Acta Anaesthesiol Scand 1992: 36: 142- 144
Cerebral arteriovenous difference of oxygen during gradual and sudden increase of the concentration of isoflurane for induction of deliberate hypot ension V. Y. HARALDSTED, J. ASMUSSEN, P. HERLEVSEN and G. E. COLD Department of Neuroanaesthesiology, University Hospital of Aarhus, Denmark
In 20 patients undergoing surgery for cerebral aneurysms, hypotension was induced with either gradual (over 5 min) or sudden increase of inspiratory concentration of isoflurane from 0.5% to 3%. Both modes elicited the same speed of induction of deliberate hypotension and similar decreases of cerebral arteriovenous difference of oxygen (AVDo,). The overall median values of mean arterial blood pressure decreased from 75.5 (range 64-90) mmHg (10 (8.5-12.0) kPa) to 55 ( 4 M 6 ) mmHg (7.3 (5.3-8.8) kPa) and the overall AVDo, decreased from 6.75 rn1/100ml (3.8-9.4 m1/100 ml) to 5.85 m1/100 ml (2.6-8.1 m1/100 ml) within 10 min. It is concluded that irrespective of gradual or sudden increase of isoflurane concentration, cerebral blood flow is in surplus of metabolism and a favourable oxygen demand/supply ratio is maintained during induction of deliberate hypotension by isoflurane below 2.5 MAC. Received 26 March, accepted for publication 20 j u g I991
Kty words: Anesthesia; arteriovenous oxygen difference, cerebral; hypotension, deliberate; isoflurane; neuroanesthesia.
The volatile anaesthetics halothane, enflurane and isoflurane have qualitatively similar, but quantitatively dissimilar effects on cerebral haemodynamics. They all exert vasodilatation and metabolic depression ( 1 ) . The reduced cerebral vascular resistance, which increases cerebral blood flow, is counteracted by hypocarbia (2-5). Use of isoflurane is characterized by a diminished enhancement of cerebral blood flow (CBF), but augmented metabolic depression compared to halothane (6). Thus isoflurane reduces the cerebral metabolic rate of oxygen (CMRo,) to approximately 50% at 1.5-2.0 MAC, at which point the EEG becomes isoelectric, whereas the CBF is unchanged or only slightly elevated (5). In the systemic circulation isoflurane causes a dose-dependent decrease of mean arterial blood pressure (MABP) due to peripheral vasodilation, whereas cardiac output is unaffected by concentrations up to 2 MAC (7). This knowledge has led to the use of isoflurane to induce deliberate hypotension during operation for cerebral aneurysms. However, a study of dogs suggests that rapid induction of profound hypotension produces a transient imbalance of oxygen demand/supply, in which the reduction of CBF by far exceeds the concomitant metabolic depression (8). The aim of this study was to
examine whether this imbalance also exists in man during rapid induction of hypotension by isoflurane.
PATIENTS AND METHODS Twenty patients undergoing surgery for cerebral aneurysms were studied. None had signs or symptoms of pulmonary or cardiac disease, and normal mental function had been restored after the acute subarachnoidal haemorrhage, which caused admission to the hospital. Informed consent from each patient and approval by the local ethics committee were obtained. Anaesthesia Diazepam 1 e 2 0 mg P.o., 1 h before surgery. Anaesthesia was induced with thiopentone 5-6 rng.kg-', fentanyl 3-5 p g . k g - ' and pancuronium 0.14.15 mg.kg-'. Prior to intubation lignocaine 1.5 mg. kg-' was administered to minimize any hypertensive response. Maintenance of anaesthesia was achieved with 66% nitrous oxide in oxygen and isoflurane 0.5-1.0%. Fentanyl 100 pg was supplemented before skin incision, and