Comparison of Etomidate, Ketamine, Midazolam, Propofol, and Thiopental on Function and Metabolism of Isolated Hearts David F. Stowe,
MD, PhD,
Zeljko J. Bosnjak, PhD, and John P. Kampine,
MD, PhD
Anesthesiology Research Laboratory, Departments of Anesthesiology and Physiology, The Medical College of Wisconsin, and the Veterans Affairs Medical Center, Milwaukee, Wisconsin
The authors examined direct myocardial and coronary vascular responses to the anesthetic induction agents etomidate, ketamine, midazolam, propofol, and thiopental and compared their effects on attenuating autoregulation of coronary flow as assessed by changes in oxygen supplyidemand relationships. Spontaneous heart rate, atrioventricular conduction time during atrial pacing, left ventricular pressure (LVP),coronary flow (CF), percent oxygen extraction, oxygen delivery, and myocardial oxygen consumption (MVo,) were examined in 55 isolated guinea pig hearts divided into five groups of 11 each. Hearts were perfused at constant pressure with one of the drugs administered at steady-state concentrations increasing from 0.5 pM to 1 mM. Adenosine was given to test maximal CF. At concentrations below 10 pM no significant changes were observed; beyond 50 pM for midazolam, etomidate, and propofol, and 100 pM for thiopental and ketamine, each agent caused progressive but differential decreases in heart rate, atrioventricular conduction time’ (leading to atrioventricular dissociation), LVP, +dLVPidt,,,, percent oxygen extraction, and MVo,. The concentrations (pM) at which +dLVPidt,,, was reduced by 50% were as follows: etomidate, 82 t 2 (mean t SEM); propofol, 91 ? 4; midazolam, 105 8; thiopental, 156 k 11; and ketamine, 323 2 7; the rank order of
*
N
onvolatile anesthetic induction agents can cause cardiovascular depression in humans after intravenous administration (1-5). Decreased blood pressure with reflex tachycardia is
Supported in part by grants from the National Institutes of Health (HL 34708, HL01901), the American Heart Association, Wisconsin Affiliate (88-GA-06), and an Anesthesiology Research Training Grant (GM 08377). Preliminary reports appear in abstract form in Anesthesiology 1990;73:A589, and Anesth Analg 1991;72:S281. Accepted for publication December 10, 1991. Address correspondence to Dr. Stowe, MFRC, Room A1000, Medical College of Wisconsin, Milwaukee Regional Medical Center, 8701 West Watertown Plank Road, Milwaukee, WI 53226.
0003-2999/92/$5.00
potency was etomidate = propofol = midazolam > thiopental > ketamine; results were similar for LVP. At the 100 pM concentration, CF was decreased 11% 2 2% by ketamine and 5% t 3% by thiopental but was increased 17% 6% by etomidate, 21% k 5% by midazolam, and near maximally to 57% i- 10% by propofol; MVo, was decreased 8% -+ 4% by thiopental, 10% k 5% by ketamine, 19% 5% by midazolam, 29% 7% by etomidate, and 37% k 5% by propofol; oxygen deliveryiMVo, was unchanged by thiopental and ketamine but was increased 62% ? 7% by midazoiam, 71% k 9% by etomidate, and 150% -+ 15% by propofol. Between 100 pM and 1 mM, thiopental and ketamine did not increase CF but decreased MVo, and percent oxygen extraction, whereas propofol maximally increased CF and decreased MVo, and midazolam and etomidate had intermediate effects. These results indicate that on a molar basis, propofol, and less so midazolam and etomidate, depress cardiac function moderately more than thiopental and ketamine, and that propofol markedly attenuates autoregulation by causing coronary vasodilation. With doses used to induce anesthesia, propofol and thiopental appear to depress cardiac function more than ketamine or etomidate.
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(Anesth Analg 1992;74:547-58)
often observed. The degree of hypotension is dependent o n dose a n d speed of administration and appears to vary greatly among the commonly used drugs: thiopental, etomidate, midazolam, propofol, a n d ketamine. The variability in hypotension produced by these drugs could result from their variable effects o n peripheral arteriolar vasodilation a n d venodilation or from direct myocardial depression or both. The global cardiac mechanical effects of these five induction agents have not been compared in dosedependent fashion. Several mechanical models, i.e., isolated heart a n d papillary and ventricular muscle of various species (6-12), have been used to examine cardiac contractile effects of etomidate, midazolam,
Anesth Analg 1992;74:547-58
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548
STOWE ET AL DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
ketamine, and thiopental. There are only a few preliminary reports (13,14) on the direct in vitro effect of propofol on cardiac contractile function. No known reports have appeared that examine the isolated, dose-dependent effects of these induction agents simultaneously on myocardial excitability, contractility, coronary flow, and oxygen utilization. To determine differential depressant effects of these induction agents on global cardiac function, it is best to use a model in which mechanical function is unaffected by changes in diastolic volume, afterload impedance, autonomic nervous tone, and humoral factors. To adequately assess vasodilatory responses, maximal coronary reserve should be tested with a drug, i.e., adenosine, that can maximally increase coronary flow. Measurement of myocardial oxygen extraction in addition to coronary flow is necessary to elucidate the direct vasodilatory effect of the induction agents because these agents exert effects on cardiac work and metabolism. With the assumption that myocardial oxygen utilization reflects the contribution of autoregulatory factors, such as local metabolites, nutrients, and oxygen, to coronary blood flow (15), an imbalance of oxygen delivery relative to oxygen consumption reflects a change in coronary vascular tone. The isolated, perfused guinea pig heart model was used to examine changes in spontaneous heart rate, atrioventricular (AV) conduction time, isovolumetric left ventricular pressure (LVP) and its derivative, coronary flow, percent oxygen extraction, and the oxygen supply-to-demand ratio. The specific aims of this study were (a) to compare direct cardiac effects of increasing equimolar concentrations of etomidate, ketamine, midazolam, propofol, and thiopental on electrical and mechanical function and coronary flow; (b) to examine coronary flow responses as a function of maximal coronary reserve, as determined by adenosine administration; and (c) to examine the relative effectiveness of each of these agents on altering oxygen supply and myocardial oxygen demand. Our results demonstrate that although there are moderate quantitative differences in the effects of these drugs on electrical activity and myocardial contractility at equivalent molar concentrations, there are major differences in their effects on coronary flow and oxygen supply-to-demand ratios. Because of large differences in plasma concentrations required for induction of anesthesia, caution must be exercised in extrapolating these results to clinical situations.
