Brain blood flow autoregulation and metabolism during halothane anesthesia in monkeys HIDE0 MORITA, EDWIN M. NEMOTO, ACHIEL L. BLEYAERT, AND S. WILLIAM of Anesthesiology/Critical Care Medicine Program University of Pittsburgh Department School of Medicine, Pittsburgh, Pennsylvania 15261
M. NEMOTO, ACHIEL L. BLEYAERT, Brain blood fZow autoregulation and metabolism during halothane anesthesia in monkeys. Am. J. Physiol. 233(6): H670-H676, 1977 or Am. J. Physiol.: Heart Circ. Physiol. 2(6): H670-H676, 1977. -Past studies suggest that halothane causes cerebrovascular dilatation and increased cerebral blood flow (CBF); these properties may be relevant to its use for neurosurgical procedures. We studied CBF autoregulation in monkeys during anesthesia with 66% N,0/33% 0, and with 0.5%, l.O%, and 2.0% inspired halothane at various cerebral perfusion pressures (CPP) achieved by infusion of trimethaphan camsylate or phenylephrine. CBF was measured by monitoring brain xenon-133 clearance after intra-arterial injection of the isotope in saline. CBF autoregulation was intact during N,O/O, and during 0.5% halothane/ N,O/O, anesthesia at CPPs ranging from 50 to 100 mmHg, but began to fail at 1.0% halothane. Complete loss of autoregulation occurred during 2% halothane/N,O/O, anesthesia. Estimated brain 0, consumption fell by 30%, 40%, and 50% during 0.5%, l.O%, and 2.0% halothane anesthesia, respectively, compared to 0, consumption during N,O/O, anesthesia (100%). MORITA, HIDEO, EDWIN AND S. WILLIAM STEZOSKI.
STEZOSKI
and 2.0% in 66% N,0/33% 0,. CBF autoregulation was intact at inspired halothane of 0.5%, but began to fail during 1.0% halothane anesthesia with complete loss of autoregulation at 2.0% halothane. CMROz fell by 30%, 40%, and 50% at inspired halothane of 0.5%, l.O%, and 2.0%, respectively. METHODS
Nine prequarantined female rhesus monkeys 5.6-11 kg body wt (Primate Imports, Inc.) were fed Purina monkey chow during an additional go-day quarantine and tuberculin testing in a holding facility. The day before the study, a monkey was transferred to a cage in the laboratory and fasted overnight with water ad libitum. Surgical preparations. Between 7 and 8 A.M. of the following day, the monkey was placed in a small transport cage insufflated with 70% N,0/30% 0,. Pancuronium bromide (Pavulon; Organon, Inc.) was injected intramuscularly (0.06 mg/kg); when the monkey appeared sufficiently relaxed, it was quickly intubated rhesus monkey; brain 0, consumption; cerebrovascular resistwith a cuffed Portex endotracheal tube lubricated with ance 5% lidocaine jelly (Astra Pharmaceutical Products). The monkey was ventilated by a fixed-volume piston respirator (Harvard Apparatus) on 66% N,0/33% 0, at HALOTHANE, inspite of its many desirable features, such a tidal volume of ca. 20 ml/kg body wt and rate of as easy induction and rapid postanesthestic recovery about 20 breaths/min. CO, added to the inspired gas (ll), is a potent myocardial depressant (7); sensitizes maintained end-tidal CO, (continuously monitored by a Beckman LB-l the myocardium to epinephrine-induced arrhythmias infrared analyzer) between 5% and (10); and causes cerebrovascular dilatation and an in- 6%. Bipolar ECG leads were attached to the monkey crease in cerebral blood flow (CBF) in animals (9, 12, and a rectal thermistor was inserted ca. 5 cm into the 19) and man (5, 14, 23). The effect of halothane on CBF rectum. An electric heating blanket maintained rectal autoregulation via its cerebrovasodilatory action is es- temperature between 37 and 39°C. The femoral-inguinal region was shaved, scrubbed pecially important in patients with intracranial mass with Zephiran, and infiltrated with 5 ml of 1% lidocaine lesions, in whom it markedly increases intracranial (Xylocaine; Astra Pharmaceutical Products). Polyethpressure (1, 8, 16) which could critically reduce CBF especially when combined with myocardial depression. ylene catheters were inserted into a femoral artery and vein 5-10 min later for arterial pressure monitoring, Previous investigators have not studied CBF autoregulation at various depths of halothane anesthesia and blood sampling, drug infusion, and fluid replacement. The region of the submandibular and carotid trigones over a range of cerebral perfusion pressures (CPP), but have shown increased CBF in spite of reduced CPP. medial to the sternocleidomastoid muscle was shaved, sterilized, and infiltrated with 5 ml of 1% lidocaine. A Thus, halothane may be a more potent cerebrovasodilator than presently appreciated and could have a catheter was wedged retrogradely into the superior jugular bulb for cerebral venous blood sampling and profound effect on CBF autoregulation. pressure monitoring without occlusion of the internal We evaluated CBF autoregulation and estimated cerebral metabolic rate of 0, (CMRO,) during anesthe- jugular vein proximal to the bulb. A catheter was sia at inspired halothane concentrations of 0.5%, l.O%, inserted retrogradely and occlusively into the external H670
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HALOTHANE
AND
CBF
H671
AUTOREGULATION
carotid artery with the tip at the bifurcation of the common carotid artery for 133Xe-in-saline injection into the internal carotid for CBF measurements. All surgical wounds were treated with polymyxin-B-bacitracin-neomycin powder prior to closure with no. 4-O silk. Experimental protocol. Following surgery, the monkey was ventilated on 66% N,O/33% 0, for a 30-min stabilization period with normalization of arterial blood gases (Pao, > 100 mmHg; PacoZ, 35-45 mmHg), pH (7.30-7.45), base deficit ( t 5 meq/liter), and mean arterial pressure (MAP) (80-120 mmHg). Thereafter, the first set of control measurements of CBF, MAP, ECG, cerebral venous pressure, arterial PO,, PcoZ, base excess, and pH, and arterial and cerebral venous blood 0, content (Lexicon oxygen analyzer) were made and were followed by a second set of control measurements 60 min later (see Table 1). After the second control measurements, the monkey was either continued on 66% N,O/33% OS, or halothane (Fluothane, Ayerst Laboratories) was added to the inspired gas at concentrations of 0.5%, or l.O%, or 2.0%. In each study, CBF autoregulation was evaluated at only one concentration of inspired halothane. Twenty minutes after halothane exposure, MAP was randomly manipulated to either 50, 100, or 150 mmHg by titrated intravenous infusion of trimethaphan camsylate (Arfonad; Hoffman-LaRoche) ‘or phenylephrine (Neo-Synephrine; Winthrop Laboratories). Phenylephrine does not affect CMRO, (18), whereas Arfonad is rapid and short-acting and blood pressure can be easily and quickly manipulated. All CBF measurements were made 5-10 min after stabilization of MAP at the desired level. Three sequential CBF measurements were made at each sampling period to verify a steady state. Arterial and cerebral venous blood were sampled for CMRO, arterial blood gases, and pH immediately preceding the second measurement. Only the second CBF value was used to calculate CMRO, to ensure appropriate matching of CBF with metabolic sampling since the time required for the three sequential CBF measurements ranged from 40 to 60 min. The variation between CBFs in each group of three sequential measurements ranged between 4.5 and 6.3% (Table 2). The number of CBF 1. Experimental design for evaluation of CBF autoregulation during halothane anesthesia TABLE
Study
Control Period, ca. 2 h
Group 4
N,O/O,S
0.5%
Halothane
*
Extl
.
9
N,O/O,
N,O/O,
0.5 Halothane/Nz0/02
TABLE 2. Percent variation between three sequential cerebral blood flow measurements at each level of inspired halothane Halothane,
N,O/Oz
1 .O% Halothane/N,O/O,
2.0%
N,O/Oz
2.0%
Halothane
% of variation
nt
61 58 78 63
5.5 5.8 6.3 4.5
+ + k f
6 4 4.8 3
Percent variation values are means + SE. Cerebral blood flow was measured by external scintillation monitoring over ipsilateral hemisphere following internal carotid artery injection of 200-500 j&i 133Xe in saline (0.2 ml). * Combined with 66% N,0/33% 0, with CO, added to keep end-tidal CO, between 5-6%. t n, number of observations; see Table 4 for number of monkeys studied at each level of halothane.
3. Halothane levels in rhesus monkeys
TABLE Inspired
halothane,
%*
0.5
1.0
2.0
Alveolar
halothane,
%t
0.3
0.5
1.0
5.6 + 0.4
9.6 +0.4
19.3 * 1.1
(n = 7)
(n = 15)
(12 = 10)
Blood halothane, 100 ml, ji
mg/
4. Number and distribution at each level of inspired halothane TABLE
Halothane 0%
1.0% Halothane
%*
0 0.5 1.0 2.0
Blood halothane values are means + SE. n is the number of monkeys studied at each halothane level. * With 66% N,0/33% “f Calculated from blood-to-air partition coefficient of 2.3 (6). 02.