increments of pancuronium were given to allow recovery of only the first twitch response to train-of-four stimulation. Ventilation was controlled by a Servo ventilator 900 B (Siemens Elema, Sweden) to maintain moderate hypocapnia with end-tidal PCO,4-4.5 kPa. The gas mixture was delivered via a circle system with a fresh gas flow as high as 6 I/min to speed up the uptake of isoflurane, thus minimizing the delaying effect of the circle. Endexpiratory concentration of isoflurane (Normac, Datex) was continuously recorded. A cannula was placed in the radial artery for MABP recording and arterial blood sampling. The patients were randomly allocated to two different schemrs
CEREBRAL AVDo, DURING HYPOTENSION BY ISOFLURANE for achieving deliberate hypotension. In Group I the inspiratory concentration of isoflurane was increased stepwise by 0.5% every minute from 0.5-1.0% to 2.5-3.0% to attain a MABP of 50-60 mmHg (6.7-8.0 kPa). In Group I1 the same level of hypotension was achieved by an instant increase of the inspiratory concentration of isoflurane to 2.5-3.0%. Measurements of AVDo, After induction of anaesthesia the right internal jugular vein was cannulated percutaneously using the Seldinger technique, and a catheter was advanced in the cephalic direction to the base of the skull for placement in the jugular bulb. Blood samples were withdrawn simultaneously from the vein and the artery, and blood gases were analysed immediately (ABL 300, Radiometer, Copenhagen, Denmark). AVDo, was calculated as the difference of oxygen content in arterial and venous blood samples. Samples were taken at 0, 1, 3, 5, 7, and 10 min after the increase of the concentration of isoflurane (t=O is the time at which gradual increase starts or suddent increase is implemented). Statistics
Values are given as median with range or quartilespans. For evaluation non-parametric statistics were applied. Within each group the Page test (9, 10) was used to assess the variation with time for a given parameter. In contrast to Friedman’s test, the Page test utilizes the fact that the x-axes in Fig. I are in fact ordinal scales (increasing levels of isoflurane). Inter-group comparisons were made by the Mann-Whitney rank sum test for unpaired data. P< 0.05 was considered significant.
RESULTS As shown in Table 1, the groups were comparable with regard to age, weight, sex and doses of thiopentone and fentanyl administered before induction of hypotension. There were no inter-group differences with regard to Paco, at the beginning and at the end of induction of hypotension, but within both groups the Paco, decreased, despite the fact that ventilation was unaltered. The decrease in Paco, was significant in Group 11. As expected (Fig. l ) , the end-expiratory concentration of isoflurane increased at a significantly higher rate in Group I1 than in Group I. Within both groups a significant reduction of MABP and AVDo, was seen Table I Demographic data. Anaesthetic requirement before hypotension and Paco, levels at the start (t=O) and at the end ( t = 10) of induction of hypotension. I Age (Yr) Weight (kg) Sex ratio (M/F) Thiopentone (mg) Fentanyl (pg) Paco, (kPa, t = 0 ) Paco, (kPa, t = 10 min)
51 (43-65) 60 (5Cb85) 2/8 412.5 (25&525) 400 (30Cb500) 4.26 (3.52-4.46) 4.11 (3.32-4.44)
I1
47.5 (32-65) 63 (47-75) 1i9
425 375 4.26 3.88
(30Cb500) (325-500) (3.4H.71) (3.324.15)*
Group I: Gradual increase (over 5 min) of inspiratory concentration of isoflurane from 0.5% to 3%. Group 11: Suddent increase from 0.5% to 3%. Values are given as median (range). Asterisk denote intra-group I1 change (PcO.05).
