Acta anaesth. scand. 1975, 19, 310-315
Whole-Brain Blood Flow and Oxygen Metabolism in the Rat After Halothane Anesthesia A. GJEDDEand B. HINDFELT Cercbrovascular Research Center, Department of Neurology, The New York Hospital-Cornell Medical Center, New York, U.S.A. and Department of Neurology, University Hospital, Lund, Swcdcn
A recent modification of the Kety-Schmidt wash-out technique for ' 33xenon was used to measure whole-brain blood flow (CBF) and oxygen consumption (CMR,,) 1 to 4 hours after termination of halothane anesthesia in 15 Wistar rats. I n this 3-hour experimental period, mean CBF and CMRo, were reduced to 29 and 43% of control values, respectively. CBF and CMR,, determincd at the beginning and end of the experimental period were not significantly different from each other. Cerebral venous O2 tension was significantly higher than in the control group, supporting recent suggestions of a primary, intrinsic effect of halothane on the homeostatic control of this variable. It is concluded that halothane is not useful for cerebral metabolic studies in the rat.
Received 15 April, accepted f o r publication 2 June 1975.
The effects of common anesthetics on cerebral blood flow (CBF) and cerebral metabolic rate (CMR) has been the object of much research by physiologists and clinicians. Physiologists, in particular, have sought an agent with potent analgesic properties but without depressant effects on CBF or CMR,, (cerebral oxygen consumption). I n most instances, these properties have been mutually exclusive. For example, N,O, a widely used anesthetic agent, has slight effects on CBF and CMR,, but in many species, probably including the laboratory rat, concentrations sufficient to produce surgical analgesia are incompatible with adequate 1972, STEFFEY oxygenation (SHIM& ANDERSEN et al. 1974). I n a previous study, henceforth termed the control group, we determined values for CBF and CMR,, in the Wistar rat strain under N,O and local anesthesia (GJEDDEet al. 1975). I n the present study, henceforth termed the experimental group, we used the same surgical and experimental technique except that vaporized halothane was added to the ventilatory gases during surgical prepara-
tion of the animals. Halothane was chosen because the effects of this gaseous anesthetic are reported to wear off in minutes (THEYE & MICHENFELDER 1968a, HOWSE et al. 1974). MATERIALS AND METHODS Experimrnts were performed on 15 male Wistar rats weighing 380k 16 g ( k s.e. mean). The animals wcrc fed a standard laboratory diet and water ad libitum and were not starved prior to surgery. Anesthesia was induced with 3 ml diethyl ethcr in a 3 1 jar. When the animals no longer responded to tilting of the jar, they were rapidly paralyzed, atropinized, tracheotomized and artificially ventilated with 0.8-1.2% halothane (minimum alveolar concentration 1) (WAIZERet al. 1973) vaporized in a mixturc ol' 30-40% O2 and 60-70% N 2 0 . During surgery and normo- and hypercapnic procedures, tidal volume was maintained at approximately 4.5-5 ml at a rate of 50 breaths/min. Hypocapnia was obtained by a 50"/, increase of tidal volume. Rectal temperature was monitored with a thermistor probe and maintained at 37 f 0.3"C ( f s.e. mean) with a heat lamp. The tail artery was cannulated for blood prcssure and pulse measurements with a pressure transducer attachcd to an oscillograph and for anaerobic sampling of blood for measurement of pH, Pao, and Paco,. The animal was then prepared lor continuous and simultaneous sampling of blood from the iliac artery and the transversc
CEREBRAL BLOOD FLOW AFTER H A L O l H A N E
31 1
concentrations, and R Q , were calculated. I n three of the 15 animals, duplicate dctcrminations of CBF and CMRo, wcre carried out a t 1 and 4 hours after discontinuation of halothane administration, and individually averaged for inclusion in Tables 2 and 3 . This protocol was dcsigncd to mcet two objectives: First, to show changes with time in the postanesthesia rirects of halothane, and, second, to duplicatc closely the conditions under which values were obtained in thc control group. All blood sampling was done anaerobically. Determinations on appropriatc animals, as outlined above, included arterial and venous oxygen tcnsions and concentrations, artcrial arid venous carbon dioxide tensions. The concentration of C O , in blood was calculated from pH and Pco, according to the Henderson-Hasselbalch equation. All acid-base and blood gas determinations wcrc carried out on animals in the steady-state in which blood samples obtaincd at lcast 10 minutcs apart agreed within 10%.
