Summary. Nitrous oxide and isoflurane have different effects on absolute cerebral blood flow (CBF) and regional distribution of CBF in humans. In this study we.
British Journal of Anaesthesia 1997; 78: 407–411
Regional cerebral blood flow (SPECT) during anaesthesia with isoflurane and nitrous oxide in humans P. REINSTRUP, E. RYDING, L. ALGOTSSON, L. BERNTMAN AND T. USKI
Summary Nitrous oxide and isoflurane have different effects on absolute cerebral blood flow (CBF) and regional distribution of CBF in humans. In this study we examined the effects of isoflurane in combination with nitrous oxide on CBF. We studied 10 patients (two groups of five patients, ASA I) anaesthetized with 50% nitrous oxide and either 0.5 or 1.0 MAC of isoflurane during normocapnia (PaCO2 5–7 kPa) using two-dimensional CBF measurement (CBFxenon) (i.v. 133xenon washout technique) and a threedimensional method for measurement of regional CBF (rCBF) distribution with SPECT (single photon emission computer-aided tomografy with 99mTcHMPAO). The results were compared with 1.0 MAC of isoflurane from a previous study performed in exactly the same way as the present investigation. During normocapnia, anaesthesia with 50% nitrous oxide and 0.5 MAC of isoflurane resulted in a mean CBFxenon of 45 (SEM 5) ISI units. Increasing the isoflurane concentration to 1.0 MAC had no significant effect on mean CBFxenon (53 (5) ISI units). Both flow values were significantly (P:0.01) higher than the CBFxenon value obtained when 1 MAC of isoflurane was administered alone (33 (3) ISI units). There were no significant differences in rCBF distribution regardless of whether or not isoflurane was given alone or together with nitrous oxide at 0.5 or 1 MAC. In all situations there were higher relative flows in subcortical regions (thalamus and basal ganglia, 10%) and in the pons (7–10% above average). rCBF in the cerebellum was approximately 10% greater than average. In summary, we have found that mean CBF was greater with combined nitrous oxide and isoflurane anaesthesia than previously found with isoflurane alone; however, relative flow distribution was similar. (Br. J. Anaesth. 1997; 78: 407–411). Key words Anaesthetics volatile, isoflurane. Anaesthetics gases, nitrous oxide. Brain, blood flow. Measurement techniques, tomography.
Nitrous oxide has been used for anaesthesia during neurosurgical procedures for half a century as it was thought to have only little effect on the cerebral
circulation.1 2 However, by the 1970s it was shown that nitrous oxide had marked effects on intracranial pressure (ICP)3 4 but the literature on the effects of nitrous oxide on the brain is confusing, probably because of species differences, but also because of interactions with other drugs or interventions.5 6 However, in humans, evidence supporting the conclusion that nitrous oxide is a cerebral vasodilator, in the absence of other interventions, has been obtained previously from cerebral blood flow (CBF) studies.7–9 Recent studies have shown that nitrous oxide increases blood flow velocity also when it is added to propofol or isoflurane anaesthesia.10 11 The reason for this vasodilatation is still unknown, but it may theoretically be caused by increased cerebral metabolism10–13 or by an indirect effect on the cerebral vessels9 14 as it is known that nitrous oxide is totally inert on isolated human pial arteries.9 The aim of this study was to evaluate the effect of isoflurane in combination with 50% nitrous oxide on absolute CBF measured by i.v. 133xenon15 combined with recording of the three-dimensional rCBF distribution with SPECT and 99mTc-HMPAO in normocapnic patients.
Patients and methods We studied 10 male patients, ASA I, undergoing inguinal herniorrhaphy. The study was approved by the Ethics Committee of the Medical Faculty and the Isotope Committee of the University of Lund. Written informed consent was obtained from each participant. EXPERIMENTAL PROCEDURE
Ten patients were allocated randomly to one of two groups (n:5 in each group), to receive 50% nitrous oxide and 0.5 or 1 MAC of isoflurane during normocapnia. The group who received isoflurane alone also comprised five patients who have been reported PETER REINSTRUP, MD, PHD (Department of Anaesthesiology and Department of Clinical Pharmacology); LARS ALGOTSSON, MD, PHD, MD, PHD LEIF BERNTMAN, (Department of Anaesthesiology); ERIK RYDING, MD, PHD (Department of Clinical Neurophysiology); TORE USKI, MD, PHD (Department of Clinical Pharmacology and Department of Neurosurgery); University Hospital, S 221 85 Lund, Sweden. Accepted for publication: December 20, 1996. Correspondence to P. R.