143
together with a significant increase of heart rate, but no inter-group differences were found. DISCUSSION Our concern, that rapidly induced hypotension might also elicit a transient mismatch between CBF (11)and CMRo, (1) in man, has not been confirmed by the present study. We have shown that gradual and sudden increase of the inspiratory concentration of isoflurane to the highest clinically relevant concentration caused the same speed of induction of hypotension. The desired level of MABP was obtained in 10 min. During the induction of hypotension the AVDo, decreased in both groups, thus excluding insufficiency of flow to meet the metabolic demand. Several studies have described how CBF is unaltered or slightly increased and CMRo, depressed at increasing levels of isoflurane during moderate hypocapnia (3-6). In contrast to these findings, a dog study (8) demonstrated 50% reduction of CBF lasting 10 min accompanied by 25% reduction of CMRo, (i.e. an increase of AVDo,), when MAPB was reduced rapidly from 1 10 to 45 mmHg (14.7 to 6.0 kPa) by isoflurane over a 1-5-min period. When the same level of hypotension was induced over 6-10 min, CBF was unchanged and CMRo, reduced by 25%. According to the equation CMRo, = AVDo, x CBF, AVDo, increased when hypotension was induced rapidly, but decreased when hypotension was induced gradually. The level ofisoflurane necessary to produce rapid and profound hypotension in the dog study is not stated. The discrepancy between the impact of isoflurane on AVDo, in this and in our study may be due to very high concentrations of isoflurane to induce rapid hypotension in (6), thereby severely restricting cerebral perfusion pressure, outweighing cerebral vasodilation. Paco, is governed by the ratio between production and elimination of CO,. Since ventilation was not altered, the reduction of Paco, during induction of hypotension in Group I1 reflects decreased overall metabolism of the tissues. Our conclusions, based on changes in AVDo,, are not invalidated by this reduction in Paco,, which tends to reduce CBF and hence increase AVDo,. In other words, had the Paco, remained unchanged, the observed decrease in AVDo, would probably have been further exaggerated. We believe that the large inter-individual variability ofcerebral AVDo,, which has also been found by others (6), is responsible for the different starting points of the AVDo, curves, whereas the parallel downhill courses represent the same impact of isoflurane on the balance between flow and metabolism in both groups. In conclusion, both sudden and gradual increase of
144
V Y HARALDSTED E T AL
___
0
1
3
5
7
10
0
Time after increase of concentration of isoflurane (min.)
1
3
5
~~
~
7
10
Time after increase of concentration of isoflurance (min.)
Fig. 1. End-tidal concentration of isoflurane, mean arterial blood pressure, heart rate and cerebral arteriovenous difference of oxygen during induction of hypotension by gradual (solid lines) and sudden (stippled lines) increase of inspiratory concentration of isoflurane. Medians with quartile spans. Only significant inter-group differences at various time points are shown. Asterisks denote P i 0.05.
inspiratory concentration of isoflurane to 3% elicit the same speed of induction of hypotension in man, during which AVDo, decreases slightly, indicating a surplus of flow relative to metabolism. It has not been excluded, however, that very rapid induction of (more pronounced) hypotension by higher concentrations of isoflurane may cause insufficiency of flow with respect to metabolism. Ifso, this hazard is still hypothetical in daily practice using concentrations of isoflurane below 2.5 MAC. REFERENCES I . Murphy F L Jr, Kennel1 E M, Johnstone R E. The effects of enflurane, isoflurane and halothane on cerebral blood flow and metabolism in man. Abstracts of Scientific Papers, Annual Meeting of the American Society of Anesthesiologists, 1974: 61-62. 2. Shapiro H M. Anesthesia effects on cerebral blood flow, cerebral metabolism, EEG and evoked potentials. In: Miller R D. Anesthesia, 2nd ed. New York: Churchill Livingstone, 1986: 1249- 1288. 3. Todd M M, Drummond J C. A comparison of the cerebrovascular and metabolic effects of halothane and isoflurane in the cat. Anesthesiology 1984: 60: 276-282.
B, Gelb A W, Lam A M. The effect of isofluraneinduced hypotension on cerebral blood flow and cerebral metabolic rate for oxygen in humans. Anesthesiology 1986: 64: 307-3 10. Newberg L A, Milde J H, Michenfelder J D. The cerebral metabolic effects of isoflurane at and above concentrations that suppress cortical electrical activity. Anesthesiology 1983: 59: 23-28. Algotsson L, Messeter K, Nordstrom C H, Ryding E. Cerebral blood flow and oxygen consumption during isoflurane and halothane anesthesia in man. Acta Anaesfhesiol &and 1988: 32: 15-20. Edmond I, Eger 11. Isoflurane: a review. Anesthesiology 1981: 55: 559-576. Hickey R, Bunegin L, Albin M S, Gelineau J, Rausrhhuber R. Cerebral blood flow responses during varying rates of isofluraneinduced hypotension. Anesthesiology 1986: 65: 3.4 A580. Andersen D, Havsteen B, Juhl E, Riis P. Laegevidenskabelig forskning. Kebenhavn, Arhus, Odense: FADL's Forlag, 1987. 119-200. Hollander M, Wolfe D A. Nonparametrical statistical methods. New York: Wiley, 1973: 147-150.
4. Newman
5.
6.
7. 8.
9.
10.