sinus of the brain as described for the control group (GJEDDEet al. 1975). Local anesthetics were not used, and preparation lasted approximately 1 h. The administration of halothane was then discontinued, and the animal was allowed to rest for hour before further manipulation. At the start of each CBF determination, the animals breathed a mixture of 10 mCi '33xenon added to 3040% O2 and 60-70% N 2 0 in a 30 1 Douglas bag. For the determination of CBF during hypercapnia, 5-10% COz replaced a corresponding amount of NzO. In all experiments, CBF and CMRo, were dctcrmined by arterial and cerebral venous sampling during 133xenon desaturation, as described for thc control group. In 15 animals, CBF and CMRo, were measured at normocapnia from 1 to 4 hours after discontinuation of halothane administration. In seven of these animals, CBF andCMRo, were also determined a t hypocapnia, and in eight of the 15 animals also at hypercapnia. The combination of these determinations in individual animals was random but always took place from 1 to 4 hours after discontinuation of halothane administration. I n six of the 15 animals, arteriovenous differences for oxygen tension, pH, oxygen and carbon dioxidc
RESULTS I n three animals, norrnocapnic CBF and
251 CBF= 1.57 x Paco, + 7.92 r =0.90 SE= 14.38 -
201
-c
//
.-
/'
151
&
--
0 ?4 0
//
E
1
L L
M
101
'
b
0
/
51
I
I
0
E
I
I
I
I
25
I
I
I
1
1
1
50 Paco, (mm Hg)
1
1
75
1
1
1
100
Fig. 1. Changc in CBI: as a function of change in Pacoz in rats subjcctcd to lialothane administration 1 to 4 hours before determination of CBF (unbrokcn line). Broken line reprcsents the CO,-response of CBF of control group of rats not subjected to prcvious halothane anesthesia (GJEIIDE et al. 197.5). The lines represent the linear regression of values of individual rats.
312
A . GJEDDE AND B. HINDFELT
Table 1 Duplicate determinations of CBF and CMRo, at normocapnia at 1 and 4 hours after the discontinuation of halothane anesthesia ( n = 3). Hour(s) postanesthesia
I
CBF (m1/100g/min) s.e. mean CMRo, (m1/100g/min) s.e. mean
1h 65 6 2.8 0.3
I
4h 65 3 3.3 0.2
CMR,, determined 1 and 4 hours after discontinuation of halothane administration, showed no change (Table 1). In six animals, arterial and venous blood gas and acid-base values obtained at least 1 hour following halothane anesthesia (exferimental group) were compared to the same variables measured in animals exposed to nitrous oxide alone (control group). Only arterial p H and cerebral venous Po2 were
significantly different in the experimental group (Table 2). In the total experimental group of 15 animals, arterial blood gas and acid-base values, CBF and CMR,, were compared to the same variables measured in the control group at normo-, hypo- and hypercapnia. At normo- and hypercapnia, CBF and CMIIoI were significantly lower in the experimental group while at hypocapnia, only CMRo2was lower (Table 3). The response of CBF of the experimental group to changes in Paco2averaged 2% ofthe normocapnic CBF/mmHg change of PacO2, or approximately 1.5 ml/mmHg (Fig. 1). Cerebral vascular resistance of the experimental group, approximated from mean arterial blood pressure and CBF (MABP/ CBF) during normo-, hypo- and hypercapnia, was compared to the vascular resistance of brains in the control group, and revealed a uniform 25-35% increase (Table 4).
Table 2 Arterial and cerebral venous blood values a t normocapnia in the control group (n = 9) and the experimental group 0 2 = 6). (*Calculated from means rather than in individual animals.)