Methods Approval from the institutional Animal Studies Committee was obtained before initiation of this study. Isolation and preparation of hearts as used for this
ANESTH ANALG 1992;74:547-58
study have been detailed in recent reports (16,17). Fifty-five hearts were prepared and perfused at an aortic root perfusion pressure of 55 mm Hg. The perfusate, a modified Krebs-Ringer salt solution was filtered (5-pm pore size) in-line (Astrodisc, Gelman Scientific, Ann Arbor, Mich.) and had the following composition (in mM): Na+ 137, K+ 4.5, Mg2+ 1.2, Ca2+ 2.5, C1- 134, HC0,- 15.5, H,PO,- 1.2, glucose 11.5, pyruvate 2, mannitol 16, ethylenediaminetetraacetic acid (EDTA) 0.05, and insulin 5 U/L. Perfusate and bath temperature were maintained at 37 t 0.3"C. Each perfusate solution was equilibrated with a gas mixture of 96% 0, + 4% CO, at a flow rate of 3 Limin. Spontaneous atrial rate, AV conduction time, and systolic left ventricular pressure (LVP) and its derivative were measured as detailed previously (16,17). Hearts were also paced at 240 beats/min for 1 min during each experimental maneuver to examine changes in AV conduction time at a constant atrial rate. Coronary (retrograde aortic) inflow was measured electromagnetically as detailed previously (16,17). Adenosine (0.2 mL of a 2 mM solution) was injected into the aortic (coronary perfusion) cannula before and after drug administration to assess maximal coronary flow as an index of abolition of coronary autoregulation. Coronary inflow and outflow (coronary sinus) 0, tensions (mm Hg) were measured continuously on-line and verified off-line as described in detail previously (16,17). Oxygen delivery, percent oxygen extraction, and myocardial oxygen consumption were calculated as noted previously (16,17). All drugs were obtained commercially in their vehicles (etomidate, 2 mg/mL; ketamine, 100 mg/mL; midazolam, 5 mgimL; propofol, 10 mg/mL; and thiopental, powder). Each drug was diluted in KrebsRinger perfusate to make 5 mM solutions that were divided into 50-mL aliquots, frozen at -15"C, and thawed for daily use. Vehicle preparations (etomidate, 350 mg/mL propylene glycol in H,O; ketamine, 0.8% NaCl; midazolam, 0.01% disodium edetate and 1%benzyl alcohol in H,O, adjusted to pH of 3 with 0.1 N HC1; propofol, Intralipid, i.e., soybean oil 100 mgimL + glycerol 22.5 mg/mL + egg lecithin 12 mgimL in H,O; thiopental, 0.8% NaCl) were also prepared and administered in some hearts at the same concentrations corresponding to the three highest drug concentrations given in this study (250, 500, and 1000 pM). Measured volumes of the 5 mM concentration of each drug or its vehicle were diluted into a known volume of perfusate to obtain perfusate drug concentrations of 0.5, 1, 5, 10, 50, 100, 250, 500, and 1000 pM. The vehicles for each drug, except midazolam, had no effect on the measured variables. Only the vehicle concentration corresponding to 1000 pM midazolam, 0.18% benzyl alcohol, decreased LVP
STOWE ET AL. DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
ANESTH ANALG 1992:74:347-58
and its peak derivatives approximately 25%. This effect of the vehicle was not subtracted from the drug effects as displayed in the results because these variables were nearly maximally depressed by 1000 pM midazolam. Hearts prepared for this study were randomly assigned to one of five groups: etomidate ( n = ll), ketamine ( n = ll),midazolam ( n = ll),propofol ( n = ll), or thiopental ( n = 11). In four hearts of each group, the vehicle for a given drug was also administered either before or after the drug. After a 30-min period of stabilization (initial control), each heart was perfused with the selected drug administered in increasing concentrations from 0.5 to 1000 pM for 10 min at each concentration to obtain steady-state dose-dependent responses. Between drug concentrations of 50 and 100 pM and after 1000 pM, a 20-min drug-free control period was allowed to assess return of variables to the initial control level. Measurements were recorded during the last minute of the 30-min initial control period (control l), the last minute of each drug concentration, and the last minute of the final 20-min postcontrol period (control 2). Adenosine was injected into the inflow perfusate during the initial and final control periods. For all hearts mean coronary arterial (inflow) pH was 7.44 0.01 (SEM), Pco, was 28 2 1 mm Hg, and Po, was 523 ? 12 mm Hg; there were no significant differences among the five groups. All data are expressed as mean ? standard error of the mean (SEM). Mean values were considered significant at P < 0.05. Within-group (concentration effects) and among-group (drug effects) comparisons were made. Within-group comparisons assessed the dose-dependent effect of the individual drug groups for the change in a given variable from the lowest concentration (0.5 pM) of the drugs that produced no effects. Analysis of variance with repeated measures was used to determine significance; if the F test was significant, Fisher’s least significant difference test was used to compare means (Statview, Abacus Concepts, Calabasas, Calif.). These concentration-dependent effects are detailed statistically in Tables 1 and 2. Among-group comparisons assessed the differential effects of one drug with the other drugs at a given concentration only. Statistical differences among the five drug groups were determined on the change from the initial control for each variable by two-way analysis of variance and means comparison tests (CLR ANOVA, Clear Lake Research, Houston, Tex.). A complete comparison of significance tests among the five groups for a given variable at a given concentration is displayed in Table 3 where the plus sign denotes significance and the zero sign denotes nonsignificance. Significance for the incidence of AV dissociation (Figure 1) was determined by ,$-analysis.