408 previously.16 Subjects in the previous study were anaesthetized with 1 MAC of isoflurane alone, but otherwise treated in the same way as patients in the present investigation. No premedication was given. Anaesthesia was induced with pethidine 0.75 mg kg91 i.v. and propofol 2–2.5 mg kg91. Suxamethonium 1 mg kg91 was used to facilitate tracheal intubation. Mechanical ventilation was with a Servo ventilator (Siemens 900 C, Siemens Elema, Solna, Sweden). End-tidal carbon dioxide and concentrations of isoflurane were recorded on a Normocap 102-24-02 and a Normac gas monitor (Datex, Helsinki, Finland), respectively. Anaesthesia was maintained with isoflurane and 50% nitrous oxide in oxygen. End-tidal concentrations of isoflurane and carbon dioxide ( P E ′CO2) were maintained as close as possible to the final experimental condition throughout anaesthesia. At 10–20 min before the end of surgery, patients were kept anaesthetized with either 0.5 or 1 MAC of isoflurane and 50% nitrous oxide in oxygen for at least 30 min. When stable conditions were achieved and surgery had finished, mean CBF was measured using i.v. radioactive 133xenon clearance (CBFxenon). 99m Tc-HMPAO was given immediately after the CBFxenon measurement and anaesthesia was maintained for 5 min more. No patient was studied sooner than 60 min after induction of anaesthesia (mean 69 min, range 60–85 min). After a postanaesthetic recovery period of 1–2 h, patients were brought to the neurophysiological department for SPECT scanning. During measurement of mean CBFxenon, haemoglobin concentration and arterial blood-gas samples were analysed using an ABL 500 (Radiometer, Copenhagen, Denmark). Temperature, heart rate and systemic arterial pressure were monitored throughout the procedure. MEASUREMENT OF MEAN CEREBRAL BLOOD FLOW
Mean CBFxenon was measured by injection of 0.5 Gbq (10 mCi) of 133xenon into a cubital vein, followed by rapid injection of 20 ml of isotonic saline. Uptake and clearance of the tracer substance were recorded with a scintillation detector with wide collimation (approximately 90⬚ view), placed on the right side of the head over the parieto-temporal region, including most of the brain in its field. Clearance through the lungs was recorded from expired air. A Novo Cerebrograph l0a (Simonsen Medical A/S, Randers, Denmark) was used for data collection with a sampling time of 11 min and subsequent flow calculation. CBFxenon was expressed as the initial slope index (ISI)17 as it represents blood flow of all tissue recorded, but is highly dominated by gray matter blood flow and influenced little by extracerebral components.17 MEASUREMENT OF THREE-DIMENSIONAL CEREBRAL BLOOD FLOW DISTRIBUTION
Regional distribution of CBF was measured by injection of a tracer substance, 99mTc- HMPAO 0.5 Gbq (10 mCi) (Ceretec, Amersham, UK) into a cubital
British Journal of Anaesthesia vein, followed by rapid injection of 20 ml of isotonic saline. This tracer substance is lipid soluble at the time of injection and is distributed in proportion to blood flow. In brain cells the carrier molecule HMPAO is converted within a few minutes to a water-soluble form which cannot cross the cell membrane. Hence, the amount of 99mTc (half-life of 6 h) which remains trapped in the brain cells is proportional to rCBF distribution. Cerebral 99mTc distribution was recorded three-dimensionally with a single photon emission computer-aided tomography (SPECT) scanner (Tomomatic 564, Medimatic A/S, Denmark) giving a picture of rCBF distribution at the time of 99mTc-HMPAO injection.18 19 Threedimensional distribution of 99mTc-HMPAO in the brain was recorded in 10 contiguous, approximately 1-cm thick, slices parallel to the orbitomeatal (OM) line, with the centre of the lowest slice located 1 cm below the OM line. The head position was controlled with light beams on the external auditory meatus and the nasion. Slices were recorded in two interlacing sets of five slices each with a recording time of 10 min for each set, which gave approximately 106 counts/slice and an intra-slice resolution of approximately 1 cm. The regions of interest were positioned automatically within each slice, with adjustment to the subject’s brain size. CALCULATIONS AND STATISTICAL METHODS
