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Volatile Anesthetics and Coronary Collateral Circulation
Volatile Anesthetics and Coronary Collateral Circulation Judy R. Kersten,* J. Craig Hartrnan,t Paul S. Pagel,* and David C. Warltier*,$,§ Depmtments of “Anesthesiology, $Pharmacology, and $Medicine The Medical College of Wisconsin Milwaukee, Wisconsin 53226 ?The Upjohtz Company Kalamazoo, Michigan 49001
1. Introduction Volatile anesthetics may alter coronary collateral blood flow to ischemic myocardium by several direct and indirect mechanisms. Decreases in arterial pressure resulting from declines in systemic vascular resistance or cardiac output produced by volatile anesthetics can reduce the driving pressure at the origin of collateral vessels and cause a decrease in collateral blood flow. Reflex increases in heart rate during anesthesia may also decrease coronary collateral flow because of a reduction in the duration of diastole. Direct vasodilation of coronary arterioles induced by volatile anesthetics may result in a redistribution of flow away from collateraldependent, ischemic zones to normal areas. A decrease in coronary collateral flow during large increases in flow to normal zones via direct vasodilation has been termed “coronary steal.” The purpose of this investigation was to evaluate the effects of a new volatile anesthetic, sevoflurane, on coronary collateral blood flow using chronically instrumented dogs with an experimentally produced “coronary steal prone anatomy” ( I ) . The model included a total occlusion of the left anterior descending coronary artery, a stenosis of the adjacent artery of origin of the collaterals (left circumflex coronary artery), and a Adua,rr-c\ in Pharrrr~iroki~v.. Volnrw 31 Copyrighi ri 1994 by Academic Press. Inc. All right, of lepioduclion in any form reserved
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well-developed coronary collateral circulation. This anatomical configuration has been previously shown to favor the development of coronary steal induced by potent coronary vasodilators including adenosine and dipyridamole (2,3). The actions of sevoflurane were compared to those produced by isoflurane and the small vessel coronary vasodilator adenosine in separate experimental groups. This multivessel disease model also allowed direct comparison of the conscious and anesthetized states without the potentially confounding influences of acute surgical intervention or the use of baseline anesthetic agents.
II. Chronic Animal Instrumentation Mongrel dogs of either sex were anesthetized with sodium thiamylal (10 mg/kg i.v.) and halothane (1.0-2.0%) in 100% oxygen. A left thoracotomy was performed under sterile conditions. Catheters were implanted in the left atrium, right atrium, and descending thoracic aorta for administration of radioactive microspheres, drug administration, and withdrawal of reference arterial flow samples used in the calculation of regional myocardial blood flow. A balloon cuff vascular occluder was positioned immediately distal to the aortic catheter for control of arterial pressure via constriction of the thoracic aorta. The heart was suspended in a pericardial cradle, and 2-cm sections of the proximal left anterior descending and left circumflex coronary arteries were dissected free of surrounding tissue. A Doppler (20 MHz) ultrasonic flow transducer was placed around each vessel for measurement of coronary blood flow velocity. A balloon cuff occluder was positioned immediately distal to the left anterior descending coronary flow transducer. This device was used to produce repetitive brief coronary artery occlusions to induce collateral development. In addition, on the day of the experiment, the balloon cuff was used to produce sustained total coronary artery occlusion. An ameroid constrictor was positioned around the left circumflex coronary artery distal to the flow velocity transducer to form a fixed stenosis of the artery of origin of the coronary collaterals perfusing the left anterior descending bed. A miniature micromanometer (Model P7, Konigsberg Instruments, Pasadena, CA) was inserted into the left ventricle via a small incision through the apex. A fluid-filled catheter was also inserted into the left ventricle for calibration of the micromanometer in uiuo and for administration of adenosine in specific experiments. Pairs of ultrasonic segment length transducers were implanted in the subendocardium in the perfusion territories supplied by the left anterior descending and left circumflex coronary arter-
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ies for measurement of regional contractile function. Electrodes were sutured to the right atrium for atrial pacing. The instrumentation was exteriorized between the scapulae, and the chest wall was closed in layers. All animals were treated with analgesics as required and antibiotics to prevent infection. Each dog was fitted with a jacket to prevent damage to the implanted instruments, which were enclosed in an aluminum box. Each dog was allowed to recover for 2 days after surgery prior to daily hemodynamic monitoring.
111. Regional Myocardial Function and Perfusion Regional contractile function was evaluated by ultrasonic segment length transducers. All signals were simultaneously monitored via ultrasonic amplifiers (Crystal Biotech, Hopkinton, MA). Using left ventricular dP/ dt, end diastolic segment length (EDL) was measured immediately prior to the onset of left ventricular isovolumic contraction, and end systolic length (ESL) was determined at peak - dP/dt. Percent systolic shortening (%SS) was calculated from the following equation:
%SS
[(EDL
-
ESL)/EDL] x 100
Regional myocardial blood flow in normal, stenotic, and totally occluded (coronary collateral blood flow) regions was measured by the radioactive microsphere technique (4).At specific intervals, radioactive microspheres were injected into the left atrium as a bolus. A withdrawal of arterial blood from the aortic catheter was started at a flow rate of 7 ml/min immediately prior to the injection of microspheres and continued for 3 min. At the conclusion of each experiment, India ink and Monastral blue suspension dye were injected into the coronary circulation immediately distal to the ameroid constrictor and hydraulic occluder, respectively, at pressures of 100 mmHg to delineate the perfusion territories of the totally occluded, stenotic, and normal zones. Tissue samples from these areas were subdivided into subepicardial, midmyocardial, and subendocardial specimens of approximately equal weight. Tissue blood flow ((3,; ml/min/g) was calculated from the equation Qm
=
CmQ,/C,
where Qr is the rate of withdrawal (ml/min) of the reference blood flow sample, Cr is the activity [counts per minute (cpm)] of the reference blood flow sample, and Cm is the activity (cpm/g) of the myocardial tissue sample.
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Starting on the second postoperative day, each dog was monitored for changes in systemic and coronary hemodynamics. Once an hour, eight times each day, repetitive, brief ( 2 min) left anterior descending coronary artery occlusions were performed by inflation and subsequent deflation of the hydraulic balloon cuff coronary occluder. This process has been previously used to induce coronary collateral growth (1,5.6). Coronary collateral development was assessed daily by measurement of the reactive hyperemic response following brief coronary artery occlusion and by assessment of segment shortening in the left anterior descending perfusion territory during the period of coronary artery occlusion. In addition, the severity of left circumflex coronary artery stenosis was also assessed by measurement of coronary reserve on each experimental day (7). The increase in left circumflex flow velocity after a bolus injection of adenosine (25, 50, and 100 pg) into the left atrium was measured. Repetitive occlusions and stenosis development continued for a variable amount of time (10 to 20 days). On the day that the left circumflex coronary artery stenosis was considered critical (minimal changes in resting coronary blood flow but near abolition of coronary vascular reserve as assessed by the ability to dilate following administration of adenosine), a coronary steal prone anatomy was established. In the presence of a well-developed collateral circulation and stenosis of the artery of origin of the coronary collaterals (left circumflex coronary artery), the left anterior descending coronary artery was totally occluded by inflation of the hydraulic balloon cuff occluder for the duration of the experiment. Systemic and coronary hemodynamics and regional myocardial perfusion and function in collateral-dependent, stenotic, and normal zones were measured in the conscious state 30 min after left anterior descending coronary artery occlusion. After control measurements were completed, dogs received either isoflurane, sevoflurane, or adenosine in three separate groups of experiments. Anesthesia was induced by inhalation using the volatile anesthetic at high flow rates (8 literdmin oxygen). After tracheal intubation, anesthesia was maintained with isoflurane or sevoflurane in room air enriched with oxygen during positive pressure ventilation using a semiclosed anesthesia circuit. The oxygen flow rate, respiratory rate, and tidal volume were adjusted to maintain arterial blood gas tensions within conscious levels. Two concentrations of each anesthetic (1 .O and 1.5 MAC) producing decreases of approximately 25 and 35 mmHg of arterial pressure were studied. End-tidal gas and anesthetic concentrations were continuously monitored with an infrared gas analyzer (Datex Capnomac, Helsinki, Finland). The first concentration of isoflurane or sevoflurane was allowed to equilibrate for a period of 30 min to provide a steady state, and hemodynamics,
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myocardial blood flow, and regional contractile function were recorded. Anesthetic depth was then adjusted to produce a greater decrease in arterial pressure, maintained at steady state for an additional 30 min, and measurements repeated. Finally, at the highest concentration of anesthetic agent, hemodynamics were restored to levels present in the conscious control state. Arterial pressure was increased by inflation of the aortic balloon cuff occluder. Baroreflex reduction in heart rate was avoided by atrial pacing to rates present in the conscious state. In this fashion, the direct effects of isoflurane and sevoflurane on the regional distribution of coronary blood flow were assessed independently of changes in systemic hemodynamics. In a separate group of experiments, the effects of adenosine on regional myocardial blood flow were studied. Systemic and coronary hemodynamics, myocardial perfusion, and contractile function were measured in the conscious control state and during low (range 0.25 to I mg/min) and high (range 1.0 to 2.5 mg/min) doses of adenosine. The doses of adenosine were administered through the left ventricular catheter by a continuous infusion. The dose ranges were selected to provide declines of approximately 10 and 20 mmHg in mean arterial pressure. Measurements were also completed during the high dose of adenosine with control of arterial pressure and heart rate as described above. At the conclusion of all experiments, each dog was euthanized by intravenous administration of an overdose of sodium pentobarbital. The heart was excised, stained, and fixed for 24 to 48 h in 10% formaldehyde prior to obtaining tissue specimens for analysis of myocardial blood flow. A total of 3 1 dogs were used in the investigation to produce 21 successful experiments for data analysis (group size of 6 to 8 animals). Dogs were excluded because of ventricular fibrillation during coronary artery occlusion or failure of instrumentation. Systemic and coronary hemodynamics, myocardial blood flow, and regional contractile function data were analyzed by analysis of variance with repeated measures (ANOVA) followed by Duncan’s multiple range test and were considered significant when p values were below 0.05.