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549
Software programs were run on a computer (Macintosh SE30 computer, Apple Computer, Cupertino, Calif .). In addition, for the variables of LVP (Figure 2) and its maximal positive derivative (Figure 3), sigmoidal dose-response curves were plotted for the five drugs. The curves were best fitted using a four-parameter logistic equation and were statistically compared simultaneously (Allfit, version 2.7, Laboratory of Theoretical and Physical Biology, National Institutes of Health, Bethesda, Md.). Maximal responses were considered to be the drug-free control; minimal responses were assumed to be 0% of control. The molar concentration of each drug that depressed these variables to 50% of the initial control (EC,,) was determined from the fitted curves. Statistical differences among the EC,, values were determined by analysis of variance and means comparison tests. The multiple of peak free concentration of each drug that might be expected to decrease cardiac contractility by 50% was estimated as the individual EC,, values for +dLVP/dt,,, divided by published values for peak plasma concentrations in vivo. Similarly, the multiple of peak free concentration of each drug that might be expected to increase coronary flow to 50% of the maximum response to adenosine was estimated as the individual 50% response to the initial dose of adenosine divided by published values for peak plasma concentrations in vivo.
Results Efectrophysiologzc and Mechanical Function Table 1 displays average effects and significance of increasing concentrations of individual induction agents on cardiac electrophysiologic and mechanical variables. Statistical comparisons among the induction agents at equimolar concentrations for each variable are summarized in Table 3. The 0.5 pM concentration of each drug produced no change in any variable compared to the initial control values. Intrinsic sinoatrial rate was unaffected by concentrations of these drugs lower than 100 pM, except for propofol, which decreased heart rate at concentrations greater than 5 pM. Etomidate (1000 pM) and propofol(500 and 1000 pM)caused sinus arrest in all hearts. Propofol depressed heart rate more than the other drugs at equimolar concentrations between 5 and 100 pM (Table 3). Atrioventricular conduction time during atrial pacing at 240 beatslmin was unaffected by each drug below 250 pM, with the exception of 50 and 100 pM propofol and 100 pM midazolam, which significantly increased AV time. Propofol (100 pM) increased AV time more than the other agents; 250 pM concentrations of each drug, except ketamine, increased AV
550
STOWE ET AL. DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
ANESTH ANALG 1992:74:547-58
Table 1. Effects of Equimolar Concentrations of Anesthetic Induction Drugs on Cardiac Rate, Conduction, and Mechanical Function
PM
Drug
HR (bea tslmin)
0.5 0.5 0.5 0.5 0.5
E tomida te Ketamine Midazolam Propofol Thiopental
210 215 201 205 204
1 1
t4
t6 t5 t 5
74 72 74 71 77
Etomidate Ketarnine Midazolam Propofol Thiopental
209 + 7 210 t 8 199 t 6 205 + 4 200 t 5
76 72 74 71 77
+4
211 f 7 207 + 8 196 t 5 196 + 5 200 + 5
76 74 71 72 77
+3
5
Etomidate Ketamine Midazolam Propofol Thiopen tal
10 10 10 10 10
Etornidate Ketarnine Midazolarn Propofol Thiopen tal
211 + 7 204 t 9 189 + 6 191 t 5" 199 + 5
50 50 50 50 50
Etomidate Ketamine Midazolam Propofol Thiopental
207 197 190 179 194
100 100 100 100 100
Etomidate Ketarnine Midazolam Propofol Thiopental
195 t 186 t 168 t 158 t 187 t
250 250 250 250 250
Etomidate Ketamine Midazolam Propofol Thiopental
162 t 7'' 173 t 9" 144 t 9" 141 f 2'' 146 t 5"
9 1 + 5" 78 + 6 97 t 4l
500 500 500 500 500
Etomidate Ketarnine Midazolam Propofol Thiopental
121 t 12" 140 t 9" 128 t 10"
93 t (Y' 89 t 4 l 123 t 7'
SA arrest 129 t 5''
AVD AVD
1000 1000 1000 1000 1000
Etornidate Ketamine Midazolam Propofol Thiopental
SA arrest 105 t 7'' 130 t 12'' SA arrest 103 t 14"
PC PC PC PC PC
Etomidate Ketarnine Midazolarn
225 205 205 178 213
1 1 1
5 5 5 5
Propofol Thiopental
t 7 t8
AV time (ms)
t 7
t9 t6 + 7" t4
7" 9" 6'' 6"
4"
t7 t8 t7 t 7'' t5
LVP
(mm Hg) 93 97 106 97 93
t8 t6 t6
92 95 105 98 92
t 7
+3 +2 +3
t7 t6
+3
97 95 97 96 89
76 75 75 73 78
t3 t3 t2 2 3 +3
85 90 89 93 86
t7 t6 t 4"
77 77 75 76 78
f
3
78 78 84 95 79
f
t4 t3 t2 t3 t t t t
3 3 2 3
f3 f2
+ 3l t3
2
t4 t 2" t4 1
t3
AVD 93 t 4"
t 0.01 t 0.02 t 0.11 t 0.09 t 0.14
1.88 1.86 2.04 1.73 1.83
2.12 2.28 2.24 2.03 2.00
t 0.15 t 0.11 t 0.15 f 0.11 + 0.18
1.86 t 0.09 1.89 f 0.08 1.95 + 0.10 1.71 t 0.10 1.68 t 0.15
2.01 2.30 1.86 1.97 1.95
?