The mean CBFxenon value recorded from our detector corresponded to a weighted average of different brain regions, with the weight of each region in the average determined mainly by its 133xenon content and distance from the detector.20 Consequently, the CBFxenon value from the parietal detector was an average between CBF in the closest cortical tissue (parietal cortex) and mean CBF, with dominance for the parietal cortex. In the SPECT 99mTc-HMPAO measurements, the average CBF level, calculated as the average number of counts through all regions, gray and white matters, was defined as 100% for presentation of relative flow values. Regions of interest were outlined in the brain slices by a program which was constructed from anatomical templates in a CT brain atlas.21 Three- dimensional cerebral regions of interest were calculated from adjoining regions of interest in different brain slices representing the same structure. The program gave the mean value in each region of interest and the size of the region of interest. With the SPECT 99mTc-HMPAO measurements, parietal and average CBF had virtually the same value (99100%) and therefore it was justifiable to approximate the recorded CBFxenon value to parietal cortical CBF. Regional CBF values were calculated from CBFxenon mean flow values and 99mTcHMPAO rCBF distribution, as described by Reinstrup and colleagues.16 Thus CBFxenon values were equated with parietal values in the regional distribution obtained with SPECT. The conversion factor from kPa to mm Hg was 0.1333. All values are given as mean (sem). Mean
CBF during anaesthesia with isoflurane and nitrous oxide
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CBFxenon values were tested by factorial design ANOVA, initially on global anaesthesia effects and post hoc on the addition of nitrous oxide to isoflurane anaesthesia. Regional CBF (99mTc-HMPAO distribution) was analysed by repeated measures ANOVA with anaesthetic type as between-group factor and regions of interest as within-group factors. P:0.05 was considered statistically significant.
Results Physiological values of the three groups, at the time of mean CBF measurement, are presented in table 1. EFFECTS OF NITROUS OXIDE AND ISOFLURANE ON MEAN CBFXENON USING 133XENON
There was a significant (F:5.36, P:0.022 ANOVA) effect on CBFxenon of anaesthesia type. Patients without any surgical stress anaesthetized with 50% nitrous oxide and 0.5 MAC of isoflurane (0.6%) had a mean CBFxenon of 45 (5) ISI units during normocapnia. CBFxenon during isoflurane anaesthesia at 1 MAC (1.2%) and during 50% Table 1 Physiological values for the three groups (n:5 in each group). Values are mean (SEM or range) N2O;0.5 MAC N2O;1.0 MAC 1.0 MAC of of isoflurane of isoflurane isoflurane Age (yr) 30 (21–45) PaCO2 (kPa) 5.7 (0.1) PaO2 (kPa) 35 (2) pH 7.39 (0.01) Hb (g litre91) 146 (6) Temptympanic (⬚C) 36.0 (0.1) MAP (mmHg) 80 (3)
33 (20–44) 5.8 (0.3) 30 (2) 7.38 (0.02) 147 (4) 36.2 (0.2) 76 (3)
43 (37–50) 5.4 (0.1) 32 (8) 7.41 (0.02) 148 (3) 35.7 (0.4) 71 (2)
Figure 2 Regional cerebral blood flow (rCBF) (ISI units) during anaesthesia with 50% nitrous oxide and 0.5 MAC of isoflurane, 50% nitrous oxide and 1.0 MAC of isoflurane or 1.0 MAC of isoflurane without nitrous oxide16 at normocapnia. Values represent regional distribution recalculated to absolute values (see methods) and are presented as mean (SEM) (n:5 in each group).