IV. Coronary Steal Prone Anatomy Model Repetitive left anterior descending coronary artery occlusions resulted in a significant ( p < 0.05) diminution of peak postocclusive reactive hyperemic flow. The duration of the flow increase above baseline levels and reactive hyperemic debt repayment were also significantly decreased despite a constant oxygen debt accrued during each 2-min occlusion (Fig. I ) . In
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DAY 4
. LL?jlLI 2 MIN
-
DAY 8
DAY 12
(Hz LAD BFV 100) loo[
(Hz
-
100)
ss = 0 %
,v??
LENGTH
(mm)
LV dP/dt (mmHg / sac)
14
-3000 U 1 SEC
Fig. 1 Left anterior descending (LAD) and left circumflex coronary artery (LCCA) blood flow velocity (BFV) during the reactive hyperemic response after a 2-min coronary artery occlusion. Repetitive coronary artery occlusions were performed once each hour, 8 times each day. Sample data from days 4, 8, and 12 are shown. During repetitive coronary artery occlusions, the reactive hyperemic response is slowly reduced as collateral growth is enhanced. Similarly, segment shortening (SS) during the period of coronary artery occlusion is initially severely depressed; however, with enhancement of collateral growth, contraction is sustained in the ischemic zone during the period of coronary artery occlusion. LV, Left ventricle. [Reprinted with permission from Hartman er a / . ( I ) . ]
some dogs, a total loss of reactive hyperemia following brief coronary artery occlusion occurred. A reduction in reactive hyperemia was indicative of a decrease in the intensity of ischemia during the period of coronary artery occlusion secondary to enhanced collateral development. Examination of regional contractile function during occlusion initially revealed paradoxical systolic aneurysmal bulging during repetitive coronary artery occlusions. Over the period of collateral development, however, aneurysmal bulging was replaced by akinesis and, eventually, by effective systolic shortening in the left anterior descending perfusion territory despite total arterial occlusion (Fig. 1). The progressive improvement in regional contractile function in the ischemic zone also indicated growth and development of coronary collaterals, leading to a reduction in the intensity of ischemia. As coronary collateral development continued, the ameroid constrictor on the left circumflex coronary artery formed a stenosis that became
Volatile Anesthetics and Coronary Collateral Circulation 2
DAY
CBFV
60r
3
4
5
275 6
7
,
Fig. 2 Coronary blood flow velocity (CBFV) in the left anterior descending (LAD) and left circumflex arteries (LCCA) during left atrial bolus administrationof adenosine ( 100 p g ) over 7 days. Note the diminution in flow response to adenosine caused by progressive stenosis of the left circumflex coronary artery via an ameroid constrictor. The flow response in the LAD remains unchanged. [Reprinted with permission from Hartman et a / . (71.1
continuously more severe over several days. There was a progressive decline in coronary vascular reserve in the left circumflex artery although no change in resting coronary blood flow occurred. This resulted in a diminution of the coronary flow response to bolus injections of adenosine over several days (Fig. 2). In contrast, the flow response to adenosine in the left anterior descending coronary artery remained unchanged over the course of left circumflex stenosis development.
V. Hernodynamic Effects of Isoflurane, Sevoflurane, and Adenosine The systemic and coronary hernodynamic actions of isoflurane, sevoflurane, and adenosine are summarized in Tables 1-111. lsoflurane produced a dose-dependent decline in mean arterial pressure, left ventricular systolic pressure, and left ventricular dPldt,,. Despite a large reduction in mean arterial pressure, left circumflex coronary blood flow velocity remained unchanged, reflecting a reduction in coronary vascular resistance. With the exception of left ventricular dPldr,,, hemodynamics remained unchanged from the conscious state during control of arterial pressure and heart rate. Sevoflurane caused systemic and coronary hemodynamic effects which were similar to those of isoflurane. Sevoflurane produced no change in heart rate and dose-dependent declines in mean arterial pressure, left
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Table I Effects of Isoflurane on Hemodynamics and Transmural Myocardial Perfusion” Isoflurane (MAC) Preocclusion 106
MAP (mmHg)
96
LVSP (mmHg)
123
dP/dtso(mmHg/sec)
LCCA DBFV (Hz x lo2) Transmural perfusion (ml/min/g) Normal region Stenotic region Occluded region
1960
f9 ?
2‘
f3 ?
130
40 2 9
1 .o
Postocclusion
113
f
9
102 t 4 I28
f
5
1890
f
170
46 2 10
1.21 f 0.11 1.05 f 0.10 0.64 f 0.10
I .5
119 t 6
1.5 ( B P T )
108 t 6
116
5
8
75 2 4b
66 t 4’
100
f3
99 f 5’
89 t 5‘
117
f
1520 ? 140b
43
f
10
1.07 2 0.10 1.01 t 0.11
0.50
f
0.13
4
1170 t 140h
1170 f 120’
38 2 10
44 +. I 1
0.85 0.76 0.41
?
0.15’
?
0.11’ 0.11’
?
1.18 5 0.10 1.06 2 0.11 0.69 5 0.12
Values are means f SEM. Abbreviations: HR, heart rate; MAP, mean arterial pressure; LVSP, left ventricular systolic pressure; LCCA DBFV, left circumflex coronary artery diastolic blood flow velocity; (BP T ), arterial pressure and heart rate adjusted to postocclusion levels. Significantly different ( p < 0.05) from postocclusion.
ventricular systolic pressure, and left ventricular dPldr,,. Left circumflex coronary blood flow velocity was unchanged despite sevoflurane-induced decreases in perfusion pressure. Left ventricular dPldt,, remained significantly depressed, and coronary blood flow velocity remained unchanged from the conscious state during restoration of arterial pressure and heart rate to conscious levels. Adenosine infusions caused decreases in left ventricular systolic pressure and mean arterial pressure which were of lesser magnitude than those observed during isoflurane and sevoflurane anesthesia (Table 111). Heart rate and left ventricular dPldt,, were unchanged by the administration of adenosine. Blood flow through the stenotic left circumflex coronary artery was unaffected by vasodilation with adenosine. There was no significant increase in flow through the stenotic left circumflex coronary artery when arterial pressure was controlled to levels obtained prior to the infusion of adenosine.