0.15 t 0.09" t 0.13" t 0.12 t 0.15
1.82 1.88 1.82 1.67 1.74
k 0.08 t 0.10 t 0.10 k 0.09 t 0.17
1.71 1.83 1.58 1.62 1.73
t 0.08 t 0.09
t9
1.91 + 0.15 2.16 -1- 0.10 1.86 t 0.10'' 1.85 t 0.12" 1.92 + 0.15
64 84 76 75 73
t 5" t 51' t 4" t 8" t 8"
1.35 t 0.09" 1.85 t 0.12" 1.50 t 0.10" 1.28 t 0.09" 1.55 t 0.15"
1.29 t 0.06" 1.68 t 0.08" 1.35 t 0.06" 1.28 + 0.06' 1.41 t 0.12''
41 77 49 46 62
t 4"
0.92 + 1.68 t 1.01 t 0.92 t 1.31 t
0.90 1.52 0.91 0.93 1.19
t8 t9 t6 t5 t8 t9
t5 t9 t9
2 9
t 4'' t 3" ? 6" 2 7"
11 t 2" 63 2 6" 28 2 5'' 17 t 9" 32 t 5"
5 t 2" 39 18 0 17
t 4"
t 2" t 0" 2 2"
AVD
0 t 0" 17 t 3" 5 I 2" 0 t 0" 2 t 1"
74 72 74 76 74
+4 t2 t2
t3 t3
-dLVPIdt (mm Hgis) ( X 1000)
2.07 2.20 2.28 1.98 2.05
114 t 6 '
AVD AVD AVD
+ dLVPIdt (mm Hgls) ( X 1000)
86 88 104 98 82
t7 t6
4 t 10 9 2
0.07" 0.09" 0.06" 0.09" 0.12"
t 0.09 t 0.09 t 0.15 t 0.10 + 0.13
+ 0.07b t 0.09 t 0.13
t 0.06' 0.06" t 0.06" t 0.09" t 0.10"
+
0.41 t 0.06" 1.19 + 0.13" 0.62 t 0.09" 0.29 t 0.09" 0.77 + 0.09"
0.39 t 0.05' 0.86 t 0.06" 0.57 t 0.09" 0.27 k 0.09' 0.71 ? 0.07"
0.20 0.74 0.51 0.14 0.45
t t t t t
0.03'' 0.09" 0.07" 0.02" 0.07"
0.18 0.77 0.44 0.14 0.44
0.09 0.38 0.21 0.14 0.18
?
0.05"
t 0.02" t 0.06"
0.06 t 0.03" 0.38 t 0.05" 0.17 t 0.04" 0.12 ? 0.02" 0.17 f 0.06"
1.97 t 0.17 2.12 t 0.09 2.21 t 0.12 2.00 t 0.17 1.91 t 0.17
1.71 0.12 1.80 + 0.07 1.86 t 0.09 1.62 t 0.13 1.68 t 0.17
t 0.06" t 0.07"
t 0.03" t 0.07" 2 0.06" t 0.02" f 0.07"
+
HR, intnnsic heart rate in beatsimin; AV, atrioventricular conduction; LVP, isovolumetric left ventncular pressure; +dLVP/dt, maximal positive derivative of left ventricular pressure, -dLVP/dt, maximal negative derivahve of left ventricular pressure; PC, postconmil; AVD, atrioventricular dissociation; SA, sinoatrial. Data are mean 2 S E K All data except intrinsic heart rate were obtained during atrlal pacing at 240 h e a t s h i n . ","For each variable, significance is shown hv increase ( a ) and decrease ((7) i o r changes from the lowest concentration (0.5 pM) of a given drug. See Table 3 for statistical comparisons among drugs at a given concentration.
STOWE ET AL. DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
ANESTH ANALG 1992;74:547-58
551
Table 2. Effects of Equimolar Concentrations of Anesthetic Induction Drugs on Coronary Flow a n d Oxygen Utilization PM
Drug
Cor flow (mt.min-'.g-')
Po, cs (mm Hg)
MVo, (,.&min-'.g
181 t 15 185 f 20 177 t 11 157 ? 19 179 t 14
(% )
Do,/MVo,
43 t 4 45 2 1 55 t 4 41 2 3 42 f 3
64.5 t 3.8 63.8 t 4.0 67.2 t 1.8 69.4 t 4.1 65.4 t 2.8
1.61 t 0.11 1.63 2 0 . 1 1 1.50 t 0.05 1.49 t 0.10 1.55 2 0.07
67.5 t 3.8 67.7 23.5" 64.9 t 1.9 71.2 t 3.5 69.6 f 2.0"
1.53 t 0.10 1.52 t 0.09" 1.55 t 0.05 1.43 t 0.07 1.45 t 0.04" 1.51 t 0.09 1.60 t 0.10 1.56 t 0.04 1.47 t 0.08 1.45 t 0.04"
8.2 t 0.8"
0.5 0.5 0.5 0.5 0.5
Adenosine (all groups) Etomidate Ketamine Midazolam Propofol Thiopental
4.7 5.5 5.2 4.4 4.5
1 1 1 1 1
Etomidate Ketamine Midazolam Propofol Thiopental
4.6 ? 0.5 5.2 t 0.5 5.1 t 0.4 4.1 ? 0.5 4.1 t 0.3"
167 t 165 t 189 t 148 2 158 t
14 17" 10 16 11"
42 46 50 40 40
t4 t5
5 5 5 5 5
Etomidate Ketamine Midazolam Propofol Thiopental
4.6 4.9 5.5 4.1 4.1
t 0.4
165 t 181 t 191 t 165 t 160 t
14 18 10 18 10"
42 43 53 41 40
2
10 10 10 10 10
Etomidate Ketamine Midazolam Propofol Thiopental Etomidate Ketamine Midazolam Propofol Thiopental
4.6 5.0 5.6 4.3 4.1
t 0.4
50 50 50 50 50
100 100 100 100 100 250 250 250 250 250 500 500 500 500 500 1000 1000 1000 1000 1000 PC PC PC PC
rc
0, extraction I)
t 0.5 t 0.5 ?