Period,? ca. 4 h
N,O/O,
measurements in each anesthetic group is also shown. Arterial blood samples (0.5 ml) were obtained periodically for blood halothane analysis by gas chromatography (22). Alveolar halothane concentrations calculated using a blood-to-air partition coefficient of 2.3 (6) were ca. 50% of inspired concentrations (Table 3). The total blood volume sampled throughout each study was about 30 ml or about 5% of the total blood volume of the smallest monkey (i.e., 5.6 kg). Table 4 shows the number of studies done for each anesthetic combination and the distribution of the monkeys (identified by number). With the exception of three monkeys, each was used in more than one study with 6-12 days between studies on the same monkey to allow spontaneous replacement of erythrocytes. A total of 16 studies was done on the nine monkeys. Cerebral blood fZow measurements. CBF measurements were made by external scintillation monitoring of brain 133Xe clearance in the hemisphere ipsilateral to the injection of 133Xe in saline (200-500 &i in 0.2 ml
* CBF, CVR, and CMROz values obtained during normotension (MAP 80-120 mmHg) in control period used to calculate percent control in experimental period. t MAP randomly manipulated by titrated intravenous infusion of trimethaphan camsylate or phenylephrine to approximately 50, 100, and 150 mmHg. $ 66% N,0/33% 0, in all cases.
Ml5 236 236 143 3,535
Levels
0.5%
Monkey Halothane/N,O/O,
143 3,529 74
of monkeys
1.0%
tdentgfication
2.0%
numbers G-63 3,536 G-63 3,529 143
Inspired gas was composed of halothane with CO, to keep end-tidal CO, at 5-6%.
plus
3,536 3,535 423
66% N,0/33%
0,
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H672
MORITA,
followed by a flush volume of 0.4 ml of heparinized saline). A 1.25 x 1 inch NaI (Tl) scintillation probe (flat-field collimation with a dorsolateral “view” of the hemisphere and centered over the parietal cortex) was used with a Nuclear Chicago Spectrometer-Ratemeter and the output was recorded on a Leeds and Northrup strip-chart recorder. The ratemeter time constant was set at 1 s for the 1st min of the 133Xe clearance curve then at 5 s for the ensuing 15-20 min. In almost all cases the 133Xe clearance curve returned to base line within 15-20 min and did not require correction for the subsequent CBF. CBF was calculated from the recorded clearance curves by the initial-slope method according to the following formula (21):
NEMOTO,
1.08 x 0.695 x 600
= x
T,,,
(~1
=
Tl,,
5. Arterial acid- base balance m.onkeys d uring anesthesia
TABLE
rhesus
Anesthetx*/Perlod
ho,
9
mmHg
(n = 8)
N,O/O,/Control
RESULTS
pace,and experimental
Pa,, were similar between control and periods within each group and between groups (Table 5) with PacOz ca. 40 mmHg and Pa,,, 96155 mmHg. Arterial pH was lower during the experimental compared to the control period in the N,O/O,, l.O%, and 2.0% halothane groups, but base excess (BE)
STEZOSKI
pa02
9
PHa
mmHg
(n = 8) 120 + 7
in
= 8) 7.47 kO.02 (n = 13) (n = 12) (n = 12: 39 + 1 118 + 5 7.36 +O.Ol$
N,O/OJExptl
(s)
The 1.08 value of X is the weighted average of the brain-to-blood partition coefficient for whole brain. Although the initial-slope method of CBF calculation was thought to be biased for gray matter flow (i.e., highflow compartment), Waltz et al. (21) compared it with stochastic and compartmental analytical methods and found good agreement among all three methods. It has also been reasoned that the external scintillation method for CBF after an intracarotid 133Xe-insaline injection gives regional cortical blood flow. This may be true in man because of the usually small portion of the brain “seen” by the probe and the thickness of the human brain. However, in 24 simultaneous measurements of CBF in two halothane-anesthetized, normal monkeys by the method used in this study, CBF was 102 t 4% (mean k SE) of total CBF measured by continuous monitoring of 133Xe in cerebral venous blood (torcula). Therefore, the CBF method used in this study on monkeys appears to give a reasonable estimate of total CBF at least in normal brain. Data analysis. CBF and CMRO, values obtained in the first two sets of control measurements during 66% N,O/33% 0, anesthesia and at normal MAP (80-120 mmHg), prior to either continued ventilation on N,O/ 0, or with added halothane, served as control values in each study (see Table 1). All CBF and CMRO, values at various levels of CPP were evaluated as percent of the values obtained in the first two sets of control measurements. In all cases in which data are presented as percent of control, the absolute control values are also given. CPP was calculated as MAP minus cerebral venous pressure. Statistical analyses were done by ttest for unpaired comparisons, with a maximum acceptable significant P value of .05.
AND
values were similar. Rectal temperatures ranging from 37.6 to 384°C were similar between and within all groups. Table 6 shows changes in CBF and CVR during normotension (CPP range of 80-120 mmHg) as percent of values obtained during the control period on N,O/O, before halothane exposure or continued ventilation on N,O/O, in the experimental period (see Experimental
39 + 2
CBF (ml/100 g per min) log, 2 (100) (60)
BLEYAERT,
N 010 /Control 2 2 0.5 H/N,O/O,/ Exptl
N,O/O,/Control
(n
(n = 7) 7.41 kO.02 (n = 17) (n = 14) (n = 14: 40 + 1 118 + 5 7.35 kO.02
N,O/O,/Control
(n = 7) (n = 7) 1.1 38.1 21.8 Ito. (n = 14) (n = 14) -3.2 37.9 21.2 kO.1
(n = 6) 39 + 2
(n = 6) 98 z!z 7
(n = 6) (n = 6) 2.2 38.0 k1.3 20.3 (n = 21) (n = 21) -1.1 38.3 kO.7 kO.01
(n = 5) 40 2 2
(n = 5) 121 + 6
(n = 5) (n = 5) -0.4 38.4 +l.O kO.2 (n = 15) (n = 15) -4.1 38.1 21.4 +O.l
(n = 5) 7.39 kO.02 (n = 14) (n = 14) (n = 15) 40 A 1 155 + 18 7.33 +0.02$
2.0 H/N,O/O,/ Exptl
= 8) (n = 8) 3.9 37.9 +1.6 kO.2 (n = 12) (n = 13) -3.0 37.6 kO.7 +O.l (n
(n = 7) (n = 7) 41 + 4 135 + 16
(n = 6) 7.44 kO.02 (n = 24) (n = 21) (n = 21) 39 + 1 96 2 5 7.39 kO.Olt-
1.0 H/N,O/O,/ Exntl
T rep “C
BE,
meq/liter
Values
are means + SE. n is the number of observations. * 66% in all cases, H = halothane in percent. tP < .05 compared to preceding N20/02 control period. $P < .OOl compared to preceding N,O/O, control period.
N,o/33% 0,
TABLE 6. Halothane-induced cerebrovascular alterations in rhesus monkeys CPP, mmHg
CBF, %
CVR, %
(n = 27) 104+2
(n = 27) 98+3
(n = 27) 98+4
(n = 15) 99+2
b-2 = 15) 8122
(n = 15) 112+3t
1% H/N,O/O,
(n = 41) lOOkl.5
(n = 41) 126+1.5$
(n = 41) 77?2.9$
2% H/N,O/O,
(n = 17) 89*1.4$
(n = 17) 197+5.3$
(n = 17) 46+0.9$
Anesthetic
Group
N,O/O,*
0.5%
H/N,O/O,
Values are means or: SE. n is the number of observations. For absolute N,O/O, control values see legends of Figs. l-4 for appropriate anesthetic group. CPP, cerebral perfusion pressure (range 80120 mmHg). CBF, cerebral blood flow. CVR, cerebrovascular resistance as percent of values obtained during preceding N,O/O, control period prior to halothane exposure (see Table 1). * 66% N,0/33% 0, in all cases. H, halothane. t P < .05, $ P < .OOl, compared to corresponding N,O/O, value.