Table II Effects of Sevoflurane on Hemodynamics and Transmural Myocardial Perfusion“ Sevoflurane (MAC) Preocclusion HR (bpm) MAP (mmHg) LVSP (mmHg)
dP/dr5,(mmHgisec) LCCA DBFV (Hz x 10:)
106 t 11’
I .o
Postocclusion
1.5
145 t 15
142 f 7
152 -t I I
2 56
I15 t 6
73 I 6”
61 t 4 h
113 t 6
116 2 S b
131 f 7
84
71 t 6’
126 t 8
2140 2 100
2160 t 120
41 2 9h
67 t 8
97
Transmural perfusion (ml/min/g) Normal region Stenotic region Occluded region
-
1.54 t 0.24 1.74 t 0.27
-
0.29 t 0.06
-t
132 t 9
1.5 ( BP f 1
6h
I050 t 140”
1340 ? 140”
60
2
14
1.17
-t
0.28
58 t 9
1.05 t 0.20 1.02 t 0.16’’ 0.22 t 0.05
1.15 t 0.25
0.22 2 0.07
1160 t 140b 81 t 16
1.69 t 0.26
1.82 t 0.25
0.51 t 0.12”
~~
”
Values are means t SEM. See Table I for explanation of abbreviations. different ( p < 0.05) from postocclusion.
” Significantly
Table 111 Effects of Adenosine on Hemodynamics and Transmural Myocardial Perfusion“
Preocclusion
Postocclusion
0.68
1.4
HR (bpm)
97 t 7h
I15 t 6
118 2 9
MAP (mmHg)
97 -c 3
95 t 5
92 2 8
LVSP (mmHg)
124 t 5
117t 5
110 2 6
dP/dr,, (mmHgisec)
LCCA DBFV (Hz x 10’) Transmural perfusion (mliminig) Normal Stenotic Occluded region
2210
f
130
33 t 6
1990 -+ 130 37
2
7
1 . 1 1 t 0.10
0.86 t 0.12 0.25 t 0.04
2020
2
160
41 t 10
1.59 2 0.19 1.19 t 0.18’
0.23
?
0.04
121 t 7 83
*9
1.4 ( B P f ) 115 t 6
98
2
7
100 t 8”
117 t 4
1700 t 290
1370 t 360
41 t I I
48 t 13
2.36 t 0.38” 1.13 2 0.17’ 0.17 ? 0.06
Values are means t SEM. See Table I for explanation of abbreviations. Significantly different ( p < 0.05) from postocclusion.
2.53 f 0.6Ih 1.26 t 0.20’ 0.16 k 0.04’
Judy R. Kersten et a/.
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VI. Regional Myocardial Perfusion: Isoflurane, Sevoflurane, and Adenosine The effects of isoflurane, sevoflurane, and adenosine on the weighted average of subepicardial, midmyocardial, and subendocardial perfusion (expressed as transmural myocardial blood flow) are summarized in Tables I , 11, and 111, respectively. Isoflurane decreased transmural perfusion in normal, stenotic, and occluded zones at 1.5 but not 1.0 MAC. When arterial pressure was increased to levels present in the conscious control state, no significant alteration in transmural myocardial perfusion was observed during isoflurane anesthesia (Table I). Sevoflurane produced somewhat different results than isoflurane (Table 11). Sevoflurane at 1 and 1.5 MAC had no effect on myocardial perfusion in normal regions. In contrast, blood flow distal to the left circumflex coronary artery stenosis was significantly reduced at 1.5 MAC, but no significant change in coronary collateral blood flow occurred. During control of arterial pressure and heart rate, myocardial perfusion in the normal and stenotic zones was not different than levels observed in the conscious state, but coronary collateral blood flow was increased significantly. Adenosine caused a dose-related increase in myocardial perfusion of the normal zone (Table 111). Small but significant increases in flow were also observed in the area distal to the coronary artery stenosis. The increases in stenosis zone flow were unaffected by control of arterial pressure and heart rate. Adenosine produced a decrease in coronary collateral
0.7 06
I4
T
T
1
0.0J
CONTROL 1.0
1.5
1.5 (BP?)
ISOFLURANE (MAC)
Fig. 3 Ratio of flow between occluded and normal zones as determined by the radioactive microsphere technique in the conscious state and during low and high doses of isoflurane in the absence or presence (BP 7 ) of control of arterial pressure.
279
Volatile Anesthetics and Coronary Collateral Circulation
T
0.0
'
CONTROL 1.0
1.5
1.5 (BP?)
SEVOFLURANE (MAC)
Fig. 4 Ratio of flow between occluded and normal zones as determined by the radioactive microsphere technique in the conscious state and during low and high doses of sevoflurane in the absence or presence (BP t ) of control of arterial pressure.
blood flow in the occluded zone despite maintenance of arterial pressure and heart rate. Neither isoflurane nor sevoflurane (Fig. 3 and 4) caused redistribution of blood flow away from the collateral-dependent region (decrease in occluded to normal zone flow ratio). In sharp contrast, adenosine caused a dose-related decline in the occluded to normal zone flow
T
0.0
'
CONTROL 0.7 1.4 1.4 (BP?) ADENOSINE (mglmin)
Fig. 5 Ratio of flow between occluded and normal zones as determined by the radioactive microsphere technique in the conscious control state and during low and high doses of adenosine in the absence or presence (BP T ) of control of arterial pressure. *Significantly different ( p < 0.05) from control.
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Judy R. Kersfen ef a/.
ratio (Fig. 5). This maldistribution of perfusion between occluded and normal zones remained present during infusion of the high dose of adenosine despite control of arterial pressure and heart rate, consistent with coronary steal.
VII. Discussion The results of this investigation demonstrate that isoflurane and sevoflurane cause similar systemic hemodynamic effects during acute coronary artery occlusion in chronically instrumented dogs. Neither agent produces marked coronary vasodilation, and neither agent causes an abnormal redistribution of coronary blood flow away from collateral-dependent zones. Interestingly, coronary collateral blood flow was significantly increased in the presence of sevoflurane during the maintenance of driving pressure for collateral perfusion, suggesting that sevoflurane may provide beneficial effects in myocardium distal to a total coronary artery occlusion. The results obtained with the volatile anesthetics were in direct contrast to those obtained with the small vessel coronary vasodilator adenosine. Adenosine markedly decreased collateral blood flow, resulting in a redistribution of flow away from the collateral-dependent zone during vasodilation of normal regions. This maldistribution of flow was independent of decreases in arterial pressure and occurred despite maintenance of arterial pressure at predrug levels. The present results were obtained in an experimental model of multivessel coronary artery disease which simulated steal prone coronary anatomy by using a total occlusion of one major coronary artery with adequate distal collateralization arising from an adjacent stenotic coronary artery ( I ) . This model has been shown to correlate well with the abnormal anatomic configuration of the coronary vasculature in approximately 25% of patients presenting for coronary artery bypass graft surgery (8). The tendency for coronary steal to occur with vasodilator drugs is readily apparent in this model, and it occurs independently of alterations in heart rate and diastolic aortic pressure (2). Coronary steal is directly dependent on the degree of vasodilation in the area distal to the coronary artery stenosis and on the severity of the stenotic lesion. Vasodilation in the region supplied by the stenotic artey causes a decrease in coronary artery pressure distal to the stenosis. The decrease in distal coronary pressure results in a reduction in driving pressure for collateral flow into the totally occluded zone. The greater the severity of the stenosis, the larger the drop in perfusion pressure at the origin of the collaterals with a n y given degree of vasodilation (9). Even minor degrees of vasodilation distal to a severe stenosis can decrease collateral blood flow. Steal of perfusion away
Volatile Anesthetics and Coronary Collateral Circulation
28 1
from a collateral-dependent zone can also occur in the absence of a stenosis of the artery of origin of coronary collaterals (2,lO). During maximal coronary vasodilation in the absence of a stenosis, there is a decrease in distal coronary artery pressure because the length of the epicardial coronary artery becomes a more significant factor in the overall calculation of coronary resistance. Agents that produce coronary vasodilation can act at one or more regions in the coronary vasculature. Arterioles are the primary vessels controlling resistance in the coronary circulation, and, thus, arteriolar dilators such as adenosine, dipyridamole, and chromonar are capable of producing maximal increases in flow and a redistribution of flow away from collateraldependent zones (1,2,10-12). Chromonar causes intense and selective coronary vasodilation and may increase myocardial infarct size by a coronary steal mechanism even in the absence of stenosis of the artery of origin of collaterals (10). Dipyridamole may exacerbate recovery of function of stunned myocardium by causing a steal of collateral perfusion during a period of coronary occlusion (13). In contrast, nitroglycerin, a large coronary artery, conduit, and collateral vessel dilator, does not produce coronary steal and may even increase coronary collateral perfusion (14). Volatile anesthetics, including isoflurane, enflurane, and halothane, have been shown to cause coronary vasodilation, primarily of small resistance vessels (15). This property makes these agents potential candidates for the production of coronary steal. Isoflurane has been particularly scrutinized and has been previously shown to cause a relatively small redistribution of flow away from collateral-dependent regions in certain experimental models (16). Halothane has also been shown to cause direct coronary vasodilation in uitro (17,181; however, the possibility that this volatile anesthetic may produce coronary steal has never been seriously entertained because halothane causes several indirect hemodynamic actions which directly oppose the actions of this agent as a coronary vasodilator (19). Potent inhalational anesthetics are direct negative inotropes and decrease aortic blood pressure by the combined effects of reductions in cardiac output and peripheral vascular resistance. Volatile anesthetics also depress sinoatrial (SA) node and cardiac conduction tissue function in uitro, and they may cause an overall reduction in heart rate unless baroreflex-mediated tachycardia occurs simultaneously with decreases in arterial pressure. Volatile anesthetic-induced reductions in myocardial contractility, left ventricular afterload, and heart rate contribute to a reduction in myocardial oxygen consumption and lead to a concomitant increase in coronary vascular resistance via metabolic autoregulation. Thus, the sum of indirect and direct effects in uivo determines the observed alterations in coronary blood flow and vascular resistance (20).