nitrous oxide did not differ significantly from the flow value with 0.5 MAC (53 (5) ISI units). Compared with 1 MAC of isoflurane alone (CBF:33 (3) ISI units)16 both CBFxenon values with nitrous oxide in addition to isoflurane were significantly increased (F:8.16, P:0.014). EFFECTS OF NITROUS OXIDE AND ISOFLURANE ON THREE-DIMENSIONAL CBF DISTRIBUTION
Nitrous oxide and 0.5 or 1.0 MAC of isoflurane anaesthesia resulted in a pattern with an inhomogeneous CBF distribution (F:61.6, P:0.0001). During nitrous oxide and isoflurane anaesthesia, the regions with the highest relative CBF were the thalamus, basal ganglia and cerebellum (10% greater than average) followed by the pons (7–10% greater than average). This distribution did not differ from that found during anaesthesia with 1 MAC of isoflurane.16 rCBF distributions are presented in figure 1. Absolute rCBF values throughout the same regions were calculated from the two- and threedimensional blood flow measurements, and are presented in figure 2, together with rCBF values obtained when isoflurane was administered alone.16
Discussion Figure 1 Regional cerebral blood flow (rCBF) distribution (% of mean relative CBF) during anaesthesia with 50% nitrous oxide and 0.5 MAC of isoflurane, 50% nitrous oxide and 1.0 MAC of isoflurane or 1.0 MAC of isoflurane without nitrous oxide16 at normocapnia. Results are presented as mean (SEM) (n:5 in each group).
We have found that anaesthesia during normocapnia with 50% nitrous oxide and 0.5 or 1.0 MAC of isoflurane resulted in a global CBF of 44 and 53 ISI units, respectively. These values were significantly higher compared with a global CBF value of 33 ISI
410 units obtained with 1.0 MAC of isoflurane without nitrous oxide under otherwise identical conditions.16 This latter CBF value was lower than that in the awake state,9 which is in accordance with other recent reports22 23 and contradicts the previous common opinion that isoflurane increases CBF. In contrast, inhalation of 50% nitrous oxide in healthy young men increased global CBF from 55 to 67 ml 100 g91 min91. during normocapnia.9 This increase in CBF during nitrous oxide administration is in agreement with results from investigations on cortical blood flow in humans.7 8 The CBF values found in this study were intermediate between values obtained when nitrous oxide and isoflurane are used alone. The finding that addition of nitrous oxide to a basic anaesthetic increases CBF has been established previously24 25 using twodimensional methods. In these studies the effect of nitrous oxide was evaluated by substituting an equipotent dose of volatile anaesthetic in order to maintain an unchanged anaesthetic level. Recent studies have shown that nitrous oxide increases blood flow velocity also when it is added to an otherwise unchanged propofol or isoflurane anaesthesia.10 11 We found that substituting 0.5 MAC of isoflurane with 50% nitrous oxide increased CBF and that a further, but non-significant, augmentation occurred when the concentration of isoflurane was increased to 1 MAC. Hence, the nitrous oxide-induced effect on blood flow is not attenuated by increasing anaesthetic depth with isoflurane up to 1 MAC. The finding that CBF tended to be higher when the isoflurane concentration was doubled may be explained by a direct vasodilator effect on vascular smooth muscle, caused by increased isoflurane concentrations.26 We have reported previously that the global increase in CBF induced by nitrous oxide alone was distributed unevenly, with the main increase in the frontal, temporal and parietal cortex but also in the basal ganglia, insula and in the thalamic region.9 The flow pattern gave the impression that inhalation of nitrous oxide augmented flow through regions associated anatomically with the limbic system,27 probably because of selective activation of these areas.9 This pattern was entirely different from that seen with isoflurane. During 1 MAC of isoflurane anaesthesia, rCBF distribution showed higher CBF levels in the pons and subcortical structures (thalamus and basal ganglia) compared with the cortex.16 If nitrous oxide stimulates metabolism in some areas of the brain, the effect might be alleviated by addition of other anaesthetics which depress metabolism.13 28 This fits well with our present finding that nitrous oxide did not alter rCBF distribution induced by isoflurane anaesthesia. Isoflurane and halothane induced different patterns of rCBF.16 The reason for the selective difference in relative flow through different regions during isoflurane and halothane anaesthesia is unknown. The most likely explanation is based on the fact that the normal brain has a tight coupling between brain metabolism and flow29 and that the two volatile anaesthetics have different effects on metabolism in various parts of the brain. A flow
British Journal of Anaesthesia metabolism relationship is evident during both isoflurane and halothane anaesthesia in the rat.30 Assuming that volatile anaesthetics have different effects on metabolism in various brain regions, together with the observations that addition of nitrous oxide to isoflurane increases CBF uniformly and that nitrous oxide has no effect on isolated cerebral arteries,9 we conclude that our study supports the hypothesis that nitrous oxide exerts an indirect vasodilator effect in the brain.31 Identification of the mediator(s) of this vasodilator effect merits further investigation.