Address: Viggo Yang Haraldsted Holme Byvej 8 DK-8270 Hejbjerg Denmark
Cerebral arteriovenous difference of oxygen during gradual and sudden increase of the concentration of isoflurane for induction of deliberate hypot ension V. Y. HARALDSTED, J. ASMUSSEN, P. HERLEVSEN and G. E. COLD Department of Neuroanaesthesiology, University Hospital of Aarhus, Denmark
In 20 patients undergoing surgery for cerebral aneurysms, hypotension was induced with either gradual (over 5 min) or sudden increase of inspiratory concentration of isoflurane from 0.5% to 3%. Both modes elicited the same speed of induction of deliberate hypotension and similar decreases of cerebral arteriovenous difference of oxygen (AVDo,). The overall median values of mean arterial blood pressure decreased from 75.5 (range 64-90) mmHg (10 (8.5-12.0) kPa) to 55 ( 4 M 6 ) mmHg (7.3 (5.3-8.8) kPa) and the overall AVDo, decreased from 6.75 rn1/100ml (3.8-9.4 m1/100 ml) to 5.85 m1/100 ml (2.6-8.1 m1/100 ml) within 10 min. It is concluded that irrespective of gradual or sudden increase of isoflurane concentration, cerebral blood flow is in surplus of metabolism and a favourable oxygen demand/supply ratio is maintained during induction of deliberate hypotension by isoflurane below 2.5 MAC. Received 26 March, accepted for publication 20 j u g I991
Kty words: Anesthesia; arteriovenous oxygen difference, cerebral; hypotension, deliberate; isoflurane; neuroanesthesia.
The volatile anaesthetics halothane, enflurane and isoflurane have qualitatively similar, but quantitatively dissimilar effects on cerebral haemodynamics. They all exert vasodilatation and metabolic depression ( 1 ) . The reduced cerebral vascular resistance, which increases cerebral blood flow, is counteracted by hypocarbia (2-5). Use of isoflurane is characterized by a diminished enhancement of cerebral blood flow (CBF), but augmented metabolic depression compared to halothane (6). Thus isoflurane reduces the cerebral metabolic rate of oxygen (CMRo,) to approximately 50% at 1.5-2.0 MAC, at which point the EEG becomes isoelectric, whereas the CBF is unchanged or only slightly elevated (5). In the systemic circulation isoflurane causes a dose-dependent decrease of mean arterial blood pressure (MABP) due to peripheral vasodilation, whereas cardiac output is unaffected by concentrations up to 2 MAC (7). This knowledge has led to the use of isoflurane to induce deliberate hypotension during operation for cerebral aneurysms. However, a study of dogs suggests that rapid induction of profound hypotension produces a transient imbalance of oxygen demand/supply, in which the reduction of CBF by far exceeds the concomitant metabolic depression (8). The aim of this study was to
examine whether this imbalance also exists in man during rapid induction of hypotension by isoflurane.
PATIENTS AND METHODS Twenty patients undergoing surgery for cerebral aneurysms were studied. None had signs or symptoms of pulmonary or cardiac disease, and normal mental function had been restored after the acute subarachnoidal haemorrhage, which caused admission to the hospital. Informed consent from each patient and approval by the local ethics committee were obtained. Anaesthesia Diazepam 1 e 2 0 mg P.o., 1 h before surgery. Anaesthesia was induced with thiopentone 5-6 rng.kg-', fentanyl 3-5 p g . k g - ' and pancuronium 0.14.15 mg.kg-'. Prior to intubation lignocaine 1.5 mg. kg-' was administered to minimize any hypertensive response. Maintenance of anaesthesia was achieved with 66% nitrous oxide in oxygen and isoflurane 0.5-1.0%. Fentanyl 100 pg was supplemented before skin