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Judy
R. Kersten ef a!.
Several experimental studies indicate that the profound indirect effect of volatile anesthetics on the coronary vasculature offset the direct action of these agents as direct coronary vasodilators. This phenomenon is well established for halothane, has been described for desflurane (21) and, in this investigation, for sevoflurane as well. In contrast, isoflurane produces a small, transient degree of coronary vasodilation in the intact heart; however, the influence of the systemic hemodynamic actions of this agent on myocardial oxygen consumption and coronary autoregulation counterbalance the vasodilator effects of isoflurane so that little overall change in coronary blood flow occurs (19). In addition, minimal alteration in the distribution between coronary blood flow to collateral-dependent, stenotic, and normal zones would be expected with such a small degree of vasodilation during isoflurane administration. In contrast to the present findings, however, other investigators have shown that volatile anesthetics may cause prominent increases in coronary blood flow when suddenly administered in large doses via an intracoronary route (22). This observation occurs with not only isoflurane but also halothane through an unknown mechanism. Volatile anesthetics may have differential effects on the release of nitric oxide from vascular endothelium (23,24), but it is doubtful whether this property can be solely responsible for the large increases in coronary flow observed by Crystal and coworkers (22). Direct nitric oxide donors, including SIN-1, produce only minimal increases in coronary blood flow. Furthermore, these agents tend to affect large vessel dilation significantly more than resistance vessels. In the present investigation, sevoflurane was shown to increase coronary collateral blood flow during maintenance of heart rate and arterial pressure at levels observed in the conscious state. In contrast, coronary collateral blood flow remains constant with correction of heart rate and blood pressure during isoflurane or desflurane anesthesia. The basis for the increase in collateral perfusion produced by sevoflurane is unknown; however, the relative vasodilation of collateral vessels as compared to small resistance vessels may represent a potential explanation for the present results. The hypothesis that sevoflurane-induced increases in collateral flow are beneficial for ischemic myocardium has yet to be tested, but the increase in oxygen delivery may contribute to a reduction in the overall severity of myocardial ischemia. In summary, the present results have demonstrated that isoflurane and a new volatile anesthetic, sevoflurane, do not abnormally redistribute collateral blood flow away from an area distal to a total coronary artery occlusion. In fact, sevoflurane produces an increase in flow to an ischemic zone in a canine model of multivessel coronary artery obstruction. These findings contrast sharply with those obtained with adenosine, which
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caused marked redistribution of coronary collateral flow away from acutely ischemic myocardium.
References 1. Hartman, J. C . , Kampine, J. P., Schmeling, W. T., and Warltier, D. C. (1991). Stealprone coronary circulation in chronically instrumented dogs: Isoflurane versus adenosine. Anesthesiology 74,744-756. 2. Gross, G. J., and Warltier, D. C. (1981). Coronary steal in four models of single or multiple vessel obstruction in dogs. Am. J . Cardiol. 48, 84-92. 3. Becker, L. C. (1978). Conditions for vasodilator induced coronary steal in experimental myocardial ischemia. Circulation 57, 1103-1 110. 4. Domenech, R. J., Hoffman, J. J., Nobel. M. I . . Saunders, K. B., Henson. J . R., and Subijanto, S. (1969). Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ. Res. 25, 581-596. 5 . Fujita, M., McKown, D. P.. McKown. M . D., Hartley, J. W., and Franklin, D. (1987). Evaluation of coronary collateral development by regional myocardial function and reactive hyperaemia. Cardiouasc. Res. 21, 377-384. 6. Mohri, M., Tomoike, H., Noma, M.. h o v e . T.. Hisano, K., and Nakamura. M. (1989). Duration of ischemia is vital for collateral development: Repeated brief coronary artery occlusions in conscious dogs. Circ. Res. 64, 287-296. 7. Hartman, J. C., Kampine, J. P., Schmeling. W. T.. and Warltier, D. C. (1991). Alterations in collateral blood flow produced by isoflurane in a chronically instrumented canine model of multivessel coronary artery disease. Anesthesiology 74, 120- 133. 8. Buffington, C. W., Davis, K. B., Gillispie, S., and Pettinger, M. (1988). The prevalence of steal-prone coronary anatomy in patients with coronary artery disease: An analysis of the Coronary Artery Surgery Study Registry. Anesthesiology 69, 721-727. 9. Warltier, D. C., Hardman, H. F.. and Gross. G. J. (1979).Transmural perfusiongradients distal to various degrees of coronary artery stenosis during resting flow or at maximal vasodilation. Basic Res. Cardiol. 74, 494-508. 10. Warltier, D. C., Gross, G . J., and Brooks, H . L. (1980). Coronary steal-induced increase in myocardial infarct size after pharmacologic coronary vasodilation. A m . J . Cardiol. 46, 83-90. I t . Warltier. D. C., Gross, G. J., and Brooks, H. L. (1981). Pharmacologic- vs. ischemiainduced coronary artery vasodilation. Am. J . Physiol. 240, H767-H774. 12. Gross, G. J., Buck, J. D., Warltier, D. C.. and Hardman, H. F. (1982). Separation of overlap and collateral perfusion of ischemic canine myocardium: Important considerations in the analysis of vasodilator induced coronary steal. J . Cardiouasc. Pharmacol. 4, 254-263. 13. Kenny, D., Wynsen, J . C., Brooks, H . L., and Warltier, D. C. (1991). Dipyridamoleinduced decrement of functional recovery of positischemic reperfused myocardium in conscious dogs with well-developed coronary collateral circulation. Am. Heart J . 121, 1339- 1347. 14. Gross, G. J., Warltier, D. C., and Lamping, K. A. (1993). Comparative effects of the potassium channel opener-nitrate, nicorandil, nifedipine and nitroglycerin on coronary collateral blood flow in dogs with well-developed collateral vessels. Pharmacol. Commun. 2 , 353-360. 15. Conzen, P. F., Habazettl. H., Vollmar, B . . Christ, M., Baier. H., and Peter, K. (1992). Coronary microcirculation during halothane, enflurane, isoflurane, and adenosine in dogs. Anesthesiology 76, 261-270.
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16. Buffington. C. W., Romson, J . L., Levine, A,, Duttlinger, N . C.. and Huang, A. H.
17. 18.
19.
20. 21.
22. 23. 24.