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HALOTHANE
AND
CBF
H673
AUTOREGULATION
in METHODS). CBF decreased by 17% and CVR increased by 14% during 0.5% halothane anesthesia. One percent halothane increased CBF by 28% and decreased CVR by 21%. Two percent halothane increased CBF twofold and decreased CVR 52% in spite of a 14% decrease in CPP. Alterations in CBF and CVR at various CPPs during N,O/O, anesthesia and at the three levels of inspired halothane are illustrated in Fig. l-4. During 66% N,O/ 33% 0, anesthesia, CBF autoregulation was maintained over a CPP range from 50 to 150 mmHg (Fig. 1). Within this range, CVR increased linearly up to a CPP of 150 mmHg, but decreased at higher CPPs. CBF autoregulation was intact during 0.5% halothane/N,O/O, (Fig. Z), but CBF was decreased at normal CPPs (80-120 mmHg) (see Table 3). CVR changes suggested greater cerebrovascular reactivity and tone during 0.5% halothane (CVR/CPP slope = 0.894) compared to N,O/O, anesthesia (CVR/CPP slope = 0.600). One percent halothane caused increased CBF with increasing CPP (CBF/CPP slope = 0.952) and impaired cerebrovascular reactivity (CVR/CPP slope = 0.327) (Fig. 3). These results suggest that failure of CBF autoregulation starts at 1% halothane anesthesia. Two percent halothane abolished CBF autoregulation resulting in a steep linear relationship between CBF and CPP (Fig. 4). Complete loss of cerebrovascular tone was demonstrated by a constant CVR over a CPP range of ca. 30-100 mmHg. CMRO, was reduced at all concentrations of inspired halothane compared to control values obtained during 66% N,O/33% 0, (Fig. 5). During 0.5%, l.O%, and 2.0% halothane/66% N,0/33% 0, anesthesia, CMRO, was
protocoZ
I
180-
I
80
&
60
u
40
I
n=68
I
I
I
~y=O362xt60I-------+
160-
e
I
I
I
22 100 I$ 80 ; 60
r,* -+m&om
”
n
‘m 00 0
mm
n
n=40 Iy=.l78x =0.552 t 65.1
-
li
JO II h=lO) JO. 12(n=l2) IO I5 (n=Ifil
LL al v
n=40 r =0.926 y=.894 x t I9 I
0' 0
I
I
I
20
40
60
I
I
I
80 100 120 CPP (mmHg)
I
I
I
140
160
180
FIG. 2. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in percent of control (i.e., values obtained during 66% N,O/ 33% 0, anesthesia in control period preceding exposure to 0.5% halothane) during 0.5% halothane/66% N,0/33% 0, anesthesia at various cerebral perfusion pressures (CPP) in 3 rhesus monkeys. CPP was manipulated by titrated intravenuous infusion of trimethaphan camphorsulfonate and phenylephrine. Mean control values * SE for n = 17: CBF = 72 + 4 ml/100 g*min-‘; CVR = 1.61 * .07 mmHg/ml. 100 g-l min+; at CPP = 112 * 3 mmHg. l
180 360 : 140 z 0 120 El00 ‘g 80 ”
60 40
o
r=0.662
t 0
/
20 I 0. 160-
?
.
‘0
I
I
I
I
20
40
60
1
I
80 100 CPP (mmHg)
I
I
I
I
120
140
160
180
I
FIG. 3. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in percent of control (i.e., values obtained during 66% N,O/ 33% 0, anesthesia in control period preceding exposure to 1% halothane) during 1% halothane/66% N,0/33% 0, anesthesia at various cerebral perfusion pressures (CPP) in 4 rhesus monkeys. CPP was manipulated by titrated intravenous infusion of trimethaphan camphorsulfonate and phenylephrine. Mean control values + SE for n = 23: CBF = 105 * 5 ml/100 g*min-l; CVR = 1.04 + .05 mmHg/ml. 100 g-l min+; at CPP = 106 + 2 mmHg. l
“0
20
40
60
80 100 CPP (mmHg)
120
140
160
180
FIG. 1. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in percent of control (i.e., percent of values obtained at cerebral perfusion pressures between 80 and 120 mmHg) at various cerebral perfusion pressures (CPP) in 3 rhesus monkeys during 66% N,0/33% 0, anesthesia. CPP was manipulated by titrated intravenous infusion of trimethaphan camphorsulfonate and phenylephrine. Mean control values + SE for n = 30: CBF = 97 ? 9 ml/100 g* min-l; CVR = 1.35 t .ll mmHg/ml 100 g-l min-l; at CPP = 106 * 2 mmHg. l
l
reduced by approximately 30%, 40%, and 50%, respectively. The cumulative mean CMRO, during N,O/O, breathing in all four groups was 197 t 14 pmol/lOO g=min+ (i.e., 4.4 -+ 0.3 ml/l00 g.min+). DISCUSSION
CBF and CBF autoregulation. We studied the effect of a combination of anesthetics, namely, N,O and halothane on CBF autoregulation and CMRO,. It is impor-
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H674
MORITA, 240t
I
I
1
I
-I/
'
I
II0 gE 160 g
140
; 120 - 100 k v 80 60
n=64 I =0.865 y=2.274
xtl
25
40
2
IOO-
E 9 s
go-
b\
BLEYAERT,
(6)
40
60
80 100 CPP (mmHg)
120
140
STEZOSKI
\
\.\
(7)
160
180
FIG. 4. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in percent of control; (i.e., values obtained during 66% N,O/ 33% 0, anesthesia in control period preceding exposure to 2% halothane) during 2.0% halothane/66% N,0/33% 0, anesthesia at various cerebral perfusion pressures (CPP) in 4 rhesus monkeys. CPP was manipulated by titrated intravenous infusion of trimethaphan camphorsulfonate and phenylephrine. Mean control values + SE for n = 8: CBF = 74 k 10 ml/100 gamin-l; CVR = 1.49 or .24 mmHg/ml 100 g-l. min-l; at CPP = 94 2 3 mmHg.
tant that this be appreciated because N,O itself affects CBF. N,O reportedly increases CBF in dogs (20), decreases it slightly (i.e., estimated at less than 10%) in rats (4), and is without effect in man (23). The 17% decrease in CBF we observed at 0.5% halothane is similar to the 20% reduction reported by Harp et al. (9) in rats. McDowall (12) initially reported a 13% decrease in CVR, but in a later study found a clear-cut increase in CVR and reduction in CBF. Apparently, at concentrations of 0.5% or less, halothane induces an increase in cerebrovascular tone and a reduction in CBF. In contrast to the reduction in CBF observed with halothane concentrations of 0.5% or less, 1% halothane uniformly increases CBF in man (5, 14, 23) and animals (19). Christensen et al. (5) reported a 27% increase in CBF at a CPP of 73 mmHg, which compares favorably with the 26% increase we observed. An increase of only 15% in CBF was reported by Wollman et al. (23), but CPP fell to 56 mmHg. Correcting for the fall in CPP using our own data, at a CPP of 100 mmHg, a 24% increase in CBF should have occurred. Theye and Michenfelder (19) reported a 19% increase and a 43% increase in CBF at end-expired halothane concentrations of 0.4-0.8% and 0.9%-1.3%, respectively. Thus, in general, it appears that 1% halothane increases CBF by about 25%. The relationship between CBF and CPP during 1% halothane anesthesia was quite variable at CPPs between 80 and 100 mmHg. This variability may explain part of the difficulty in obtaining quantitative agreement in different studies and may be attributable to the fact that 1% halothane is close to the “threshold” of loss of CBF autoregulation. Thus, slight differences in
=2SEM
\
700" 5" v
6050-
20
AND
(5) \ \\
80 -
(II)
I 0
-0
NEMOTO,
I
I 0.5 INSPIRED
I 1.0 (PERCENT)
HALOTHANE
I 2.0
5. Cerebral metabolic rate for 0, (CMRO,) in percent of control (i.e., CMRO, value obtained during 66% N,0/33% 0, anesthesia in control period preceding exposure to various concentrations of halothane) with increasing depth of halothane anesthesia. Numbers in parentheses indicate number of observations for each point. ** P < .OOl compared to CMRO, during 66% N,0/33% 0,. FIG.
