extent. They concluded that halothane and sevoflurane have similar cerebrovascular effects. The study design of Berkowitz et al. (20) differed from our study in the respect that each patient received either sevoflurane or halothane, and comparisons were made between absolute CBFV values of different patients of a wide age range. Therefore, those results might have been influenced by individual differences and age-dependency of the absolute values. In addition, the doses of the anesthetic in the study of Berkowitz et al. (20) were not well defined with respect to the age-dependency of minimal alveolar concentration. Also, N2O (which itself can influence CBFV) was used with halothane and sevoflurane, and the CBFV-measurements were performed during high flow and before reaching steady-state. Our study design eliminated these problems.
In summary, this study evaluated and compared CBFV values in children during inhaled anesthesia with sevoflurane and halothane. Our results show that sevoflurane causes significantly decreased effects on CBFV, and therefore presumably CBF, compared with halothane. These results may be clinically relevant for the choice of volatile anesthetic in children with risk of increased ICP, neurosurgery, craniofacial osteotomies, or brain injury.
We thank the staff of the Department of Anesthesia, the nurses and surgeons of the Department of Pediatric Surgery, University Children’s Hospital, Zürich, and the surgeons of the Department of Orthodontics , University Hospital, Zürich for their collaboration and support in performing this study.
1. Helfaer MA, Kirsch JR, Traystman RJ. Anesthetic modulation of cerebral hemodynamic and evoked responses to transient middle cerebral artery occlusion in cats. Stroke 1990; 21: 795–800.
2. Reinstrupp P, Ryding E, Algottson L, et al. Distribution of cerebral blood flow during anesthesia with isoflurane or halothane in humans. Anesthesiology 1995; 82: 359–66.
3. Bode H, Ummenhofer W, Frei F. Effect of halothane anesthesia on cerebral blood flow velocity in children. Ultraschall Med 1994; 15: 233–6.
4. Matta BF, Mayberg TS, Lam AM. Direct cerebrovasodilatory effects of halothane isoflurane and desflurane during propofol-induced isoelectric electroencephalogram in humans. Anesthesiology 1995; 83: 980–5.
5. Jorch G, Woike H, Rabe H, Reinhold P. Influence of anesthetic induction with halothane and isoflurane on internal carotid blood flow velocity in early infancy. Dev Pharmacol Ther 1989; 13: 150–8.
6. Johannesson GP, Floren M, Lindahl SG. Sevoflurane for ENT-surgery in children. Acta Anaesthesiol Scand 1995; 39: 546–50.
7. Conzen PF, Vollmar B, Habazettl H, et al. Systemic and regional hemodynamics of isoflurane and sevoflurane in rats. Anesth Analg 1992; 74: 79–88.
8. Crawford MW, Lerman J, Saldivia V, Carmichael FJ. Hemodynamic and organ blood flow responses to halothane and sevoflurane anesthesia during spontaneous ventilation. Anesth Analg 1992; 75: 1000–6.
9. Scheller MS, Nakakimura K, Fleischer JE, Zornow MH. Cerebral effects of sevoflurane in the dog: comparison with isoflurane and enflurane. Br J Anaesth 1990; 65: 388–92.
10. Scheller MS, Tateishi A, Drummond JC, Zornow MH. The effects of sevoflurane on cerebral blood flow cerebral metabolic rate for oxygen, intracranial pressure and the electroencephalogram are similar to those of isoflurane in the rabbit. Anesthesiology 1988; 68: 548–51.
11. Takahashi H, Murata K, Ikeda K. Sevoflurane does not increase intracranial pressure in hyperventilated dogs. Br J Anaesth 1993; 71: 551–5.
12. Kitaguchi K, Ohsumi H, Kuro M, et al. Effects of sevoflurane on cerebral circulation and metabolism in patients with ischemic cerebrovascular disease. Anesthesiology 1993; 79: 704–9.
13. Young WL, Prohovnik I, Correll JW, et al. A comparison of cerebral blood flow reactivity to CO2 during halothane versus isoflurane anesthesia for carotid endarterectomy. Anesth Analg 1991; 73: 416–21.
14. Kurokawa H, Fujii K, Nakagawa I, et al. Effects of sevoflurane on blood flow velocity in the vertebral artery. Masui 1994; 43: 1515–9.
15. Lerman J, Sikich N, Kleinmann S, Yentis S. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994; 80: 814–24.
16. Newell DW, Aaslid R. Transcranial Doppler. 1st Edition. New York: Raven Press Ltd., 1992: 67–82.
17. Kuroda Y, Murakami M, Tsuruta J, et al. Blood flow velocity of middle cerebral artery during prolonged anesthesia with halothane, isoflurane and sevoflurane in humans. Anesthesiology 1997; 87: 527–32.
18. Kochs E, Hoffmann WE, Werner C, et al. Cerebral blood flow velocity in relation to cerebral blood flow, cerebral metabolic rate of oxygen and electroencephalo-gram analysis during isoflurane anesthesia in dogs. Anesth Analg 1993; 76: 1222–6.
19. Brouwers P, Vriens EM, Musbach M, et al. Transcranial pulsed Doppler measurements of blood flow velocities in the middle cerebral artery. Reference values at rest and during hyperventilation in healthy children and adolescents in relation to age and sex. Ultrasound Med Biol 1990; 16: 1–8.
© 2001 International Anesthesia Research Society
20. Berkowitz RA, Hoffman WE, Cunningham F, Mc Donald T. Changes in cerebral blood flow velocity in children during sevoflurane and halothane anesthesia. J Neurosurg Anesthesiol 1996; 8: 194–8.