(1987). Isoflurane induces coronary steal in a canine model ofchronic coronary occlusion. Anesthesiology 66, 280-292. Bollen, B. A,. McKlveen, R. E., and Stevenson, J. A. (1992). Halothane relaxespreconstricted small and medium isolated porcine coronary artery segments more than isoflurane. Anesth. Analg. 75, 9-17. Bollen, B. A., McKlveen, R. E., and Stevenson, J. A. (1992). Halothane relaxes previously constricted human epicardial coronary artery segments more than isoflurane. Anesth. Analg. 75, 4-8. Kenny, D., Proctor, L. T., Schmeling. W. T., Kampine, J. P.. and Warltier, D. C. (1991). Isoflurane causes only minimal increases in coronary blood flow independent of oxygen demand. Anesthesiology 75, 640-649. Larach, D. R., Schuler, H. G., Skeehan, T. M., and Peterson, C. J. (1990). Direct effects of myocardial depressant drugs on coronary vascular tone: Anesthetic vasodilation by halothane and isoflurane. J . Phorrnacol. Exp. Ther. 254, 58-64. Pagel, P. S., Kampine. J. P.. Schmeling. W. T., and Warltier, D. C. (1991). Comparison of the systemic and coronary hemodynamic actions of desflurane, isoflurane, halothane. and enflurane in the chronically instrumented dog. Anesthesiology 74, 539-55 1. Crystal, G . J . , Kim, S.-J., Czinn, E. A,, Salem, M. R., Mason, W. L.. and AbdelLatif, M. (19911. Intracoronary isoflurane causes marked vasodilation in canine hearts. Anesthesiology 74, 757-765. Blake, G., Sill, J. C., Nugent, M., Van Dyke, R. A.. and Vanhoutte, P. M. (1987). Isoflurane causes endothelium-dependent inhibition of contractile responses of canine coronary arteries. Anesrhesiologv 67, 5 13-5 17. Witzeling. T. M . , Sill, J. C., Hughes, J. M., Blake, G. A,, Nugent, M., and Rorie, D. K. (1990). lsoflurane and halothane attenuate coronary artery constriction evoked by serotonin in isolated porcine vessels and in intact pigs. Anesthesiology 73, 100-108.
1. Introduction Volatile anesthetics may alter coronary collateral blood flow to ischemic myocardium by several direct and indirect mechanisms. Decreases in arterial pressure resulting from declines in systemic vascular resistance or cardiac output produced by volatile anesthetics can reduce the driving pressure at the origin of collateral vessels and cause a decrease in collateral blood flow. Reflex increases in heart rate during anesthesia may also decrease coronary collateral flow because of a reduction in the duration of diastole. Direct vasodilation of coronary arterioles induced by volatile anesthetics may result in a redistribution of flow away from collateraldependent, ischemic zones to normal areas. A decrease in coronary collateral flow during large increases in flow to normal zones via direct vasodilation has been termed “coronary steal.” The purpose of this investigation was to evaluate the effects of a new volatile anesthetic, sevoflurane, on coronary collateral blood flow using chronically instrumented dogs with an experimentally produced “coronary steal prone anatomy” ( I ) . The model included a total occlusion of the left anterior descending coronary artery, a stenosis of the adjacent artery of origin of the collaterals (left circumflex coronary artery), and a Adua,rr-c\ in Pharrrr~iroki~v.. Volnrw 31 Copyrighi ri 1994 by Academic Press. Inc. All right, of lepioduclion in any form reserved
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well-developed coronary collateral circulation. This anatomical configuration has been previously shown to favor the development of coronary steal induced by potent coronary vasodilators including adenosine and dipyridamole (2,3). The actions of sevoflurane were compared to those produced by isoflurane and the small vessel coronary vasodilator adenosine in separate experimental groups. This multivessel disease model also allowed direct comparison of the conscious and anesthetized states without the potentially confounding influences of acute surgical intervention or the use of baseline anesthetic agents.
II. Chronic Animal Instrumentation Mongrel dogs of either sex were anesthetized with sodium thiamylal (10 mg/kg i.v.) and halothane (1.0-2.0%) in 100% oxygen. A left thoracotomy was performed under sterile conditions. Catheters were implanted in the left atrium, right atrium, and descending thoracic aorta for administration of radioactive microspheres, drug administration, and withdrawal of reference arterial flow samples used in the calculation of regional myocardial blood flow. A balloon cuff vascular occluder was positioned immediately distal to the aortic catheter for control of arterial pressure via constriction of the thoracic aorta. The heart was suspended in a pericardial cradle, and 2-cm sections of the proximal left anterior descending and left circumflex coronary arteries were dissected free of surrounding tissue. A Doppler (20 MHz) ultrasonic flow transducer was placed around each vessel for measurement of coronary blood flow velocity. A balloon cuff occluder was positioned immediately distal to the left anterior descending coronary flow transducer. This device was used to produce repetitive brief coronary artery occlusions to induce collateral development. In addition, on the day of the experiment, the balloon cuff was used to produce sustained total coronary artery occlusion. An ameroid constrictor was positioned around the left circumflex coronary artery distal to the flow velocity transducer to form a fixed stenosis of the artery of origin of the coronary collaterals perfusing the left anterior descending bed. A miniature micromanometer (Model P7, Konigsberg Instruments, Pasadena, CA) was inserted into the left ventricle via a small incision through the apex. A fluid-filled catheter was also inserted into the left ventricle for calibration of the micromanometer in uiuo and for administration of adenosine in specific experiments. Pairs of ultrasonic segment length transducers were implanted in the subendocardium in the perfusion territories supplied by the left anterior descending and left circumflex coronary arter-
Volatile Anesthetics and Coronary Colloterol Circulation
27 I
ies for measurement of regional contractile function. Electrodes were sutured to the right atrium for atrial pacing. The instrumentation was exteriorized between the scapulae, and the chest wall was closed in layers. All animals were treated with analgesics as required and antibiotics to prevent infection. Each dog was fitted with a jacket to prevent damage to the implanted instruments, which were enclosed in an aluminum box. Each dog was allowed to recover for 2 days after surgery prior to daily hemodynamic monitoring.
111. Regional Myocardial Function and Perfusion Regional contractile function was evaluated by ultrasonic segment length transducers. All signals were simultaneously monitored via ultrasonic amplifiers (Crystal Biotech, Hopkinton, MA). Using left ventricular dP/ dt, end diastolic segment length (EDL) was measured immediately prior to the onset of left ventricular isovolumic contraction, and end systolic length (ESL) was determined at peak - dP/dt. Percent systolic shortening (%SS) was calculated from the following equation:
%SS
[(EDL
-
ESL)/EDL] x 100
Regional myocardial blood flow in normal, stenotic, and totally occluded (coronary collateral blood flow) regions was measured by the radioactive microsphere technique (4).At specific intervals, radioactive microspheres were injected into the left atrium as a bolus. A withdrawal of arterial blood from the aortic catheter was started at a flow rate of 7 ml/min immediately prior to the injection of microspheres and continued for 3 min. At the conclusion of each experiment, India ink and Monastral blue suspension dye were injected into the coronary circulation immediately distal to the ameroid constrictor and hydraulic occluder, respectively, at pressures of 100 mmHg to delineate the perfusion territories of the totally occluded, stenotic, and normal zones. Tissue samples from these areas were subdivided into subepicardial, midmyocardial, and subendocardial specimens of approximately equal weight. Tissue blood flow ((3,; ml/min/g) was calculated from the equation Qm
=
CmQ,/C,
where Qr is the rate of withdrawal (ml/min) of the reference blood flow sample, Cr is the activity [counts per minute (cpm)] of the reference blood flow sample, and Cm is the activity (cpm/g) of the myocardial tissue sample.