incision, and increments of pancuronium were given to allow recovery of only the first twitch response to train-of-four stimulation. Ventilation was controlled by a Servo ventilator 900 B (Siemens Elema, Sweden) to maintain moderate hypocapnia with end-tidal PCO,4-4.5 kPa. The gas mixture was delivered via a circle system with a fresh gas flow as high as 6 I/min to speed up the uptake of isoflurane, thus minimizing the delaying effect of the circle. Endexpiratory concentration of isoflurane (Normac, Datex) was continuously recorded. A cannula was placed in the radial artery for MABP recording and arterial blood sampling. The patients were randomly allocated to two different schemrs
CEREBRAL AVDo, DURING HYPOTENSION BY ISOFLURANE for achieving deliberate hypotension. In Group I the inspiratory concentration of isoflurane was increased stepwise by 0.5% every minute from 0.5-1.0% to 2.5-3.0% to attain a MABP of 50-60 mmHg (6.7-8.0 kPa). In Group I1 the same level of hypotension was achieved by an instant increase of the inspiratory concentration of isoflurane to 2.5-3.0%. Measurements of AVDo, After induction of anaesthesia the right internal jugular vein was cannulated percutaneously using the Seldinger technique, and a catheter was advanced in the cephalic direction to the base of the skull for placement in the jugular bulb. Blood samples were withdrawn simultaneously from the vein and the artery, and blood gases were analysed immediately (ABL 300, Radiometer, Copenhagen, Denmark). AVDo, was calculated as the difference of oxygen content in arterial and venous blood samples. Samples were taken at 0, 1, 3, 5, 7, and 10 min after the increase of the concentration of isoflurane (t=O is the time at which gradual increase starts or suddent increase is implemented). Statistics
Values are given as median with range or quartilespans. For evaluation non-parametric statistics were applied. Within each group the Page test (9, 10) was used to assess the variation with time for a given parameter. In contrast to Friedman’s test, the Page test utilizes the fact that the x-axes in Fig. I are in fact ordinal scales (increasing levels of isoflurane). Inter-group comparisons were made by the Mann-Whitney rank sum test for unpaired data. P< 0.05 was considered significant.
RESULTS As shown in Table 1, the groups were comparable with regard to age, weight, sex and doses of thiopentone and fentanyl administered before induction of hypotension. There were no inter-group differences with regard to Paco, at the beginning and at the end of induction of hypotension, but within both groups the Paco, decreased, despite the fact that ventilation was unaltered. The decrease in Paco, was significant in Group 11. As expected (Fig. l ) , the end-expiratory concentration of isoflurane increased at a significantly higher rate in Group I1 than in Group I. Within both groups a significant reduction of MABP and AVDo, was seen Table I Demographic data. Anaesthetic requirement before hypotension and Paco, levels at the start (t=O) and at the end ( t = 10) of induction of hypotension. I Age (Yr) Weight (kg) Sex ratio (M/F) Thiopentone (mg) Fentanyl (pg) Paco, (kPa, t = 0 ) Paco, (kPa, t = 10 min)
51 (43-65) 60 (5Cb85) 2/8 412.5 (25&525) 400 (30Cb500) 4.26 (3.52-4.46) 4.11 (3.32-4.44)
I1
47.5 (32-65) 63 (47-75) 1i9
425 375 4.26 3.88
(30Cb500) (325-500) (3.4H.71) (3.324.15)*
Group I: Gradual increase (over 5 min) of inspiratory concentration of isoflurane from 0.5% to 3%. Group 11: Suddent increase from 0.5% to 3%. Values are given as median (range). Asterisk denote intra-group I1 change (PcO.05).