depth of halothane anesthesia and CPP may result in marked differences in CBF. The steep linear relationship between CBF and CPP observed at 2% halothane N,O-O2 suggests complete loss of autoregulation. Indeed, in spite of an 11 mmHg decrease in CPP, CBF increased by 97% (see Table 6). Harp et al. (9), however, reported a decrease instead of an increase in CBF, but MAP fell by 60 mmHg from 130 to 70 mmHg. In dogs, 2% halothane increased CBF by 24% despite a 30% fall in MAP from 138 to 97 mmHg (12). Again, correcting for this fall in MAP, CBF would increase by 120%, which compares favorably with the 130% increase we observed at a CPP of 100 mmHg (see Fig. 4). The 40 to 60% decrease in CVR corroborates our findings. The minimum CVR we observed during 2% halothane anesthesia compares favorably with values of about 0.6 mmHg/ml . g-l min-l during 1% halothane plus hypercapnia reported by Alexander et al (2). Two percent halothane anesthesia thus appears to cause maximal cerebrovascular dilatation and complete loss of autoregulation. CerebraZ metaboh rate - 0,. Before discussing the effects of halothane on CMR02, the effect of N,O itself on CMRO, should be considered. Although it is generally accepted that N,O affects CMRO, less than most other anesthetics (4, 9, IS), it has been shown to decrease CMRO, in man (23) and rats (4, 9) while increasing CMRO, in dogs (20). More importantly, it has recently been shown that N,O interacts synergistically with diazepam causing a 60% decrease in CMRO, compared to a 20% reduction by diazepam alone. Thus, the fact that our observations were made with a “background” anesthetic of N,O is again emphasized. We observed a 30% reduction in CMRO, during 0.5% halothane anesthesia and a 40% reduction at 1% halothane. Harp et al. (9) reported similar decreases in CMRO, in rats at comparable levels of halothane. In man only a 20% reduction in CMR02 was observed during 1% halothane anesthesia (5, 14). However, Wolll
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HALOTHANE
AND
CBF
H675
AUTOREGULATION
man et al. (23) reported a negligible decrease. With 2% halothane CMRO, fell by 50%, which compares favorably with the observations of Harp et al. (9) in rats. McDowall (12) reported a 30% reduction in CMRO, during 2% halothane anesthesia in dogs. The decrease in CMRO, with increasing halothane anesthesia is apparently nonlinear, with the greatest reduction in CMRO, occurring at low concentrations of halothane and little further decrease at higher concentrations. A biphasic effect of halothane on CBF is suggested by the increased CVR and reduced CBF at low concentrations (i.e., less then 0.5%) followed by cerebrovascular dilatation at higher concentration until complete loss of autoregulation occurs at 2% halothane. This biphasic effect of increasing anesthesia has also been observed with ether and cyclopropane (18). The initial vasoconstriction at low concentrations of halothane may be a result of the marked reduction in CMRO, which the vasodilatory action is unable to override. At higher concentrations of halothane, however, there is little further reduction in CMR02, and the vasodilatory action of halothane predominates with a net decrease in cerebrovascular tone until complete loss of autoregulation and maximal vasodilatation at 2% halothane. The apparent threshold of halothane-induced loss of CBF autoregulation is at an inspired halothane concentration of 1%. The potent cerebral vasodilatory effects of halothane could result in maldistribution of regional brain perfusion during deep halothane anesthesia. Indeed, there is suggestive evidence of regional maldistribution of blood flow in the maximally vasodilated state (25) and, an as yet undefined toxic effect of high halothane concentra-
tion (15). The magnitude of regional CBF maldistribution and its dependence on CPP, whether COZ, ischemia, or halothane induced, is currently unknown. The clinical implication of our findings is that although halothane has a potent vasodilatory effect on cerebral blood vessels, at any given CPP, CBF is greater compared to the unanesthetized state. Therefore, at least on the whole-brain basis, 0, and substrate delivery should exceed demand. However, impaired CBF autoregulation also renders the brain highly sensitive to changes in CPP which may be induced by postural hypotension, hypovolemia, etc. Thus, at least during moderate and deep halothane anesthesia, MAP should be carefully monitored and marked and rapid changes avoided. In patients with intracranial pathology and space-occupying lesions, a reasonable anesthetic appreach may be low inspired concentrations of halothane (i.e., less than 0.5%) combined with other anesthetic techniques such as N20, neuroleptanalgesics, and narcotics. The authors greatefully acknowledge the able and dedicated technical assistance of Mr. Henry Alexander, Mrs. Betty Jacobson, and MS Diane Samber in these studies. Ayerst Laboratories provided a generous supply of halothane (Fluothane). During the additional go-day quarantine and tuberculin-testing period, the monkeys were under the care of Gene Bingham, DVM (Director, Central Animal Facility), University of Pittsburgh School of Medicine. This study was presented to the American Physiological Society at the 58th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlantic City, N. J., April 1974. Current address of H. Morita: Dept. of Anesthesiology, Kyushu University Hospital, 1276 Katakasu, Fukuoka, Japan. Received
for publication
27 January
1977.
REFERENCES 1. ADAMS,
R. W., G. A. GRONET, T. M. SUNDT, AND J. D. MICHENHalothane, hypocapnia, and cerebrospinal fluid pressure in neurosurgery. Anesthesiology 37: 510-517, 1972. ALEXANDER, S. C., H. WOLLMAN, P. J. COHEN, P. E. CHASE, AND M. BEHAR. Cerebrovascular response to Pacoz during halothane anesthesia in man. J. AppZ. PhysioZ. 19: 561-565, 1964. CARLSSON, C., M. H~~GERDAL, A. E. KAASIK, AND B. K. SIESJ~. The effects of diazepam on cerebral blood flow and oxygen consumption in rats and its synergistic interaction with nitrous oxide. Anesthesiology 45: 319-325, 1976. CARLSSON, C., M. H~~GERDAL, AND B. K. SIESJ~. The effect of nitrous oxide on oxygen consumption and blood flow in the cerebral cortex of the rat. Acta AnaestheszoZ. Sand. 20: 91-95, 1976. CHRISTENSEN, M. S., K. HQ)EDT-RASMUSSEN, AND N. A. LASSEN. Cerebral vasodilatation by halothane anaesthesia in man and its potentiation by hypotension and hypercapnia. Brit. J. Anaesth. 39: 927-934, 1967. EGER, E. I. II. Uptake of inhaled anesthetics: the alveolar to inspired anesthetic difference. In: Anesthetx Uptake and Action. Baltimore: Williams & Wilkins, 1974, p 77-96. EGER, E. I. II, N. T. SMITH, R. K. STOELTING, D. J. CULLEN, L. B. KADIS, AND C. E. WHITCHER. Cardiovascular effects of halothane in man. Anestheszology 32: 396-409, 1970. FITCH, W., and D. G. MCDOWALL. Effect of halothane on intracranial pressure gradients in the presence of intracranial spaceoccupying lesions. Brit. J. Anaesth. 43: 904-912, 1971. HARP, J. R., L. NILSSON, AND B. K. SIESJ& The effect of halothane anaesthesia upon cerebral oxygen consumption in the rat. Acta AnesthesioZ. Sand. 20: 83-90, 1976. JOAS, T. A., AND W. C. STEVENS. Comparison of the arrhythmic doses of epinephrine during forane, halothane, and fluroxene FELDER.
2.
3.
4.
5.
6.
7.
8.
9.
10.
anesthesia in dogs. Anestheszology 35: 48-53, 1971. 11. JOHNSTONE, M. The human cardiovascular response to fluothane anesthesia. Brzt. J. Anesth. 28: 392-410, 1956. 12. MCDOWALL, D. G. The effects of clinical concentrations of halothane on the blood flow and oxygen uptake of the cerebral cortex. Brzt. J. Anaesth. 39: 186-195, 1967. 13. MCDOWALL, D. G., A. M. HARPER, AND I. JACOBSON. Cerebral blood flow during halothane anesthesia. Brtt. J. Anaesth. 35: 394-402, 1963. 14. MCHENRY, L. C., H. C. SLOCUM, H. E. BIVENS, H. A. MAYES, AND G. J. HAYES. Hyperventilation in awake and anesthetized man. Arch. NeuroZ. 12: 270-277, 1965. 15. MICHENFELDER, J. D., AND R. A. THEYE. In viva toxic effects of halothane on canine cerebral metabolic pathways. Am. J. Physzoz. 229: 1050-1055, 1975. 16. MISFELDT, B. B., P. B. JORGENSEN, AND M. RISH~J. The effect of nitrous oxide and halothane upon the intracranial pressure in hypocapnic patients with intracranial disorders. Brzt. J. Anaesth. 46: 853-858, 1974. 17. SMITH, A. L., J. L. NEIGH, J. C. HOFFMAN, AND H. WOLLMAN. Effects of general anesthesia on autoregulation of cerebral blood flow in man. J. AppZ. Physzol. 29: 665-669, 1970. 18. SMITH, A. L., and H. WOLLMAN. Cerebral blood flow and metabolism: effects of anesthetic drugs and techniques. Anestheszology 36: 378-400, 1972. 19. THEYE, R. A., AND J. D. MICHENFELDER. The effect of halothane on canine cerebral metabolism. Anestheszology 29: 1113-1118, 1968. 20. THEYE, R. A., and J. D. MICHENFELDER. The effect of nitrous oxide on canine cerebral metabolism. Anestheszology 29: 11191124, 1968. 21. WALTZ, A. G., A. R. WANEK, AND R. E. ANDERSON. Comparison
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 21, 2019.
H676 of analytic intracarotid
methods for calculation of cerebral blood flow after injection of 133Xe. J. Nucl. Med. 13: 66-72, 1972. 22. WOLFSON, B., H. E. CICCARELLI, AND E. S. SIKER. Gas chromatography using an internal standard for the estimation of ether and halothane levels in blood. Brzt. J. Anaesth. 38: 591-595, 1966. 23. WOLLMAN, H., S. C. ALEXANDER, P. J. COHEN, P. E. CHASE, E. MELMAN, AND M. G. BEHAR. Cerebral circulation of man during halothane anesthesia. Effect of hypocarbia and d-tubocurarine. Anestheszology 25: 180-184, 1964.