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Starting on the second postoperative day, each dog was monitored for changes in systemic and coronary hemodynamics. Once an hour, eight times each day, repetitive, brief ( 2 min) left anterior descending coronary artery occlusions were performed by inflation and subsequent deflation of the hydraulic balloon cuff coronary occluder. This process has been previously used to induce coronary collateral growth (1,5.6). Coronary collateral development was assessed daily by measurement of the reactive hyperemic response following brief coronary artery occlusion and by assessment of segment shortening in the left anterior descending perfusion territory during the period of coronary artery occlusion. In addition, the severity of left circumflex coronary artery stenosis was also assessed by measurement of coronary reserve on each experimental day (7). The increase in left circumflex flow velocity after a bolus injection of adenosine (25, 50, and 100 pg) into the left atrium was measured. Repetitive occlusions and stenosis development continued for a variable amount of time (10 to 20 days). On the day that the left circumflex coronary artery stenosis was considered critical (minimal changes in resting coronary blood flow but near abolition of coronary vascular reserve as assessed by the ability to dilate following administration of adenosine), a coronary steal prone anatomy was established. In the presence of a well-developed collateral circulation and stenosis of the artery of origin of the coronary collaterals (left circumflex coronary artery), the left anterior descending coronary artery was totally occluded by inflation of the hydraulic balloon cuff occluder for the duration of the experiment. Systemic and coronary hemodynamics and regional myocardial perfusion and function in collateral-dependent, stenotic, and normal zones were measured in the conscious state 30 min after left anterior descending coronary artery occlusion. After control measurements were completed, dogs received either isoflurane, sevoflurane, or adenosine in three separate groups of experiments. Anesthesia was induced by inhalation using the volatile anesthetic at high flow rates (8 literdmin oxygen). After tracheal intubation, anesthesia was maintained with isoflurane or sevoflurane in room air enriched with oxygen during positive pressure ventilation using a semiclosed anesthesia circuit. The oxygen flow rate, respiratory rate, and tidal volume were adjusted to maintain arterial blood gas tensions within conscious levels. Two concentrations of each anesthetic (1 .O and 1.5 MAC) producing decreases of approximately 25 and 35 mmHg of arterial pressure were studied. End-tidal gas and anesthetic concentrations were continuously monitored with an infrared gas analyzer (Datex Capnomac, Helsinki, Finland). The first concentration of isoflurane or sevoflurane was allowed to equilibrate for a period of 30 min to provide a steady state, and hemodynamics,
Volatile Anesthetics and Coronary Collateral Circulation
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myocardial blood flow, and regional contractile function were recorded. Anesthetic depth was then adjusted to produce a greater decrease in arterial pressure, maintained at steady state for an additional 30 min, and measurements repeated. Finally, at the highest concentration of anesthetic agent, hemodynamics were restored to levels present in the conscious control state. Arterial pressure was increased by inflation of the aortic balloon cuff occluder. Baroreflex reduction in heart rate was avoided by atrial pacing to rates present in the conscious state. In this fashion, the direct effects of isoflurane and sevoflurane on the regional distribution of coronary blood flow were assessed independently of changes in systemic hemodynamics. In a separate group of experiments, the effects of adenosine on regional myocardial blood flow were studied. Systemic and coronary hemodynamics, myocardial perfusion, and contractile function were measured in the conscious control state and during low (range 0.25 to I mg/min) and high (range 1.0 to 2.5 mg/min) doses of adenosine. The doses of adenosine were administered through the left ventricular catheter by a continuous infusion. The dose ranges were selected to provide declines of approximately 10 and 20 mmHg in mean arterial pressure. Measurements were also completed during the high dose of adenosine with control of arterial pressure and heart rate as described above. At the conclusion of all experiments, each dog was euthanized by intravenous administration of an overdose of sodium pentobarbital. The heart was excised, stained, and fixed for 24 to 48 h in 10% formaldehyde prior to obtaining tissue specimens for analysis of myocardial blood flow. A total of 3 1 dogs were used in the investigation to produce 21 successful experiments for data analysis (group size of 6 to 8 animals). Dogs were excluded because of ventricular fibrillation during coronary artery occlusion or failure of instrumentation. Systemic and coronary hemodynamics, myocardial blood flow, and regional contractile function data were analyzed by analysis of variance with repeated measures (ANOVA) followed by Duncan’s multiple range test and were considered significant when p values were below 0.05.
IV. Coronary Steal Prone Anatomy Model Repetitive left anterior descending coronary artery occlusions resulted in a significant ( p < 0.05) diminution of peak postocclusive reactive hyperemic flow. The duration of the flow increase above baseline levels and reactive hyperemic debt repayment were also significantly decreased despite a constant oxygen debt accrued during each 2-min occlusion (Fig. I ) . In
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DAY 4
. LL?jlLI 2 MIN
-
DAY 8
DAY 12
(Hz LAD BFV 100) loo[
(Hz
-
100)
ss = 0 %
,v??
LENGTH
(mm)
LV dP/dt (mmHg / sac)
14
-3000 U 1 SEC
Fig. 1 Left anterior descending (LAD) and left circumflex coronary artery (LCCA) blood flow velocity (BFV) during the reactive hyperemic response after a 2-min coronary artery occlusion. Repetitive coronary artery occlusions were performed once each hour, 8 times each day. Sample data from days 4, 8, and 12 are shown. During repetitive coronary artery occlusions, the reactive hyperemic response is slowly reduced as collateral growth is enhanced. Similarly, segment shortening (SS) during the period of coronary artery occlusion is initially severely depressed; however, with enhancement of collateral growth, contraction is sustained in the ischemic zone during the period of coronary artery occlusion. LV, Left ventricle. [Reprinted with permission from Hartman er a / . ( I ) . ]
some dogs, a total loss of reactive hyperemia following brief coronary artery occlusion occurred. A reduction in reactive hyperemia was indicative of a decrease in the intensity of ischemia during the period of coronary artery occlusion secondary to enhanced collateral development. Examination of regional contractile function during occlusion initially revealed paradoxical systolic aneurysmal bulging during repetitive coronary artery occlusions. Over the period of collateral development, however, aneurysmal bulging was replaced by akinesis and, eventually, by effective systolic shortening in the left anterior descending perfusion territory despite total arterial occlusion (Fig. 1). The progressive improvement in regional contractile function in the ischemic zone also indicated growth and development of coronary collaterals, leading to a reduction in the intensity of ischemia. As coronary collateral development continued, the ameroid constrictor on the left circumflex coronary artery formed a stenosis that became
Volatile Anesthetics and Coronary Collateral Circulation 2
DAY
CBFV
60r
3
4
5
275 6
7
,
Fig. 2 Coronary blood flow velocity (CBFV) in the left anterior descending (LAD) and left circumflex arteries (LCCA) during left atrial bolus administrationof adenosine ( 100 p g ) over 7 days. Note the diminution in flow response to adenosine caused by progressive stenosis of the left circumflex coronary artery via an ameroid constrictor. The flow response in the LAD remains unchanged. [Reprinted with permission from Hartman et a / . (71.1
continuously more severe over several days. There was a progressive decline in coronary vascular reserve in the left circumflex artery although no change in resting coronary blood flow occurred. This resulted in a diminution of the coronary flow response to bolus injections of adenosine over several days (Fig. 2). In contrast, the flow response to adenosine in the left anterior descending coronary artery remained unchanged over the course of left circumflex stenosis development.
V. Hernodynamic Effects of Isoflurane, Sevoflurane, and Adenosine The systemic and coronary hernodynamic actions of isoflurane, sevoflurane, and adenosine are summarized in Tables 1-111. lsoflurane produced a dose-dependent decline in mean arterial pressure, left ventricular systolic pressure, and left ventricular dPldt,,. Despite a large reduction in mean arterial pressure, left circumflex coronary blood flow velocity remained unchanged, reflecting a reduction in coronary vascular resistance. With the exception of left ventricular dPldr,,, hemodynamics remained unchanged from the conscious state during control of arterial pressure and heart rate. Sevoflurane caused systemic and coronary hemodynamic effects which were similar to those of isoflurane. Sevoflurane produced no change in heart rate and dose-dependent declines in mean arterial pressure, left
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Table I Effects of Isoflurane on Hemodynamics and Transmural Myocardial Perfusion” Isoflurane (MAC) Preocclusion 106
MAP (mmHg)
96
LVSP (mmHg)
123
dP/dtso(mmHg/sec)
LCCA DBFV (Hz x lo2) Transmural perfusion (ml/min/g) Normal region Stenotic region Occluded region
1960
f9 ?
2‘
f3 ?
130
40 2 9
1 .o
Postocclusion
113
f
9
102 t 4 I28
f
5
1890
f
170
46 2 10
1.21 f 0.11 1.05 f 0.10 0.64 f 0.10
I .5
119 t 6
1.5 ( B P T )
108 t 6
116
5
8
75 2 4b
66 t 4’
100
f3
99 f 5’
89 t 5‘
117
f
1520 ? 140b
43
f
10
1.07 2 0.10 1.01 t 0.11
0.50
f
0.13
4
1170 t 140h
1170 f 120’
38 2 10
44 +. I 1
0.85 0.76 0.41
?
0.15’
?
0.11’ 0.11’
?