0.5
t 0.6 t 0.4
t3
t3 t2
4
3
67.9 t 3.7 64.7 t 3.8 64.6 t 1.6 69.7 t 3.8 69.2 f 2.0"
0.4" t 0.5" t 0.5 t 0.3"
172 2 12 168 t 16 219 t 11" 166 t 15 154 t 9"
43 t 3 43 t 4 49 2 3 40 t 4 41 f 3
66.6 t 3.1 67.3 t 3.3 59.4 t 2.4" 67.7 2 3.4 69.9 t 1.V
1.53 t 0.07 1.52 ? 0.08 1.72 t 0.08' 1.51 t 0.08 1.44 t 0.04"
5.2 t 0.5" 4.9 t 0.5'' 5.8 t 0.4" 5.6 t 0.7" 4.3 t 0.4
214 ? 20" 184 2 2 0 218 t 12z 229 t 19" 170 t 15
42 2 5 42 t 4 49 i 3 44 t 5 40 f 3
58.0 64.1 59.4 57.7 66.9
t 4.3" t 3.0
1.99 t 0.30" 1.63 t 0.11 1.71 t 0.07" 1.82 t 0.16" 1.53 t 0.07
Etomidate Ketamine Midazolam Propofol Thiopen tal
5.5 t 0.5" 4.9 t 0.5" 6.8 t 0 . F 6.7 ? 0.8z 4.3 t 0.4
279 f 21" 186 t 25 293 ? 16l 301 t 14l 167 t 14
33 40 44 38 39
t 4" t3
45.6 ? 5.2" 63.5 t 5.4 45.5 2 3.5" 42.8 t 3.2" 67.5 2 2.6
2.50 20.30' 1.71 t 0.18 2.39 2 0.29" 2.46 t 0.21" 1.51 t 0.06
Etomidate Ketamine Midazolam Propofol Thiopental
5.6 4.9 6.5 7.0 4.5
318 t 17'' 192 t 27 327 t 24l 344 t 132 209 2 2 0 "
28 40 39 35 34
t 3"
6'' 6" t 3"
39.0 60.0 40.3 34.3 59.6
4.0"
2.82 t 0.33' 1.88 f 0.20 2.90 ? 0.29' 3.14 t 0.39' 1.74 t 0.13"
Etomidate Ketamine Midazolam Propofol Thiopental Etomidate Ketamine Midazolam Propofol Thiopental Etomidate Ketamine Midazolam Propofol Thiopental
6.3 2 0.7" 5.2 t 0.6 6.7 t 0.8" 7.4 t 0.9" 4.8 t 0.5
346 t 1 2 I 239 t 2 9 355 t 22' 343 I 16' 243 t 20"
29 34 31 32 35
3'' t 3" t 3" t 5" t 4"
34.3 t 3.1'' 53.6 t 6.0" 34.1 2 4 . 2 " 33.4 t 3.9" 53.3 t 3.7"
3.23 t 0.45" 2.14 t 0.29" 3.58 20.63" 3.69 ? 0.72" 1.96 f 0.15"
6.3 ? 0.7" 5.6 f 0.7 7.2 t 1.0: 7.4 I 1.02 5.0 t 0.6
348 t 14l 281 t 29" 371 ? 20' 343 ? 16z 275 t 197
29 31 31 32 31
2
34.2 45.3 31.2 33.4 46.6
t 3.9" t 3.9"
3.25 f 0.45'' 2.81 f 0.58" 3.82 2 0.73" 3.69 t 0.72l 2.30 f 0.21"
4.2 4.5 5.1 3.7 3.9
170 t 7 147 t 14" 157 t 8" 137 t 13 146 t 9"
42 t 3 45 2 4 55 2 4 40 t 6 41 ? 4
68.9 t 1.8 71.4 t 2.5z 70.9 t 1.3 75.4 t 2.2 75.3 f 1.8"
1.46 f 0.03 1.42 f 0.05" 1.41 t 0.03 1.33 f 0.04 1.34 +- 0.03"
Adenosine (all groups)
i 0.4" ?
0.4
t 0.5 t 0.3" 2
i 0.5" t 0.5" t
0.67
t 0.8' 2
0.4
t 0.4 t t t t
0.4" 0.4 0.4 0.3"
t4 t4
t3 2
2
3"
t5 t4 t5 f
2
t
3"
t 3" t 3"
t 5" t 3"
t 5.9" t 4.2 t 2.5"
t 4.1'' t 5.4 t 4.3"
t 2.6" f
t 3.1''
t 6.0"
24.0"
7.5 t 0.9"
Cor, coronary; CS, coronary sinus; MVo,, myocardial oxygen consumption; Do,, oxygen delivery; PC, postcontrol. ?I = 11 hearts per anesthetic group. Data are mean t SEM. Adenosine was injected into the aortic cannula to measure maximal flow responses before and after drug treatment. All data were obtained during atrial pacing at 240 beatsimin. "."For each variable, significance is shown by increase (a) and decrease ( b ) for changes from the lowest concentration (0.5 pM) of a given drug. See Table 3 for statistical comparisons among drugs at a given concentration.