MORITA,
NEMOTO,
BLEYAERT,
AND
STEZOSKI
24. WOLLMAN, H., S. C. ALEXANDER, P. J. COHEN, T. C. SMITH, P. E. CHASE, AND R. A. VAN DER MOLEN. Cerebral circulation during general anesthesia and hyperventilation in man. Thiopental induction to nitrous oxide and d-tubocurarine. Anestheszology 26: 329-334, 1965. 25. YASHON, D., W. STONE, A. MAGNESS, W. E. HUNT, AND W. HAMELBERG. Paradoxic lactate production in cerebral tissue during oxygen inhalation with halothane hypotension. Am. J. Physiol. 226: 475-479, 1974.
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M. NEMOTO, ACHIEL L. BLEYAERT, Brain blood fZow autoregulation and metabolism during halothane anesthesia in monkeys. Am. J. Physiol. 233(6): H670-H676, 1977 or Am. J. Physiol.: Heart Circ. Physiol. 2(6): H670-H676, 1977. -Past studies suggest that halothane causes cerebrovascular dilatation and increased cerebral blood flow (CBF); these properties may be relevant to its use for neurosurgical procedures. We studied CBF autoregulation in monkeys during anesthesia with 66% N,0/33% 0, and with 0.5%, l.O%, and 2.0% inspired halothane at various cerebral perfusion pressures (CPP) achieved by infusion of trimethaphan camsylate or phenylephrine. CBF was measured by monitoring brain xenon-133 clearance after intra-arterial injection of the isotope in saline. CBF autoregulation was intact during N,O/O, and during 0.5% halothane/ N,O/O, anesthesia at CPPs ranging from 50 to 100 mmHg, but began to fail at 1.0% halothane. Complete loss of autoregulation occurred during 2% halothane/N,O/O, anesthesia. Estimated brain 0, consumption fell by 30%, 40%, and 50% during 0.5%, l.O%, and 2.0% halothane anesthesia, respectively, compared to 0, consumption during N,O/O, anesthesia (100%). MORITA, HIDEO, EDWIN AND S. WILLIAM STEZOSKI.
STEZOSKI
and 2.0% in 66% N,0/33% 0,. CBF autoregulation was intact at inspired halothane of 0.5%, but began to fail during 1.0% halothane anesthesia with complete loss of autoregulation at 2.0% halothane. CMROz fell by 30%, 40%, and 50% at inspired halothane of 0.5%, l.O%, and 2.0%, respectively. METHODS
Nine prequarantined female rhesus monkeys 5.6-11 kg body wt (Primate Imports, Inc.) were fed Purina monkey chow during an additional go-day quarantine and tuberculin testing in a holding facility. The day before the study, a monkey was transferred to a cage in the laboratory and fasted overnight with water ad libitum. Surgical preparations. Between 7 and 8 A.M. of the following day, the monkey was placed in a small transport cage insufflated with 70% N,0/30% 0,. Pancuronium bromide (Pavulon; Organon, Inc.) was injected intramuscularly (0.06 mg/kg); when the monkey appeared sufficiently relaxed, it was quickly intubated rhesus monkey; brain 0, consumption; cerebrovascular resistwith a cuffed Portex endotracheal tube lubricated with ance 5% lidocaine jelly (Astra Pharmaceutical Products). The monkey was ventilated by a fixed-volume piston respirator (Harvard Apparatus) on 66% N,0/33% 0, at HALOTHANE, inspite of its many desirable features, such a tidal volume of ca. 20 ml/kg body wt and rate of as easy induction and rapid postanesthestic recovery about 20 breaths/min. CO, added to the inspired gas (ll), is a potent myocardial depressant (7); sensitizes maintained end-tidal CO, (continuously monitored by a Beckman LB-l the myocardium to epinephrine-induced arrhythmias infrared analyzer) between 5% and (10); and causes cerebrovascular dilatation and an in- 6%. Bipolar ECG leads were attached to the monkey crease in cerebral blood flow (CBF) in animals (9, 12, and a rectal thermistor was inserted ca. 5 cm into the 19) and man (5, 14, 23). The effect of halothane on CBF rectum. An electric heating blanket maintained rectal autoregulation via its cerebrovasodilatory action is es- temperature between 37 and 39°C. The femoral-inguinal region was shaved, scrubbed pecially important in patients with intracranial mass with Zephiran, and infiltrated with 5 ml of 1% lidocaine lesions, in whom it markedly increases intracranial (Xylocaine; Astra Pharmaceutical Products). Polyethpressure (1, 8, 16) which could critically reduce CBF especially when combined with myocardial depression. ylene catheters were inserted into a femoral artery and vein 5-10 min later for arterial pressure monitoring, Previous investigators have not studied CBF autoregulation at various depths of halothane anesthesia and blood sampling, drug infusion, and fluid replacement. The region of the submandibular and carotid trigones over a range of cerebral perfusion pressures (CPP), but have shown increased CBF in spite of reduced CPP. medial to the sternocleidomastoid muscle was shaved, sterilized, and infiltrated with 5 ml of 1% lidocaine. A Thus, halothane may be a more potent cerebrovasodilator than presently appreciated and could have a catheter was wedged retrogradely into the superior jugular bulb for cerebral venous blood sampling and profound effect on CBF autoregulation. pressure monitoring without occlusion of the internal We evaluated CBF autoregulation and estimated cerebral metabolic rate of 0, (CMRO,) during anesthe- jugular vein proximal to the bulb. A catheter was sia at inspired halothane concentrations of 0.5%, l.O%, inserted retrogradely and occlusively into the external H670
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HALOTHANE
AND
CBF
H671
AUTOREGULATION
carotid artery with the tip at the bifurcation of the common carotid artery for 133Xe-in-saline injection into the internal carotid for CBF measurements. All surgical wounds were treated with polymyxin-B-bacitracin-neomycin powder prior to closure with no. 4-O silk. Experimental protocol. Following surgery, the monkey was ventilated on 66% N,O/33% 0, for a 30-min stabilization period with normalization of arterial blood gases (Pao, > 100 mmHg; PacoZ, 35-45 mmHg), pH (7.30-7.45), base deficit ( t 5 meq/liter), and mean arterial pressure (MAP) (80-120 mmHg). Thereafter, the first set of control measurements of CBF, MAP, ECG, cerebral venous pressure, arterial PO,, PcoZ, base excess, and pH, and arterial and cerebral venous blood 0, content (Lexicon oxygen analyzer) were made and were followed by a second set of control measurements 60 min later (see Table 1). After the second control measurements, the monkey was either continued on 66% N,O/33% OS, or halothane (Fluothane, Ayerst Laboratories) was added to the inspired gas at concentrations of 0.5%, or l.O%, or 2.0%. In each study, CBF autoregulation was evaluated at only one concentration of inspired halothane. Twenty minutes after halothane exposure, MAP was randomly manipulated to either 50, 100, or 150 mmHg by titrated intravenous infusion of trimethaphan camsylate (Arfonad; Hoffman-LaRoche) ‘or phenylephrine (Neo-Synephrine; Winthrop Laboratories). Phenylephrine does not affect CMRO, (18), whereas Arfonad is rapid and short-acting and blood pressure can be easily and quickly manipulated. All CBF measurements were made 5-10 min after stabilization of MAP at the desired level. Three sequential CBF measurements were made at each sampling period to verify a steady state. Arterial and cerebral venous blood were sampled for CMRO, arterial blood gases, and pH immediately preceding the second measurement. Only the second CBF value was used to calculate CMRO, to ensure appropriate matching of CBF with metabolic sampling since the time required for the three sequential CBF measurements ranged from 40 to 60 min. The variation between CBFs in each group of three sequential measurements ranged between 4.5 and 6.3% (Table 2). The number of CBF 1. Experimental design for evaluation of CBF autoregulation during halothane anesthesia TABLE
Study
Control Period, ca. 2 h
Group 4
N,O/O,S
0.5%
Halothane
*
Extl
.
9
N,O/O,
N,O/O,
0.5 Halothane/Nz0/02
TABLE 2. Percent variation between three sequential cerebral blood flow measurements at each level of inspired halothane Halothane,
N,O/Oz
1 .O% Halothane/N,O/O,
2.0%
N,O/Oz
2.0%
Halothane
% of variation
nt
61 58 78 63
5.5 5.8 6.3 4.5
+ + k f
6 4 4.8 3
Percent variation values are means + SE. Cerebral blood flow was measured by external scintillation monitoring over ipsilateral hemisphere following internal carotid artery injection of 200-500 j&i 133Xe in saline (0.2 ml). * Combined with 66% N,0/33% 0, with CO, added to keep end-tidal CO, between 5-6%. t n, number of observations; see Table 4 for number of monkeys studied at each level of halothane.