1.18 5 0.10 1.06 2 0.11 0.69 5 0.12
Values are means f SEM. Abbreviations: HR, heart rate; MAP, mean arterial pressure; LVSP, left ventricular systolic pressure; LCCA DBFV, left circumflex coronary artery diastolic blood flow velocity; (BP T ), arterial pressure and heart rate adjusted to postocclusion levels. Significantly different ( p < 0.05) from postocclusion.
ventricular systolic pressure, and left ventricular dPldr,,. Left circumflex coronary blood flow velocity was unchanged despite sevoflurane-induced decreases in perfusion pressure. Left ventricular dPldt,, remained significantly depressed, and coronary blood flow velocity remained unchanged from the conscious state during restoration of arterial pressure and heart rate to conscious levels. Adenosine infusions caused decreases in left ventricular systolic pressure and mean arterial pressure which were of lesser magnitude than those observed during isoflurane and sevoflurane anesthesia (Table 111). Heart rate and left ventricular dPldt,, were unchanged by the administration of adenosine. Blood flow through the stenotic left circumflex coronary artery was unaffected by vasodilation with adenosine. There was no significant increase in flow through the stenotic left circumflex coronary artery when arterial pressure was controlled to levels obtained prior to the infusion of adenosine.
Table II Effects of Sevoflurane on Hemodynamics and Transmural Myocardial Perfusion“ Sevoflurane (MAC) Preocclusion HR (bpm) MAP (mmHg) LVSP (mmHg)
dP/dr5,(mmHgisec) LCCA DBFV (Hz x 10:)
106 t 11’
I .o
Postocclusion
1.5
145 t 15
142 f 7
152 -t I I
2 56
I15 t 6
73 I 6”
61 t 4 h
113 t 6
116 2 S b
131 f 7
84
71 t 6’
126 t 8
2140 2 100
2160 t 120
41 2 9h
67 t 8
97
Transmural perfusion (ml/min/g) Normal region Stenotic region Occluded region
-
1.54 t 0.24 1.74 t 0.27
-
0.29 t 0.06
-t
132 t 9
1.5 ( BP f 1
6h
I050 t 140”
1340 ? 140”
60
2
14
1.17
-t
0.28
58 t 9
1.05 t 0.20 1.02 t 0.16’’ 0.22 t 0.05
1.15 t 0.25
0.22 2 0.07
1160 t 140b 81 t 16
1.69 t 0.26
1.82 t 0.25
0.51 t 0.12”
~~
”
Values are means t SEM. See Table I for explanation of abbreviations. different ( p < 0.05) from postocclusion.
” Significantly
Table 111 Effects of Adenosine on Hemodynamics and Transmural Myocardial Perfusion“
Preocclusion
Postocclusion
0.68
1.4
HR (bpm)
97 t 7h
I15 t 6
118 2 9
MAP (mmHg)
97 -c 3
95 t 5
92 2 8
LVSP (mmHg)
124 t 5
117t 5
110 2 6
dP/dr,, (mmHgisec)
LCCA DBFV (Hz x 10’) Transmural perfusion (mliminig) Normal Stenotic Occluded region
2210
f
130
33 t 6
1990 -+ 130 37
2
7
1 . 1 1 t 0.10
0.86 t 0.12 0.25 t 0.04
2020
2
160
41 t 10
1.59 2 0.19 1.19 t 0.18’
0.23
?
0.04
121 t 7 83
*9
1.4 ( B P f ) 115 t 6
98
2
7
100 t 8”
117 t 4
1700 t 290
1370 t 360
41 t I I
48 t 13
2.36 t 0.38” 1.13 2 0.17’ 0.17 ? 0.06
Values are means t SEM. See Table I for explanation of abbreviations. Significantly different ( p < 0.05) from postocclusion.
2.53 f 0.6Ih 1.26 t 0.20’ 0.16 k 0.04’
Judy R. Kersten et a/.
278
VI. Regional Myocardial Perfusion: Isoflurane, Sevoflurane, and Adenosine The effects of isoflurane, sevoflurane, and adenosine on the weighted average of subepicardial, midmyocardial, and subendocardial perfusion (expressed as transmural myocardial blood flow) are summarized in Tables I , 11, and 111, respectively. Isoflurane decreased transmural perfusion in normal, stenotic, and occluded zones at 1.5 but not 1.0 MAC. When arterial pressure was increased to levels present in the conscious control state, no significant alteration in transmural myocardial perfusion was observed during isoflurane anesthesia (Table I). Sevoflurane produced somewhat different results than isoflurane (Table 11). Sevoflurane at 1 and 1.5 MAC had no effect on myocardial perfusion in normal regions. In contrast, blood flow distal to the left circumflex coronary artery stenosis was significantly reduced at 1.5 MAC, but no significant change in coronary collateral blood flow occurred. During control of arterial pressure and heart rate, myocardial perfusion in the normal and stenotic zones was not different than levels observed in the conscious state, but coronary collateral blood flow was increased significantly. Adenosine caused a dose-related increase in myocardial perfusion of the normal zone (Table 111). Small but significant increases in flow were also observed in the area distal to the coronary artery stenosis. The increases in stenosis zone flow were unaffected by control of arterial pressure and heart rate. Adenosine produced a decrease in coronary collateral
0.7 06
I4
T
T
1
0.0J
CONTROL 1.0
1.5
1.5 (BP?)
ISOFLURANE (MAC)
Fig. 3 Ratio of flow between occluded and normal zones as determined by the radioactive microsphere technique in the conscious state and during low and high doses of isoflurane in the absence or presence (BP 7 ) of control of arterial pressure.
279
Volatile Anesthetics and Coronary Collateral Circulation
T
0.0
'
CONTROL 1.0
1.5
1.5 (BP?)
SEVOFLURANE (MAC)
Fig. 4 Ratio of flow between occluded and normal zones as determined by the radioactive microsphere technique in the conscious state and during low and high doses of sevoflurane in the absence or presence (BP t ) of control of arterial pressure.
blood flow in the occluded zone despite maintenance of arterial pressure and heart rate. Neither isoflurane nor sevoflurane (Fig. 3 and 4) caused redistribution of blood flow away from the collateral-dependent region (decrease in occluded to normal zone flow ratio). In sharp contrast, adenosine caused a dose-related decline in the occluded to normal zone flow
T
0.0
'
CONTROL 0.7 1.4 1.4 (BP?) ADENOSINE (mglmin)
Fig. 5 Ratio of flow between occluded and normal zones as determined by the radioactive microsphere technique in the conscious control state and during low and high doses of adenosine in the absence or presence (BP T ) of control of arterial pressure. *Significantly different ( p < 0.05) from control.
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Judy R. Kersfen ef a/.
ratio (Fig. 5). This maldistribution of perfusion between occluded and normal zones remained present during infusion of the high dose of adenosine despite control of arterial pressure and heart rate, consistent with coronary steal.