Acknowledgements Supported by grants from Tore Nilssons foundation for medical research, Swedish Medical Research Council (B91–14X00084–27A), Malmöhus läns landsting and research funds of the University of Lund. We thank Ann-Margaret Andersson for assistance with SPECT scans and isotope delivery.
References 1. Smith AL, Wohllman H. Cerebral blood flow and metabolism. Effects of anesthetic drugs and techniques. Anesthesiology 1972; 36: 378–400. 2. Harp JR, Siesjö BK. Effects of anaesthesia on cerebral metabolism. In: Gordon E, ed. A Basis and Practice Of Neuroanaesthesia. Amsterdam: Excerpta Medica, 1975; 92–93. 3. Henriksen HT, Jørgensen PB. The effect of nitrous oxide on intracranial pressure in patients with intracranial disorders. British Journal of Anaesthesia 1973; 45: 486–492. 4. Moss E, McDowall DG. ICP increases with 50% nitrous oxide in oxygen in severe head injuries during controlled ventilation. British Journal of Anaesthesia 1979; 51: 757–761. 5. Arthru AA. Cerebral blood flow and metabolism. In: Cucchiara RF, Michenfelder JD, ed. Clinical Neuroanesthesia. New York: Churchill Livingstone, 1990; 13–17. 6. Phirman JR, Shapiro HM. Modification of nitrous oxideinduced intracranial hypertension by prior induction of anesthesia. Anesthesiology 1977; 46: 150–151. 7. Deutsch G, Samra SK. Effects of nitrous oxide on global and regional cortical blood flow. Stroke 1990; 21: 1293–1298. 8. Field LM, Dorrance DE, Krzeminska EK, Barsoum LZ. Effect of nitrous oxide on cerebral blood flow in normal humans. British Journal of Anaesthesia 1993; 70: 154–159. 9. Reinstrup P, Ryding E, Algotsson L, Berntman L, Uski T. Effects of nitrous oxide on human regional cerebral blood flow and isolated pial arteries. Anesthesiology 1994; 81: 396–402. 10. Matta BF, Lam AM. Nitrous oxide increases cerebral blood flow velocity during pharmacological induced EEG silence in humans. Journal of Neurosurgical Anesthesiology 1995; 7: 89–93. 11. Hoffman WE, Charbel FT, Edelman G, Albrecht RF, Ausman JI. Nitrous oxide added to isoflurane increases brain artery blood flow and low frequency brain electrical activity. Journal of Neurosurgical Anesthesiology 1995; 7: 82–88. 12. Pelligrino DA, Miletich DJ, Hoffman WE, Albrecht RF. Nitrous oxide markedly increases cerebral cortical metabolic rate and blood flow in the goat. Anesthesiology 1984; 60: 405–412. 13. Sakabe T, Kuramoto T, Inoue S, Takeshita H. Cerebral effects of nitrous oxide in the dog. Anesthesiology 1978; 48: 195–200. 14. Fitzpatrick JH, Gilboe DD. Effects of nitrous oxide on the cerebrovascular tone, oxygen metabolism, and electroencephalogram of the isolated perfused canine brain. Anesthesiology 1982; 57: 480–484. 15. Austin G, Horn N, Rouke S, Hayward W. Description and early results of an intravenous radioisotope technique for measuring regional cerebral blood flow in man. European Neurology 1972; 8: 43–51.