552
ANESTH ANALC 1992;74:547-58
STOWE ET AL DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
Table 3. Statistical Comparisons of Five Anesthetic Induction Drugs at Equimolar Concentrations on Cardiac Variables AV conduction time
Heart rate , E K M P E -- o o o K O - - o o M o o -- o P 0 0 0 -T o o o o
lw
T
o o
o OSpM 0
.-
E , - E- Ko M o Po K O - 0 o M o o ~- 0 P 0 0 0 -T o o o o 1 PM
E K M P T E K - - + o + oF M + o -- o o 5 p M P + o o - - + T O O ~ + - 10 ClM
-
LV pressure
E , --E oK oM aP K O - 0 o M + o -- o P 0 0 + - T o o o o lw
oT o
o O.5pM
E v
500 pM
M + + -- + + 5~ P o o + - - 0 T o o + o - IOpM
rK M P - + o o - - 0 0 o -- + + o - oMooVMo
Do, IMVo,
r-
E K M P T
E K M P T
E K M E -- o o K O --o M o o -P 0 0 0 T o oIpM o
P o o o - - 0 T l o o o o -IpM
0 .
E K M P T
E + o o o
7c O2 extraction
MVo,
E K M P T
E K M P T
P T
o o o o o o 0.5pM
--
0
o --
E K M P T
E K M P T
w
E K M P T
o o o - - 0 o o o o - postwnrml
0.5pM
0
M o o ~- o o 5 p M P 0 0 0 -- 0 T o o o o -10
E K M P T
,E K M P T -- o o o o O --o a o o o -- o o I W p M
0
E K M P T
E K M P T E - - + o + o K + -- o o o
E K M P T
To
o
Table 3. Continued
T + 0 + 250pM 0 --
,E K M P T E - - o o o o K O - - 0 0 0 M o o -- 0 o IWOpM P o o o - - 0 T o o o o - postcontrol
E K M P T
5M pM
E K M P T
,E O o O o
K M P T - + o o o - - + + + o -- o o I W O w O O - - 0 o o o - poslcontrol
10 pM
10 pM
rr-
E K M P T
E K M P T E - - o o o o K O --o o o M o o -- o o MpM P 0 0 0 -- 0 T + o +pM o - -
E K M P T
E -O o
K M o o - - 0 o --
0
0
P T + + 0 0 o o 2MpM
‘r
100 p M
100 rrM
E K M P T
E K M P T
+ .- 0
w
o o5 M+ o - -
500 pM
E K M P T
El-- o o o o K M P T
E K M P
O o o o
- - o o -o o o o
o o
o o 1000pM - 0 o -
E El-K O M o P 0 T o
K M P + o o - - + + o -- o 0 0 - o o o -
T
+ o +
1WOpM
+ -
E K M P T
rE O o
K M - o o - - + o --
P T o + + o o + LWOpM 0 0 0 -- + o opostcontrol o o - -
Each drug IS compared against the others for the change in a givcn ariable f r o m the initial control at a given concentration. The right and bottom concentrations reter to significance to the right and to the left of the diagonal ( i h l i c s ) , respectively P i 0.05 = +; P > 0.05 = o (nonsignificant). E, etomidate; K, ketamine; M, rnidazolarn; P, propofol; T, thiopental; AV, atrioventricular; LL’, left ventricular; MVo,, myocardial oxygen consumptlOI1, DO?, 10.
MD, PhD,
Zeljko J. Bosnjak, PhD, and John P. Kampine,
MD, PhD
Anesthesiology Research Laboratory, Departments of Anesthesiology and Physiology, The Medical College of Wisconsin, and the Veterans Affairs Medical Center, Milwaukee, Wisconsin
The authors examined direct myocardial and coronary vascular responses to the anesthetic induction agents etomidate, ketamine, midazolam, propofol, and thiopental and compared their effects on attenuating autoregulation of coronary flow as assessed by changes in oxygen supplyidemand relationships. Spontaneous heart rate, atrioventricular conduction time during atrial pacing, left ventricular pressure (LVP),coronary flow (CF), percent oxygen extraction, oxygen delivery, and myocardial oxygen consumption (MVo,) were examined in 55 isolated guinea pig hearts divided into five groups of 11 each. Hearts were perfused at constant pressure with one of the drugs administered at steady-state concentrations increasing from 0.5 pM to 1 mM. Adenosine was given to test maximal CF. At concentrations below 10 pM no significant changes were observed; beyond 50 pM for midazolam, etomidate, and propofol, and 100 pM for thiopental and ketamine, each agent caused progressive but differential decreases in heart rate, atrioventricular conduction time’ (leading to atrioventricular dissociation), LVP, +dLVPidt,,,, percent oxygen extraction, and MVo,. The concentrations (pM) at which +dLVPidt,,, was reduced by 50% were as follows: etomidate, 82 t 2 (mean t SEM); propofol, 91 ? 4; midazolam, 105 8; thiopental, 156 k 11; and ketamine, 323 2 7; the rank order of
*
N
onvolatile anesthetic induction agents can cause cardiovascular depression in humans after intravenous administration (1-5). Decreased blood pressure with reflex tachycardia is
Supported in part by grants from the National Institutes of Health (HL 34708, HL01901), the American Heart Association, Wisconsin Affiliate (88-GA-06), and an Anesthesiology Research Training Grant (GM 08377). Preliminary reports appear in abstract form in Anesthesiology 1990;73:A589, and Anesth Analg 1991;72:S281. Accepted for publication December 10, 1991. Address correspondence to Dr. Stowe, MFRC, Room A1000, Medical College of Wisconsin, Milwaukee Regional Medical Center, 8701 West Watertown Plank Road, Milwaukee, WI 53226.