3. Halothane levels in rhesus monkeys
TABLE Inspired
halothane,
%*
0.5
1.0
2.0
Alveolar
halothane,
%t
0.3
0.5
1.0
5.6 + 0.4
9.6 +0.4
19.3 * 1.1
(n = 7)
(n = 15)
(12 = 10)
Blood halothane, 100 ml, ji
mg/
4. Number and distribution at each level of inspired halothane TABLE
Halothane 0%
1.0% Halothane
%*
0 0.5 1.0 2.0
Blood halothane values are means + SE. n is the number of monkeys studied at each halothane level. * With 66% N,0/33% “f Calculated from blood-to-air partition coefficient of 2.3 (6). 02.
Period,? ca. 4 h
N,O/O,
measurements in each anesthetic group is also shown. Arterial blood samples (0.5 ml) were obtained periodically for blood halothane analysis by gas chromatography (22). Alveolar halothane concentrations calculated using a blood-to-air partition coefficient of 2.3 (6) were ca. 50% of inspired concentrations (Table 3). The total blood volume sampled throughout each study was about 30 ml or about 5% of the total blood volume of the smallest monkey (i.e., 5.6 kg). Table 4 shows the number of studies done for each anesthetic combination and the distribution of the monkeys (identified by number). With the exception of three monkeys, each was used in more than one study with 6-12 days between studies on the same monkey to allow spontaneous replacement of erythrocytes. A total of 16 studies was done on the nine monkeys. Cerebral blood fZow measurements. CBF measurements were made by external scintillation monitoring of brain 133Xe clearance in the hemisphere ipsilateral to the injection of 133Xe in saline (200-500 &i in 0.2 ml
* CBF, CVR, and CMROz values obtained during normotension (MAP 80-120 mmHg) in control period used to calculate percent control in experimental period. t MAP randomly manipulated by titrated intravenous infusion of trimethaphan camsylate or phenylephrine to approximately 50, 100, and 150 mmHg. $ 66% N,0/33% 0, in all cases.
Ml5 236 236 143 3,535
Levels
0.5%
Monkey Halothane/N,O/O,
143 3,529 74
of monkeys
1.0%
tdentgfication
2.0%
numbers G-63 3,536 G-63 3,529 143
Inspired gas was composed of halothane with CO, to keep end-tidal CO, at 5-6%.
plus
3,536 3,535 423
66% N,0/33%
0,
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H672
MORITA,
followed by a flush volume of 0.4 ml of heparinized saline). A 1.25 x 1 inch NaI (Tl) scintillation probe (flat-field collimation with a dorsolateral “view” of the hemisphere and centered over the parietal cortex) was used with a Nuclear Chicago Spectrometer-Ratemeter and the output was recorded on a Leeds and Northrup strip-chart recorder. The ratemeter time constant was set at 1 s for the 1st min of the 133Xe clearance curve then at 5 s for the ensuing 15-20 min. In almost all cases the 133Xe clearance curve returned to base line within 15-20 min and did not require correction for the subsequent CBF. CBF was calculated from the recorded clearance curves by the initial-slope method according to the following formula (21):
NEMOTO,
1.08 x 0.695 x 600
= x
T,,,
(~1
=
Tl,,
5. Arterial acid- base balance m.onkeys d uring anesthesia
TABLE
rhesus
Anesthetx*/Perlod
ho,
9
mmHg
(n = 8)
N,O/O,/Control
RESULTS
pace,and experimental
Pa,, were similar between control and periods within each group and between groups (Table 5) with PacOz ca. 40 mmHg and Pa,,, 96155 mmHg. Arterial pH was lower during the experimental compared to the control period in the N,O/O,, l.O%, and 2.0% halothane groups, but base excess (BE)
STEZOSKI
pa02
9
PHa
mmHg
(n = 8) 120 + 7
in
= 8) 7.47 kO.02 (n = 13) (n = 12) (n = 12: 39 + 1 118 + 5 7.36 +O.Ol$
N,O/OJExptl
(s)
The 1.08 value of X is the weighted average of the brain-to-blood partition coefficient for whole brain. Although the initial-slope method of CBF calculation was thought to be biased for gray matter flow (i.e., highflow compartment), Waltz et al. (21) compared it with stochastic and compartmental analytical methods and found good agreement among all three methods. It has also been reasoned that the external scintillation method for CBF after an intracarotid 133Xe-insaline injection gives regional cortical blood flow. This may be true in man because of the usually small portion of the brain “seen” by the probe and the thickness of the human brain. However, in 24 simultaneous measurements of CBF in two halothane-anesthetized, normal monkeys by the method used in this study, CBF was 102 t 4% (mean k SE) of total CBF measured by continuous monitoring of 133Xe in cerebral venous blood (torcula). Therefore, the CBF method used in this study on monkeys appears to give a reasonable estimate of total CBF at least in normal brain. Data analysis. CBF and CMRO, values obtained in the first two sets of control measurements during 66% N,O/33% 0, anesthesia and at normal MAP (80-120 mmHg), prior to either continued ventilation on N,O/ 0, or with added halothane, served as control values in each study (see Table 1). All CBF and CMRO, values at various levels of CPP were evaluated as percent of the values obtained in the first two sets of control measurements. In all cases in which data are presented as percent of control, the absolute control values are also given. CPP was calculated as MAP minus cerebral venous pressure. Statistical analyses were done by ttest for unpaired comparisons, with a maximum acceptable significant P value of .05.
AND
values were similar. Rectal temperatures ranging from 37.6 to 384°C were similar between and within all groups. Table 6 shows changes in CBF and CVR during normotension (CPP range of 80-120 mmHg) as percent of values obtained during the control period on N,O/O, before halothane exposure or continued ventilation on N,O/O, in the experimental period (see Experimental
39 + 2
CBF (ml/100 g per min) log, 2 (100) (60)
BLEYAERT,
N 010 /Control 2 2 0.5 H/N,O/O,/ Exptl
N,O/O,/Control
(n
(n = 7) 7.41 kO.02 (n = 17) (n = 14) (n = 14: 40 + 1 118 + 5 7.35 kO.02
N,O/O,/Control
(n = 7) (n = 7) 1.1 38.1 21.8 Ito. (n = 14) (n = 14) -3.2 37.9 21.2 kO.1
(n = 6) 39 + 2
(n = 6) 98 z!z 7
(n = 6) (n = 6) 2.2 38.0 k1.3 20.3 (n = 21) (n = 21) -1.1 38.3 kO.7 kO.01
(n = 5) 40 2 2
(n = 5) 121 + 6
(n = 5) (n = 5) -0.4 38.4 +l.O kO.2 (n = 15) (n = 15) -4.1 38.1 21.4 +O.l
(n = 5) 7.39 kO.02 (n = 14) (n = 14) (n = 15) 40 A 1 155 + 18 7.33 +0.02$
2.0 H/N,O/O,/ Exptl
= 8) (n = 8) 3.9 37.9 +1.6 kO.2 (n = 12) (n = 13) -3.0 37.6 kO.7 +O.l (n
(n = 7) (n = 7) 41 + 4 135 + 16
(n = 6) 7.44 kO.02 (n = 24) (n = 21) (n = 21) 39 + 1 96 2 5 7.39 kO.Olt-
1.0 H/N,O/O,/ Exntl
T rep “C
BE,
meq/liter
Values
are means + SE. n is the number of observations. * 66% in all cases, H = halothane in percent. tP < .05 compared to preceding N20/02 control period. $P < .OOl compared to preceding N,O/O, control period.
N,o/33% 0,
TABLE 6. Halothane-induced cerebrovascular alterations in rhesus monkeys CPP, mmHg
CBF, %
CVR, %
(n = 27) 104+2
(n = 27) 98+3
(n = 27) 98+4
(n = 15) 99+2
b-2 = 15) 8122
(n = 15) 112+3t
1% H/N,O/O,
(n = 41) lOOkl.5
(n = 41) 126+1.5$
(n = 41) 77?2.9$
2% H/N,O/O,
(n = 17) 89*1.4$
(n = 17) 197+5.3$
(n = 17) 46+0.9$
Anesthetic
Group
N,O/O,*
0.5%
H/N,O/O,
Values are means or: SE. n is the number of observations. For absolute N,O/O, control values see legends of Figs. l-4 for appropriate anesthetic group. CPP, cerebral perfusion pressure (range 80120 mmHg). CBF, cerebral blood flow. CVR, cerebrovascular resistance as percent of values obtained during preceding N,O/O, control period prior to halothane exposure (see Table 1). * 66% N,0/33% 0, in all cases. H, halothane. t P < .05, $ P < .OOl, compared to corresponding N,O/O, value.