CBF during anaesthesia with isoflurane and nitrous oxide 16. Reinstrup P, Ryding E, Algotsson L, Messeter K, Asgierson B, Uski T. Distribution of cerebral blood flow during anesthesia with isoflurane or halothane in humans. Anesthesiology 1995; 82: 359–366. 17. Risberg J, Ali Z, Wilson EM, Wills EL, Halsey JH. Regional cerebral blood flow by 133xenon inhalation. Stroke 1975; 6: 142–148. 18. Holm S, Andersen AR, Vorstrup S, Lassen NA, Paulson OB, Holmes RA. Dynamic SPECT of the brain using a lipophilic technecitum-99m complex, PnAO. Journal of Nuclear Medicine 1985; 26: 1129–1134. 19. Holmes RA, Chaplin SB, Royston KG, Hoffman TJ, Volkert WA, Nowotnik DP, Canning LR, Cumming SA, Harrison RC, Highley B, Nechvatal G, Pickett RD, Piper IM, Neirinckx RD. Cerebral uptake and retention of 99Tcmhexamethylpropyleneamine oxime (99Tcm-HM-PAO). Nuclear Medicine Communications 1985; 6: 443–447. 20. Bolmsjö M. Hemisphere cross talk and signal overlapping in bilateral regional cerebral blood flow measurements using xenon 133. European Journal of Nuclear Medicine 1984; 9: 1–5. 21. Kretschmann HJ, Weirich W. Neuroanatomy and Cranial Computed Tomography. Stuttgart: Thieme Verlag, 1986. 22. Ornstein E, Young WL, Fleischer LH, Ostapkovich N. Desflurane and isoflurane have similar effects on cerebral blood flow in patients with intracranial mass lesions. Anesthesiology 1993; 79: 498–502. 23. Olsen KS, Henriksen A, Owen-Falkenberg A, Dige-Petersen H, Rosenörn J, Chrämmer-Jörgensen B. Effect of 1 or 2 MAC isoflurane with or without ketanserin on cerebral blood
411
24.
25.
26.
27.
28.
29.
30.
31.
flow autoregulation in man. British Journal of Anaesthesia 1994; 72: 66–71. Algotsson L, Messeter K, Rose’n I, Holmin T. Effects of nitrous oxide on cerebral haemodynamics and metabolism during isoflurane anaesthesia in man. Acta Anaesthesiologica Scandinavica 1992; 36: 46–52. Hansen TD, Warner DS, Todd MM, Vust LJ. Effects of nitrous oxide and volatile anaesthetics on cerebral blood flow. British Journal of Anaesthesia 1989; 63: 290–295. Reinstrup P, Uski T, Messeter K. Influence of halothane and isoflurane on the contractile response to potassium and prostaglandin2␣ in isolated human pial arteries. British Journal of Anaesthesia 1994; 72: 581–586. Angevine JB, Cotman CW. The limbic system and hypothalamus. In: Principles of Neuroanatomy. New York: Oxford University Press, 1981. Sakabe T, Kuramoto T, Kumagae S, Takeshita H. Cerebral response to the addition of nitrous oxide to halothane in man. British Journal of Anaesthesia 1976; 48: 95–961. Kuschinsky W, Wahl M. Local chemical and neurogenic regulation of cerebral vascular resistance. Physiological Reviews 1978; 58: 656–689. Hansen TD, Warner DS, Todd MM, Vust LJ. The role of cerebral metabolism in determining the local cerebral blood flow effects of volatile anesthetics: evidence for persistent flow–metabolism coupling. Journal of Cerebral Blood Flow and Metabolism 1989; 9: 323–328. Reinstrup P, Uski T. Inhalational anesthetics in neurosurgery. Current Opinion in Anesthesiology 1994; 7: 421–425.