0003-2999/92/$5.00
potency was etomidate = propofol = midazolam > thiopental > ketamine; results were similar for LVP. At the 100 pM concentration, CF was decreased 11% 2 2% by ketamine and 5% t 3% by thiopental but was increased 17% 6% by etomidate, 21% k 5% by midazolam, and near maximally to 57% i- 10% by propofol; MVo, was decreased 8% -+ 4% by thiopental, 10% k 5% by ketamine, 19% 5% by midazolam, 29% 7% by etomidate, and 37% k 5% by propofol; oxygen deliveryiMVo, was unchanged by thiopental and ketamine but was increased 62% ? 7% by midazoiam, 71% k 9% by etomidate, and 150% -+ 15% by propofol. Between 100 pM and 1 mM, thiopental and ketamine did not increase CF but decreased MVo, and percent oxygen extraction, whereas propofol maximally increased CF and decreased MVo, and midazolam and etomidate had intermediate effects. These results indicate that on a molar basis, propofol, and less so midazolam and etomidate, depress cardiac function moderately more than thiopental and ketamine, and that propofol markedly attenuates autoregulation by causing coronary vasodilation. With doses used to induce anesthesia, propofol and thiopental appear to depress cardiac function more than ketamine or etomidate.
*
*
*
(Anesth Analg 1992;74:547-58)
often observed. The degree of hypotension is dependent o n dose a n d speed of administration and appears to vary greatly among the commonly used drugs: thiopental, etomidate, midazolam, propofol, a n d ketamine. The variability in hypotension produced by these drugs could result from their variable effects o n peripheral arteriolar vasodilation a n d venodilation or from direct myocardial depression or both. The global cardiac mechanical effects of these five induction agents have not been compared in dosedependent fashion. Several mechanical models, i.e., isolated heart a n d papillary and ventricular muscle of various species (6-12), have been used to examine cardiac contractile effects of etomidate, midazolam,
Anesth Analg 1992;74:547-58
547
548
STOWE ET AL DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
ketamine, and thiopental. There are only a few preliminary reports (13,14) on the direct in vitro effect of propofol on cardiac contractile function. No known reports have appeared that examine the isolated, dose-dependent effects of these induction agents simultaneously on myocardial excitability, contractility, coronary flow, and oxygen utilization. To determine differential depressant effects of these induction agents on global cardiac function, it is best to use a model in which mechanical function is unaffected by changes in diastolic volume, afterload impedance, autonomic nervous tone, and humoral factors. To adequately assess vasodilatory responses, maximal coronary reserve should be tested with a drug, i.e., adenosine, that can maximally increase coronary flow. Measurement of myocardial oxygen extraction in addition to coronary flow is necessary to elucidate the direct vasodilatory effect of the induction agents because these agents exert effects on cardiac work and metabolism. With the assumption that myocardial oxygen utilization reflects the contribution of autoregulatory factors, such as local metabolites, nutrients, and oxygen, to coronary blood flow (15), an imbalance of oxygen delivery relative to oxygen consumption reflects a change in coronary vascular tone. The isolated, perfused guinea pig heart model was used to examine changes in spontaneous heart rate, atrioventricular (AV) conduction time, isovolumetric left ventricular pressure (LVP) and its derivative, coronary flow, percent oxygen extraction, and the oxygen supply-to-demand ratio. The specific aims of this study were (a) to compare direct cardiac effects of increasing equimolar concentrations of etomidate, ketamine, midazolam, propofol, and thiopental on electrical and mechanical function and coronary flow; (b) to examine coronary flow responses as a function of maximal coronary reserve, as determined by adenosine administration; and (c) to examine the relative effectiveness of each of these agents on altering oxygen supply and myocardial oxygen demand. Our results demonstrate that although there are moderate quantitative differences in the effects of these drugs on electrical activity and myocardial contractility at equivalent molar concentrations, there are major differences in their effects on coronary flow and oxygen supply-to-demand ratios. Because of large differences in plasma concentrations required for induction of anesthesia, caution must be exercised in extrapolating these results to clinical situations.