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HALOTHANE
AND
CBF
H673
AUTOREGULATION
in METHODS). CBF decreased by 17% and CVR increased by 14% during 0.5% halothane anesthesia. One percent halothane increased CBF by 28% and decreased CVR by 21%. Two percent halothane increased CBF twofold and decreased CVR 52% in spite of a 14% decrease in CPP. Alterations in CBF and CVR at various CPPs during N,O/O, anesthesia and at the three levels of inspired halothane are illustrated in Fig. l-4. During 66% N,O/ 33% 0, anesthesia, CBF autoregulation was maintained over a CPP range from 50 to 150 mmHg (Fig. 1). Within this range, CVR increased linearly up to a CPP of 150 mmHg, but decreased at higher CPPs. CBF autoregulation was intact during 0.5% halothane/N,O/O, (Fig. Z), but CBF was decreased at normal CPPs (80-120 mmHg) (see Table 3). CVR changes suggested greater cerebrovascular reactivity and tone during 0.5% halothane (CVR/CPP slope = 0.894) compared to N,O/O, anesthesia (CVR/CPP slope = 0.600). One percent halothane caused increased CBF with increasing CPP (CBF/CPP slope = 0.952) and impaired cerebrovascular reactivity (CVR/CPP slope = 0.327) (Fig. 3). These results suggest that failure of CBF autoregulation starts at 1% halothane anesthesia. Two percent halothane abolished CBF autoregulation resulting in a steep linear relationship between CBF and CPP (Fig. 4). Complete loss of cerebrovascular tone was demonstrated by a constant CVR over a CPP range of ca. 30-100 mmHg. CMRO, was reduced at all concentrations of inspired halothane compared to control values obtained during 66% N,O/33% 0, (Fig. 5). During 0.5%, l.O%, and 2.0% halothane/66% N,0/33% 0, anesthesia, CMRO, was
protocoZ
I
180-
I
80
&
60
u
40
I
n=68
I
I
I
~y=O362xt60I-------+
160-
e
I
I
I
22 100 I$ 80 ; 60
r,* -+m&om
”
n
‘m 00 0
mm
n
n=40 Iy=.l78x =0.552 t 65.1
-
li
JO II h=lO) JO. 12(n=l2) IO I5 (n=Ifil
LL al v
n=40 r =0.926 y=.894 x t I9 I
0' 0
I
I
I
20
40
60
I
I
I
80 100 120 CPP (mmHg)
I
I
I
140
160
180
FIG. 2. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in percent of control (i.e., values obtained during 66% N,O/ 33% 0, anesthesia in control period preceding exposure to 0.5% halothane) during 0.5% halothane/66% N,0/33% 0, anesthesia at various cerebral perfusion pressures (CPP) in 3 rhesus monkeys. CPP was manipulated by titrated intravenuous infusion of trimethaphan camphorsulfonate and phenylephrine. Mean control values * SE for n = 17: CBF = 72 + 4 ml/100 g*min-‘; CVR = 1.61 * .07 mmHg/ml. 100 g-l min+; at CPP = 112 * 3 mmHg. l
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FIG. 3. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in percent of control (i.e., values obtained during 66% N,O/ 33% 0, anesthesia in control period preceding exposure to 1% halothane) during 1% halothane/66% N,0/33% 0, anesthesia at various cerebral perfusion pressures (CPP) in 4 rhesus monkeys. CPP was manipulated by titrated intravenous infusion of trimethaphan camphorsulfonate and phenylephrine. Mean control values + SE for n = 23: CBF = 105 * 5 ml/100 g*min-l; CVR = 1.04 + .05 mmHg/ml. 100 g-l min+; at CPP = 106 + 2 mmHg. l
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FIG. 1. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in percent of control (i.e., percent of values obtained at cerebral perfusion pressures between 80 and 120 mmHg) at various cerebral perfusion pressures (CPP) in 3 rhesus monkeys during 66% N,0/33% 0, anesthesia. CPP was manipulated by titrated intravenous infusion of trimethaphan camphorsulfonate and phenylephrine. Mean control values + SE for n = 30: CBF = 97 ? 9 ml/100 g* min-l; CVR = 1.35 t .ll mmHg/ml 100 g-l min-l; at CPP = 106 * 2 mmHg. l
l
reduced by approximately 30%, 40%, and 50%, respectively. The cumulative mean CMRO, during N,O/O, breathing in all four groups was 197 t 14 pmol/lOO g=min+ (i.e., 4.4 -+ 0.3 ml/l00 g.min+). DISCUSSION
CBF and CBF autoregulation. We studied the effect of a combination of anesthetics, namely, N,O and halothane on CBF autoregulation and CMRO,. It is impor-
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FIG. 4. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in percent of control; (i.e., values obtained during 66% N,O/ 33% 0, anesthesia in control period preceding exposure to 2% halothane) during 2.0% halothane/66% N,0/33% 0, anesthesia at various cerebral perfusion pressures (CPP) in 4 rhesus monkeys. CPP was manipulated by titrated intravenous infusion of trimethaphan camphorsulfonate and phenylephrine. Mean control values + SE for n = 8: CBF = 74 k 10 ml/100 gamin-l; CVR = 1.49 or .24 mmHg/ml 100 g-l. min-l; at CPP = 94 2 3 mmHg.
tant that this be appreciated because N,O itself affects CBF. N,O reportedly increases CBF in dogs (20), decreases it slightly (i.e., estimated at less than 10%) in rats (4), and is without effect in man (23). The 17% decrease in CBF we observed at 0.5% halothane is similar to the 20% reduction reported by Harp et al. (9) in rats. McDowall (12) initially reported a 13% decrease in CVR, but in a later study found a clear-cut increase in CVR and reduction in CBF. Apparently, at concentrations of 0.5% or less, halothane induces an increase in cerebrovascular tone and a reduction in CBF. In contrast to the reduction in CBF observed with halothane concentrations of 0.5% or less, 1% halothane uniformly increases CBF in man (5, 14, 23) and animals (19). Christensen et al. (5) reported a 27% increase in CBF at a CPP of 73 mmHg, which compares favorably with the 26% increase we observed. An increase of only 15% in CBF was reported by Wollman et al. (23), but CPP fell to 56 mmHg. Correcting for the fall in CPP using our own data, at a CPP of 100 mmHg, a 24% increase in CBF should have occurred. Theye and Michenfelder (19) reported a 19% increase and a 43% increase in CBF at end-expired halothane concentrations of 0.4-0.8% and 0.9%-1.3%, respectively. Thus, in general, it appears that 1% halothane increases CBF by about 25%. The relationship between CBF and CPP during 1% halothane anesthesia was quite variable at CPPs between 80 and 100 mmHg. This variability may explain part of the difficulty in obtaining quantitative agreement in different studies and may be attributable to the fact that 1% halothane is close to the “threshold” of loss of CBF autoregulation. Thus, slight differences in
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5. Cerebral metabolic rate for 0, (CMRO,) in percent of control (i.e., CMRO, value obtained during 66% N,0/33% 0, anesthesia in control period preceding exposure to various concentrations of halothane) with increasing depth of halothane anesthesia. Numbers in parentheses indicate number of observations for each point. ** P < .OOl compared to CMRO, during 66% N,0/33% 0,. FIG.
depth of halothane anesthesia and CPP may result in marked differences in CBF. The steep linear relationship between CBF and CPP observed at 2% halothane N,O-O2 suggests complete loss of autoregulation. Indeed, in spite of an 11 mmHg decrease in CPP, CBF increased by 97% (see Table 6). Harp et al. (9), however, reported a decrease instead of an increase in CBF, but MAP fell by 60 mmHg from 130 to 70 mmHg. In dogs, 2% halothane increased CBF by 24% despite a 30% fall in MAP from 138 to 97 mmHg (12). Again, correcting for this fall in MAP, CBF would increase by 120%, which compares favorably with the 130% increase we observed at a CPP of 100 mmHg (see Fig. 4). The 40 to 60% decrease in CVR corroborates our findings. The minimum CVR we observed during 2% halothane anesthesia compares favorably with values of about 0.6 mmHg/ml . g-l min-l during 1% halothane plus hypercapnia reported by Alexander et al (2). Two percent halothane anesthesia thus appears to cause maximal cerebrovascular dilatation and complete loss of autoregulation. CerebraZ metaboh rate - 0,. Before discussing the effects of halothane on CMR02, the effect of N,O itself on CMRO, should be considered. Although it is generally accepted that N,O affects CMRO, less than most other anesthetics (4, 9, IS), it has been shown to decrease CMRO, in man (23) and rats (4, 9) while increasing CMRO, in dogs (20). More importantly, it has recently been shown that N,O interacts synergistically with diazepam causing a 60% decrease in CMRO, compared to a 20% reduction by diazepam alone. Thus, the fact that our observations were made with a “background” anesthetic of N,O is again emphasized. We observed a 30% reduction in CMRO, during 0.5% halothane anesthesia and a 40% reduction at 1% halothane. Harp et al. (9) reported similar decreases in CMRO, in rats at comparable levels of halothane. In man only a 20% reduction in CMR02 was observed during 1% halothane anesthesia (5, 14). However, Wolll
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 21, 2019.