143
together with a significant increase of heart rate, but no inter-group differences were found. DISCUSSION Our concern, that rapidly induced hypotension might also elicit a transient mismatch between CBF (11)and CMRo, (1) in man, has not been confirmed by the present study. We have shown that gradual and sudden increase of the inspiratory concentration of isoflurane to the highest clinically relevant concentration caused the same speed of induction of hypotension. The desired level of MABP was obtained in 10 min. During the induction of hypotension the AVDo, decreased in both groups, thus excluding insufficiency of flow to meet the metabolic demand. Several studies have described how CBF is unaltered or slightly increased and CMRo, depressed at increasing levels of isoflurane during moderate hypocapnia (3-6). In contrast to these findings, a dog study (8) demonstrated 50% reduction of CBF lasting 10 min accompanied by 25% reduction of CMRo, (i.e. an increase of AVDo,), when MAPB was reduced rapidly from 1 10 to 45 mmHg (14.7 to 6.0 kPa) by isoflurane over a 1-5-min period. When the same level of hypotension was induced over 6-10 min, CBF was unchanged and CMRo, reduced by 25%. According to the equation CMRo, = AVDo, x CBF, AVDo, increased when hypotension was induced rapidly, but decreased when hypotension was induced gradually. The level ofisoflurane necessary to produce rapid and profound hypotension in the dog study is not stated. The discrepancy between the impact of isoflurane on AVDo, in this and in our study may be due to very high concentrations of isoflurane to induce rapid hypotension in (6), thereby severely restricting cerebral perfusion pressure, outweighing cerebral vasodilation. Paco, is governed by the ratio between production and elimination of CO,. Since ventilation was not altered, the reduction of Paco, during induction of hypotension in Group I1 reflects decreased overall metabolism of the tissues. Our conclusions, based on changes in AVDo,, are not invalidated by this reduction in Paco,, which tends to reduce CBF and hence increase AVDo,. In other words, had the Paco, remained unchanged, the observed decrease in AVDo, would probably have been further exaggerated. We believe that the large inter-individual variability ofcerebral AVDo,, which has also been found by others (6), is responsible for the different starting points of the AVDo, curves, whereas the parallel downhill courses represent the same impact of isoflurane on the balance between flow and metabolism in both groups. In conclusion, both sudden and gradual increase of
144
V Y HARALDSTED E T AL
___
0
1
3
5
7
10
0
Time after increase of concentration of isoflurane (min.)
1
3
5
~~
~
7
10
Time after increase of concentration of isoflurance (min.)
Fig. 1. End-tidal concentration of isoflurane, mean arterial blood pressure, heart rate and cerebral arteriovenous difference of oxygen during induction of hypotension by gradual (solid lines) and sudden (stippled lines) increase of inspiratory concentration of isoflurane. Medians with quartile spans. Only significant inter-group differences at various time points are shown. Asterisks denote P i 0.05.
inspiratory concentration of isoflurane to 3% elicit the same speed of induction of hypotension in man, during which AVDo, decreases slightly, indicating a surplus of flow relative to metabolism. It has not been excluded, however, that very rapid induction of (more pronounced) hypotension by higher concentrations of isoflurane may cause insufficiency of flow with respect to metabolism. Ifso, this hazard is still hypothetical in daily practice using concentrations of isoflurane below 2.5 MAC. REFERENCES I . Murphy F L Jr, Kennel1 E M, Johnstone R E. The effects of enflurane, isoflurane and halothane on cerebral blood flow and metabolism in man. Abstracts of Scientific Papers, Annual Meeting of the American Society of Anesthesiologists, 1974: 61-62. 2. Shapiro H M. Anesthesia effects on cerebral blood flow, cerebral metabolism, EEG and evoked potentials. In: Miller R D. Anesthesia, 2nd ed. New York: Churchill Livingstone, 1986: 1249- 1288. 3. Todd M M, Drummond J C. A comparison of the cerebrovascular and metabolic effects of halothane and isoflurane in the cat. Anesthesiology 1984: 60: 276-282.
B, Gelb A W, Lam A M. The effect of isofluraneinduced hypotension on cerebral blood flow and cerebral metabolic rate for oxygen in humans. Anesthesiology 1986: 64: 307-3 10. Newberg L A, Milde J H, Michenfelder J D. The cerebral metabolic effects of isoflurane at and above concentrations that suppress cortical electrical activity. Anesthesiology 1983: 59: 23-28. Algotsson L, Messeter K, Nordstrom C H, Ryding E. Cerebral blood flow and oxygen consumption during isoflurane and halothane anesthesia in man. Acta Anaesfhesiol &and 1988: 32: 15-20. Edmond I, Eger 11. Isoflurane: a review. Anesthesiology 1981: 55: 559-576. Hickey R, Bunegin L, Albin M S, Gelineau J, Rausrhhuber R. Cerebral blood flow responses during varying rates of isofluraneinduced hypotension. Anesthesiology 1986: 65: 3.4 A580. Andersen D, Havsteen B, Juhl E, Riis P. Laegevidenskabelig forskning. Kebenhavn, Arhus, Odense: FADL's Forlag, 1987. 119-200. Hollander M, Wolfe D A. Nonparametrical statistical methods. New York: Wiley, 1973: 147-150.
4. Newman
5.
6.
7. 8.
9.
10.
Address: Viggo Yang Haraldsted Holme Byvej 8 DK-8270 Hejbjerg Denmark