Arterial Control group Mean s.e. mean
92 5
7.34 0.01
16.7 0.8
47.9 1.6
0.80
Experimental group Mean s.e. mean
99
2
7.39 0.01
16.6 0.4
50.8 1.6
1.12
P
Whole-Brain Blood Flow and Oxygen Metabolism in the Rat After Halothane Anesthesia A. GJEDDEand B. HINDFELT Cercbrovascular Research Center, Department of Neurology, The New York Hospital-Cornell Medical Center, New York, U.S.A. and Department of Neurology, University Hospital, Lund, Swcdcn
A recent modification of the Kety-Schmidt wash-out technique for ' 33xenon was used to measure whole-brain blood flow (CBF) and oxygen consumption (CMR,,) 1 to 4 hours after termination of halothane anesthesia in 15 Wistar rats. I n this 3-hour experimental period, mean CBF and CMRo, were reduced to 29 and 43% of control values, respectively. CBF and CMR,, determincd at the beginning and end of the experimental period were not significantly different from each other. Cerebral venous O2 tension was significantly higher than in the control group, supporting recent suggestions of a primary, intrinsic effect of halothane on the homeostatic control of this variable. It is concluded that halothane is not useful for cerebral metabolic studies in the rat.
Received 15 April, accepted f o r publication 2 June 1975.
The effects of common anesthetics on cerebral blood flow (CBF) and cerebral metabolic rate (CMR) has been the object of much research by physiologists and clinicians. Physiologists, in particular, have sought an agent with potent analgesic properties but without depressant effects on CBF or CMR,, (cerebral oxygen consumption). I n most instances, these properties have been mutually exclusive. For example, N,O, a widely used anesthetic agent, has slight effects on CBF and CMR,, but in many species, probably including the laboratory rat, concentrations sufficient to produce surgical analgesia are incompatible with adequate 1972, STEFFEY oxygenation (SHIM& ANDERSEN et al. 1974). I n a previous study, henceforth termed the control group, we determined values for CBF and CMR,, in the Wistar rat strain under N,O and local anesthesia (GJEDDEet al. 1975). I n the present study, henceforth termed the experimental group, we used the same surgical and experimental technique except that vaporized halothane was added to the ventilatory gases during surgical prepara-
tion of the animals. Halothane was chosen because the effects of this gaseous anesthetic are reported to wear off in minutes (THEYE & MICHENFELDER 1968a, HOWSE et al. 1974). MATERIALS AND METHODS Experimrnts were performed on 15 male Wistar rats weighing 380k 16 g ( k s.e. mean). The animals wcrc fed a standard laboratory diet and water ad libitum and were not starved prior to surgery. Anesthesia was induced with 3 ml diethyl ethcr in a 3 1 jar. When the animals no longer responded to tilting of the jar, they were rapidly paralyzed, atropinized, tracheotomized and artificially ventilated with 0.8-1.2% halothane (minimum alveolar concentration 1) (WAIZERet al. 1973) vaporized in a mixturc ol' 30-40% O2 and 60-70% N 2 0 . During surgery and normo- and hypercapnic procedures, tidal volume was maintained at approximately 4.5-5 ml at a rate of 50 breaths/min. Hypocapnia was obtained by a 50"/, increase of tidal volume. Rectal temperature was monitored with a thermistor probe and maintained at 37 f 0.3"C ( f s.e. mean) with a heat lamp. The tail artery was cannulated for blood prcssure and pulse measurements with a pressure transducer attachcd to an oscillograph and for anaerobic sampling of blood for measurement of pH, Pao, and Paco,. The animal was then prepared lor continuous and simultaneous sampling of blood from the iliac artery and the transversc
CEREBRAL BLOOD FLOW AFTER H A L O l H A N E
31 1
concentrations, and R Q , were calculated. I n three of the 15 animals, duplicate dctcrminations of CBF and CMRo, wcre carried out a t 1 and 4 hours after discontinuation of halothane administration, and individually averaged for inclusion in Tables 2 and 3 . This protocol was dcsigncd to mcet two objectives: First, to show changes with time in the postanesthesia rirects of halothane, and, second, to duplicatc closely the conditions under which values were obtained in thc control group. All blood sampling was done anaerobically. Determinations on appropriatc animals, as outlined above, included arterial and venous oxygen tcnsions and concentrations, artcrial arid venous carbon dioxide tensions. The concentration of C O , in blood was calculated from pH and Pco, according to the Henderson-Hasselbalch equation. All acid-base and blood gas determinations wcrc carried out on animals in the steady-state in which blood samples obtaincd at lcast 10 minutcs apart agreed within 10%.