HALOTHANE
AND
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AUTOREGULATION
man et al. (23) reported a negligible decrease. With 2% halothane CMRO, fell by 50%, which compares favorably with the observations of Harp et al. (9) in rats. McDowall (12) reported a 30% reduction in CMRO, during 2% halothane anesthesia in dogs. The decrease in CMRO, with increasing halothane anesthesia is apparently nonlinear, with the greatest reduction in CMRO, occurring at low concentrations of halothane and little further decrease at higher concentrations. A biphasic effect of halothane on CBF is suggested by the increased CVR and reduced CBF at low concentrations (i.e., less then 0.5%) followed by cerebrovascular dilatation at higher concentration until complete loss of autoregulation occurs at 2% halothane. This biphasic effect of increasing anesthesia has also been observed with ether and cyclopropane (18). The initial vasoconstriction at low concentrations of halothane may be a result of the marked reduction in CMRO, which the vasodilatory action is unable to override. At higher concentrations of halothane, however, there is little further reduction in CMR02, and the vasodilatory action of halothane predominates with a net decrease in cerebrovascular tone until complete loss of autoregulation and maximal vasodilatation at 2% halothane. The apparent threshold of halothane-induced loss of CBF autoregulation is at an inspired halothane concentration of 1%. The potent cerebral vasodilatory effects of halothane could result in maldistribution of regional brain perfusion during deep halothane anesthesia. Indeed, there is suggestive evidence of regional maldistribution of blood flow in the maximally vasodilated state (25) and, an as yet undefined toxic effect of high halothane concentra-
tion (15). The magnitude of regional CBF maldistribution and its dependence on CPP, whether COZ, ischemia, or halothane induced, is currently unknown. The clinical implication of our findings is that although halothane has a potent vasodilatory effect on cerebral blood vessels, at any given CPP, CBF is greater compared to the unanesthetized state. Therefore, at least on the whole-brain basis, 0, and substrate delivery should exceed demand. However, impaired CBF autoregulation also renders the brain highly sensitive to changes in CPP which may be induced by postural hypotension, hypovolemia, etc. Thus, at least during moderate and deep halothane anesthesia, MAP should be carefully monitored and marked and rapid changes avoided. In patients with intracranial pathology and space-occupying lesions, a reasonable anesthetic appreach may be low inspired concentrations of halothane (i.e., less than 0.5%) combined with other anesthetic techniques such as N20, neuroleptanalgesics, and narcotics. The authors greatefully acknowledge the able and dedicated technical assistance of Mr. Henry Alexander, Mrs. Betty Jacobson, and MS Diane Samber in these studies. Ayerst Laboratories provided a generous supply of halothane (Fluothane). During the additional go-day quarantine and tuberculin-testing period, the monkeys were under the care of Gene Bingham, DVM (Director, Central Animal Facility), University of Pittsburgh School of Medicine. This study was presented to the American Physiological Society at the 58th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlantic City, N. J., April 1974. Current address of H. Morita: Dept. of Anesthesiology, Kyushu University Hospital, 1276 Katakasu, Fukuoka, Japan. Received
for publication
27 January
1977.
REFERENCES 1. ADAMS,
R. W., G. A. GRONET, T. M. SUNDT, AND J. D. MICHENHalothane, hypocapnia, and cerebrospinal fluid pressure in neurosurgery. Anesthesiology 37: 510-517, 1972. ALEXANDER, S. C., H. WOLLMAN, P. J. COHEN, P. E. CHASE, AND M. BEHAR. Cerebrovascular response to Pacoz during halothane anesthesia in man. J. AppZ. PhysioZ. 19: 561-565, 1964. CARLSSON, C., M. H~~GERDAL, A. E. KAASIK, AND B. K. SIESJ~. The effects of diazepam on cerebral blood flow and oxygen consumption in rats and its synergistic interaction with nitrous oxide. Anesthesiology 45: 319-325, 1976. CARLSSON, C., M. H~~GERDAL, AND B. K. SIESJ~. The effect of nitrous oxide on oxygen consumption and blood flow in the cerebral cortex of the rat. Acta AnaestheszoZ. Sand. 20: 91-95, 1976. CHRISTENSEN, M. S., K. HQ)EDT-RASMUSSEN, AND N. A. LASSEN. Cerebral vasodilatation by halothane anaesthesia in man and its potentiation by hypotension and hypercapnia. Brit. J. Anaesth. 39: 927-934, 1967. EGER, E. I. II. Uptake of inhaled anesthetics: the alveolar to inspired anesthetic difference. In: Anesthetx Uptake and Action. Baltimore: Williams & Wilkins, 1974, p 77-96. EGER, E. I. II, N. T. SMITH, R. K. STOELTING, D. J. CULLEN, L. B. KADIS, AND C. E. WHITCHER. Cardiovascular effects of halothane in man. Anestheszology 32: 396-409, 1970. FITCH, W., and D. G. MCDOWALL. Effect of halothane on intracranial pressure gradients in the presence of intracranial spaceoccupying lesions. Brit. J. Anaesth. 43: 904-912, 1971. HARP, J. R., L. NILSSON, AND B. K. SIESJ& The effect of halothane anaesthesia upon cerebral oxygen consumption in the rat. Acta AnesthesioZ. Sand. 20: 83-90, 1976. JOAS, T. A., AND W. C. STEVENS. Comparison of the arrhythmic doses of epinephrine during forane, halothane, and fluroxene FELDER.
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anesthesia in dogs. Anestheszology 35: 48-53, 1971. 11. JOHNSTONE, M. The human cardiovascular response to fluothane anesthesia. Brzt. J. Anesth. 28: 392-410, 1956. 12. MCDOWALL, D. G. The effects of clinical concentrations of halothane on the blood flow and oxygen uptake of the cerebral cortex. Brzt. J. Anaesth. 39: 186-195, 1967. 13. MCDOWALL, D. G., A. M. HARPER, AND I. JACOBSON. Cerebral blood flow during halothane anesthesia. Brtt. J. Anaesth. 35: 394-402, 1963. 14. MCHENRY, L. C., H. C. SLOCUM, H. E. BIVENS, H. A. MAYES, AND G. J. HAYES. Hyperventilation in awake and anesthetized man. Arch. NeuroZ. 12: 270-277, 1965. 15. MICHENFELDER, J. D., AND R. A. THEYE. In viva toxic effects of halothane on canine cerebral metabolic pathways. Am. J. Physzoz. 229: 1050-1055, 1975. 16. MISFELDT, B. B., P. B. JORGENSEN, AND M. RISH~J. The effect of nitrous oxide and halothane upon the intracranial pressure in hypocapnic patients with intracranial disorders. Brzt. J. Anaesth. 46: 853-858, 1974. 17. SMITH, A. L., J. L. NEIGH, J. C. HOFFMAN, AND H. WOLLMAN. Effects of general anesthesia on autoregulation of cerebral blood flow in man. J. AppZ. Physzol. 29: 665-669, 1970. 18. SMITH, A. L., and H. WOLLMAN. Cerebral blood flow and metabolism: effects of anesthetic drugs and techniques. Anestheszology 36: 378-400, 1972. 19. THEYE, R. A., AND J. D. MICHENFELDER. The effect of halothane on canine cerebral metabolism. Anestheszology 29: 1113-1118, 1968. 20. THEYE, R. A., and J. D. MICHENFELDER. The effect of nitrous oxide on canine cerebral metabolism. Anestheszology 29: 11191124, 1968. 21. WALTZ, A. G., A. R. WANEK, AND R. E. ANDERSON. Comparison
Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (129.186.138.035) on January 21, 2019.
H676 of analytic intracarotid
methods for calculation of cerebral blood flow after injection of 133Xe. J. Nucl. Med. 13: 66-72, 1972. 22. WOLFSON, B., H. E. CICCARELLI, AND E. S. SIKER. Gas chromatography using an internal standard for the estimation of ether and halothane levels in blood. Brzt. J. Anaesth. 38: 591-595, 1966. 23. WOLLMAN, H., S. C. ALEXANDER, P. J. COHEN, P. E. CHASE, E. MELMAN, AND M. G. BEHAR. Cerebral circulation of man during halothane anesthesia. Effect of hypocarbia and d-tubocurarine. Anestheszology 25: 180-184, 1964.
MORITA,
NEMOTO,
BLEYAERT,
AND
STEZOSKI
24. WOLLMAN, H., S. C. ALEXANDER, P. J. COHEN, T. C. SMITH, P. E. CHASE, AND R. A. VAN DER MOLEN. Cerebral circulation during general anesthesia and hyperventilation in man. Thiopental induction to nitrous oxide and d-tubocurarine. Anestheszology 26: 329-334, 1965. 25. YASHON, D., W. STONE, A. MAGNESS, W. E. HUNT, AND W. HAMELBERG. Paradoxic lactate production in cerebral tissue during oxygen inhalation with halothane hypotension. Am. J. Physiol. 226: 475-479, 1974.
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