VII. Discussion The results of this investigation demonstrate that isoflurane and sevoflurane cause similar systemic hemodynamic effects during acute coronary artery occlusion in chronically instrumented dogs. Neither agent produces marked coronary vasodilation, and neither agent causes an abnormal redistribution of coronary blood flow away from collateral-dependent zones. Interestingly, coronary collateral blood flow was significantly increased in the presence of sevoflurane during the maintenance of driving pressure for collateral perfusion, suggesting that sevoflurane may provide beneficial effects in myocardium distal to a total coronary artery occlusion. The results obtained with the volatile anesthetics were in direct contrast to those obtained with the small vessel coronary vasodilator adenosine. Adenosine markedly decreased collateral blood flow, resulting in a redistribution of flow away from the collateral-dependent zone during vasodilation of normal regions. This maldistribution of flow was independent of decreases in arterial pressure and occurred despite maintenance of arterial pressure at predrug levels. The present results were obtained in an experimental model of multivessel coronary artery disease which simulated steal prone coronary anatomy by using a total occlusion of one major coronary artery with adequate distal collateralization arising from an adjacent stenotic coronary artery ( I ) . This model has been shown to correlate well with the abnormal anatomic configuration of the coronary vasculature in approximately 25% of patients presenting for coronary artery bypass graft surgery (8). The tendency for coronary steal to occur with vasodilator drugs is readily apparent in this model, and it occurs independently of alterations in heart rate and diastolic aortic pressure (2). Coronary steal is directly dependent on the degree of vasodilation in the area distal to the coronary artery stenosis and on the severity of the stenotic lesion. Vasodilation in the region supplied by the stenotic artey causes a decrease in coronary artery pressure distal to the stenosis. The decrease in distal coronary pressure results in a reduction in driving pressure for collateral flow into the totally occluded zone. The greater the severity of the stenosis, the larger the drop in perfusion pressure at the origin of the collaterals with a n y given degree of vasodilation (9). Even minor degrees of vasodilation distal to a severe stenosis can decrease collateral blood flow. Steal of perfusion away
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from a collateral-dependent zone can also occur in the absence of a stenosis of the artery of origin of coronary collaterals (2,lO). During maximal coronary vasodilation in the absence of a stenosis, there is a decrease in distal coronary artery pressure because the length of the epicardial coronary artery becomes a more significant factor in the overall calculation of coronary resistance. Agents that produce coronary vasodilation can act at one or more regions in the coronary vasculature. Arterioles are the primary vessels controlling resistance in the coronary circulation, and, thus, arteriolar dilators such as adenosine, dipyridamole, and chromonar are capable of producing maximal increases in flow and a redistribution of flow away from collateraldependent zones (1,2,10-12). Chromonar causes intense and selective coronary vasodilation and may increase myocardial infarct size by a coronary steal mechanism even in the absence of stenosis of the artery of origin of collaterals (10). Dipyridamole may exacerbate recovery of function of stunned myocardium by causing a steal of collateral perfusion during a period of coronary occlusion (13). In contrast, nitroglycerin, a large coronary artery, conduit, and collateral vessel dilator, does not produce coronary steal and may even increase coronary collateral perfusion (14). Volatile anesthetics, including isoflurane, enflurane, and halothane, have been shown to cause coronary vasodilation, primarily of small resistance vessels (15). This property makes these agents potential candidates for the production of coronary steal. Isoflurane has been particularly scrutinized and has been previously shown to cause a relatively small redistribution of flow away from collateral-dependent regions in certain experimental models (16). Halothane has also been shown to cause direct coronary vasodilation in uitro (17,181; however, the possibility that this volatile anesthetic may produce coronary steal has never been seriously entertained because halothane causes several indirect hemodynamic actions which directly oppose the actions of this agent as a coronary vasodilator (19). Potent inhalational anesthetics are direct negative inotropes and decrease aortic blood pressure by the combined effects of reductions in cardiac output and peripheral vascular resistance. Volatile anesthetics also depress sinoatrial (SA) node and cardiac conduction tissue function in uitro, and they may cause an overall reduction in heart rate unless baroreflex-mediated tachycardia occurs simultaneously with decreases in arterial pressure. Volatile anesthetic-induced reductions in myocardial contractility, left ventricular afterload, and heart rate contribute to a reduction in myocardial oxygen consumption and lead to a concomitant increase in coronary vascular resistance via metabolic autoregulation. Thus, the sum of indirect and direct effects in uivo determines the observed alterations in coronary blood flow and vascular resistance (20).
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R. Kersten ef a!.
Several experimental studies indicate that the profound indirect effect of volatile anesthetics on the coronary vasculature offset the direct action of these agents as direct coronary vasodilators. This phenomenon is well established for halothane, has been described for desflurane (21) and, in this investigation, for sevoflurane as well. In contrast, isoflurane produces a small, transient degree of coronary vasodilation in the intact heart; however, the influence of the systemic hemodynamic actions of this agent on myocardial oxygen consumption and coronary autoregulation counterbalance the vasodilator effects of isoflurane so that little overall change in coronary blood flow occurs (19). In addition, minimal alteration in the distribution between coronary blood flow to collateral-dependent, stenotic, and normal zones would be expected with such a small degree of vasodilation during isoflurane administration. In contrast to the present findings, however, other investigators have shown that volatile anesthetics may cause prominent increases in coronary blood flow when suddenly administered in large doses via an intracoronary route (22). This observation occurs with not only isoflurane but also halothane through an unknown mechanism. Volatile anesthetics may have differential effects on the release of nitric oxide from vascular endothelium (23,24), but it is doubtful whether this property can be solely responsible for the large increases in coronary flow observed by Crystal and coworkers (22). Direct nitric oxide donors, including SIN-1, produce only minimal increases in coronary blood flow. Furthermore, these agents tend to affect large vessel dilation significantly more than resistance vessels. In the present investigation, sevoflurane was shown to increase coronary collateral blood flow during maintenance of heart rate and arterial pressure at levels observed in the conscious state. In contrast, coronary collateral blood flow remains constant with correction of heart rate and blood pressure during isoflurane or desflurane anesthesia. The basis for the increase in collateral perfusion produced by sevoflurane is unknown; however, the relative vasodilation of collateral vessels as compared to small resistance vessels may represent a potential explanation for the present results. The hypothesis that sevoflurane-induced increases in collateral flow are beneficial for ischemic myocardium has yet to be tested, but the increase in oxygen delivery may contribute to a reduction in the overall severity of myocardial ischemia. In summary, the present results have demonstrated that isoflurane and a new volatile anesthetic, sevoflurane, do not abnormally redistribute collateral blood flow away from an area distal to a total coronary artery occlusion. In fact, sevoflurane produces an increase in flow to an ischemic zone in a canine model of multivessel coronary artery obstruction. These findings contrast sharply with those obtained with adenosine, which
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caused marked redistribution of coronary collateral flow away from acutely ischemic myocardium.
References 1. Hartman, J. C . , Kampine, J. P., Schmeling, W. T., and Warltier, D. C. (1991). Stealprone coronary circulation in chronically instrumented dogs: Isoflurane versus adenosine. Anesthesiology 74,744-756. 2. Gross, G. J., and Warltier, D. C. (1981). Coronary steal in four models of single or multiple vessel obstruction in dogs. Am. J . Cardiol. 48, 84-92. 3. Becker, L. C. (1978). Conditions for vasodilator induced coronary steal in experimental myocardial ischemia. Circulation 57, 1103-1 110. 4. Domenech, R. J., Hoffman, J. J., Nobel. M. I . . Saunders, K. B., Henson. J . R., and Subijanto, S. (1969). Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ. Res. 25, 581-596. 5 . Fujita, M., McKown, D. P.. McKown. M . D., Hartley, J. W., and Franklin, D. (1987). Evaluation of coronary collateral development by regional myocardial function and reactive hyperaemia. Cardiouasc. Res. 21, 377-384. 6. Mohri, M., Tomoike, H., Noma, M.. h o v e . T.. Hisano, K., and Nakamura. M. (1989). Duration of ischemia is vital for collateral development: Repeated brief coronary artery occlusions in conscious dogs. Circ. Res. 64, 287-296. 7. Hartman, J. C., Kampine, J. P., Schmeling. W. T.. and Warltier, D. C. (1991). Alterations in collateral blood flow produced by isoflurane in a chronically instrumented canine model of multivessel coronary artery disease. Anesthesiology 74, 120- 133. 8. Buffington, C. W., Davis, K. B., Gillispie, S., and Pettinger, M. (1988). The prevalence of steal-prone coronary anatomy in patients with coronary artery disease: An analysis of the Coronary Artery Surgery Study Registry. Anesthesiology 69, 721-727. 9. Warltier, D. C., Hardman, H. F.. and Gross. G. J. (1979).Transmural perfusiongradients distal to various degrees of coronary artery stenosis during resting flow or at maximal vasodilation. Basic Res. Cardiol. 74, 494-508. 10. Warltier, D. C., Gross, G . J., and Brooks, H . L. (1980). Coronary steal-induced increase in myocardial infarct size after pharmacologic coronary vasodilation. A m . J . Cardiol. 46, 83-90. I t . Warltier. D. C., Gross, G. J., and Brooks, H. L. (1981). Pharmacologic- vs. ischemiainduced coronary artery vasodilation. Am. J . Physiol. 240, H767-H774. 12. Gross, G. J., Buck, J. D., Warltier, D. C.. and Hardman, H. F. (1982). Separation of overlap and collateral perfusion of ischemic canine myocardium: Important considerations in the analysis of vasodilator induced coronary steal. J . Cardiouasc. Pharmacol. 4, 254-263. 13. Kenny, D., Wynsen, J . C., Brooks, H . L., and Warltier, D. C. (1991). Dipyridamoleinduced decrement of functional recovery of positischemic reperfused myocardium in conscious dogs with well-developed coronary collateral circulation. Am. Heart J . 121, 1339- 1347. 14. Gross, G. J., Warltier, D. C., and Lamping, K. A. (1993). Comparative effects of the potassium channel opener-nitrate, nicorandil, nifedipine and nitroglycerin on coronary collateral blood flow in dogs with well-developed collateral vessels. Pharmacol. Commun. 2 , 353-360. 15. Conzen, P. F., Habazettl. H., Vollmar, B . . Christ, M., Baier. H., and Peter, K. (1992). Coronary microcirculation during halothane, enflurane, isoflurane, and adenosine in dogs. Anesthesiology 76, 261-270.
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