sinus of the brain as described for the control group (GJEDDEet al. 1975). Local anesthetics were not used, and preparation lasted approximately 1 h. The administration of halothane was then discontinued, and the animal was allowed to rest for hour before further manipulation. At the start of each CBF determination, the animals breathed a mixture of 10 mCi '33xenon added to 3040% O2 and 60-70% N 2 0 in a 30 1 Douglas bag. For the determination of CBF during hypercapnia, 5-10% COz replaced a corresponding amount of NzO. In all experiments, CBF and CMRo, were dctcrmined by arterial and cerebral venous sampling during 133xenon desaturation, as described for thc control group. In 15 animals, CBF and CMRo, were measured at normocapnia from 1 to 4 hours after discontinuation of halothane administration. In seven of these animals, CBF andCMRo, were also determined a t hypocapnia, and in eight of the 15 animals also at hypercapnia. The combination of these determinations in individual animals was random but always took place from 1 to 4 hours after discontinuation of halothane administration. I n six of the 15 animals, arteriovenous differences for oxygen tension, pH, oxygen and carbon dioxidc
RESULTS I n three animals, norrnocapnic CBF and
251 CBF= 1.57 x Paco, + 7.92 r =0.90 SE= 14.38 -
201
-c
//
.-
/'
151
&
--
0 ?4 0
//
E
1
L L
M
101
'
b
0
/
51
I
I
0
E
I
I
I
I
25
I
I
I
1
1
1
50 Paco, (mm Hg)
1
1
75
1
1
1
100
Fig. 1. Changc in CBI: as a function of change in Pacoz in rats subjcctcd to lialothane administration 1 to 4 hours before determination of CBF (unbrokcn line). Broken line reprcsents the CO,-response of CBF of control group of rats not subjected to prcvious halothane anesthesia (GJEIIDE et al. 197.5). The lines represent the linear regression of values of individual rats.
312
A . GJEDDE AND B. HINDFELT
Table 1 Duplicate determinations of CBF and CMRo, at normocapnia at 1 and 4 hours after the discontinuation of halothane anesthesia ( n = 3). Hour(s) postanesthesia
I
CBF (m1/100g/min) s.e. mean CMRo, (m1/100g/min) s.e. mean
1h 65 6 2.8 0.3
I
4h 65 3 3.3 0.2
CMR,, determined 1 and 4 hours after discontinuation of halothane administration, showed no change (Table 1). In six animals, arterial and venous blood gas and acid-base values obtained at least 1 hour following halothane anesthesia (exferimental group) were compared to the same variables measured in animals exposed to nitrous oxide alone (control group). Only arterial p H and cerebral venous Po2 were
significantly different in the experimental group (Table 2). In the total experimental group of 15 animals, arterial blood gas and acid-base values, CBF and CMR,, were compared to the same variables measured in the control group at normo-, hypo- and hypercapnia. At normo- and hypercapnia, CBF and CMIIoI were significantly lower in the experimental group while at hypocapnia, only CMRo2was lower (Table 3). The response of CBF of the experimental group to changes in Paco2averaged 2% ofthe normocapnic CBF/mmHg change of PacO2, or approximately 1.5 ml/mmHg (Fig. 1). Cerebral vascular resistance of the experimental group, approximated from mean arterial blood pressure and CBF (MABP/ CBF) during normo-, hypo- and hypercapnia, was compared to the vascular resistance of brains in the control group, and revealed a uniform 25-35% increase (Table 4).
Table 2 Arterial and cerebral venous blood values a t normocapnia in the control group (n = 9) and the experimental group 0 2 = 6). (*Calculated from means rather than in individual animals.)
Arterial Control group Mean s.e. mean
92 5
7.34 0.01
16.7 0.8
47.9 1.6
0.80
Experimental group Mean s.e. mean
99
2
7.39 0.01
16.6 0.4
50.8 1.6
1.12
P