Methods Approval from the institutional Animal Studies Committee was obtained before initiation of this study. Isolation and preparation of hearts as used for this
ANESTH ANALG 1992;74:547-58
study have been detailed in recent reports (16,17). Fifty-five hearts were prepared and perfused at an aortic root perfusion pressure of 55 mm Hg. The perfusate, a modified Krebs-Ringer salt solution was filtered (5-pm pore size) in-line (Astrodisc, Gelman Scientific, Ann Arbor, Mich.) and had the following composition (in mM): Na+ 137, K+ 4.5, Mg2+ 1.2, Ca2+ 2.5, C1- 134, HC0,- 15.5, H,PO,- 1.2, glucose 11.5, pyruvate 2, mannitol 16, ethylenediaminetetraacetic acid (EDTA) 0.05, and insulin 5 U/L. Perfusate and bath temperature were maintained at 37 t 0.3"C. Each perfusate solution was equilibrated with a gas mixture of 96% 0, + 4% CO, at a flow rate of 3 Limin. Spontaneous atrial rate, AV conduction time, and systolic left ventricular pressure (LVP) and its derivative were measured as detailed previously (16,17). Hearts were also paced at 240 beats/min for 1 min during each experimental maneuver to examine changes in AV conduction time at a constant atrial rate. Coronary (retrograde aortic) inflow was measured electromagnetically as detailed previously (16,17). Adenosine (0.2 mL of a 2 mM solution) was injected into the aortic (coronary perfusion) cannula before and after drug administration to assess maximal coronary flow as an index of abolition of coronary autoregulation. Coronary inflow and outflow (coronary sinus) 0, tensions (mm Hg) were measured continuously on-line and verified off-line as described in detail previously (16,17). Oxygen delivery, percent oxygen extraction, and myocardial oxygen consumption were calculated as noted previously (16,17). All drugs were obtained commercially in their vehicles (etomidate, 2 mg/mL; ketamine, 100 mg/mL; midazolam, 5 mgimL; propofol, 10 mg/mL; and thiopental, powder). Each drug was diluted in KrebsRinger perfusate to make 5 mM solutions that were divided into 50-mL aliquots, frozen at -15"C, and thawed for daily use. Vehicle preparations (etomidate, 350 mg/mL propylene glycol in H,O; ketamine, 0.8% NaCl; midazolam, 0.01% disodium edetate and 1%benzyl alcohol in H,O, adjusted to pH of 3 with 0.1 N HC1; propofol, Intralipid, i.e., soybean oil 100 mgimL + glycerol 22.5 mg/mL + egg lecithin 12 mgimL in H,O; thiopental, 0.8% NaCl) were also prepared and administered in some hearts at the same concentrations corresponding to the three highest drug concentrations given in this study (250, 500, and 1000 pM). Measured volumes of the 5 mM concentration of each drug or its vehicle were diluted into a known volume of perfusate to obtain perfusate drug concentrations of 0.5, 1, 5, 10, 50, 100, 250, 500, and 1000 pM. The vehicles for each drug, except midazolam, had no effect on the measured variables. Only the vehicle concentration corresponding to 1000 pM midazolam, 0.18% benzyl alcohol, decreased LVP
STOWE ET AL. DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
ANESTH ANALG 1992:74:347-58
and its peak derivatives approximately 25%. This effect of the vehicle was not subtracted from the drug effects as displayed in the results because these variables were nearly maximally depressed by 1000 pM midazolam. Hearts prepared for this study were randomly assigned to one of five groups: etomidate ( n = ll), ketamine ( n = ll),midazolam ( n = ll),propofol ( n = ll), or thiopental ( n = 11). In four hearts of each group, the vehicle for a given drug was also administered either before or after the drug. After a 30-min period of stabilization (initial control), each heart was perfused with the selected drug administered in increasing concentrations from 0.5 to 1000 pM for 10 min at each concentration to obtain steady-state dose-dependent responses. Between drug concentrations of 50 and 100 pM and after 1000 pM, a 20-min drug-free control period was allowed to assess return of variables to the initial control level. Measurements were recorded during the last minute of the 30-min initial control period (control l), the last minute of each drug concentration, and the last minute of the final 20-min postcontrol period (control 2). Adenosine was injected into the inflow perfusate during the initial and final control periods. For all hearts mean coronary arterial (inflow) pH was 7.44 0.01 (SEM), Pco, was 28 2 1 mm Hg, and Po, was 523 ? 12 mm Hg; there were no significant differences among the five groups. All data are expressed as mean ? standard error of the mean (SEM). Mean values were considered significant at P < 0.05. Within-group (concentration effects) and among-group (drug effects) comparisons were made. Within-group comparisons assessed the dose-dependent effect of the individual drug groups for the change in a given variable from the lowest concentration (0.5 pM) of the drugs that produced no effects. Analysis of variance with repeated measures was used to determine significance; if the F test was significant, Fisher’s least significant difference test was used to compare means (Statview, Abacus Concepts, Calabasas, Calif.). These concentration-dependent effects are detailed statistically in Tables 1 and 2. Among-group comparisons assessed the differential effects of one drug with the other drugs at a given concentration only. Statistical differences among the five drug groups were determined on the change from the initial control for each variable by two-way analysis of variance and means comparison tests (CLR ANOVA, Clear Lake Research, Houston, Tex.). A complete comparison of significance tests among the five groups for a given variable at a given concentration is displayed in Table 3 where the plus sign denotes significance and the zero sign denotes nonsignificance. Significance for the incidence of AV dissociation (Figure 1) was determined by ,$-analysis.
*
549
Software programs were run on a computer (Macintosh SE30 computer, Apple Computer, Cupertino, Calif .). In addition, for the variables of LVP (Figure 2) and its maximal positive derivative (Figure 3), sigmoidal dose-response curves were plotted for the five drugs. The curves were best fitted using a four-parameter logistic equation and were statistically compared simultaneously (Allfit, version 2.7, Laboratory of Theoretical and Physical Biology, National Institutes of Health, Bethesda, Md.). Maximal responses were considered to be the drug-free control; minimal responses were assumed to be 0% of control. The molar concentration of each drug that depressed these variables to 50% of the initial control (EC,,) was determined from the fitted curves. Statistical differences among the EC,, values were determined by analysis of variance and means comparison tests. The multiple of peak free concentration of each drug that might be expected to decrease cardiac contractility by 50% was estimated as the individual EC,, values for +dLVP/dt,,, divided by published values for peak plasma concentrations in vivo. Similarly, the multiple of peak free concentration of each drug that might be expected to increase coronary flow to 50% of the maximum response to adenosine was estimated as the individual 50% response to the initial dose of adenosine divided by published values for peak plasma concentrations in vivo.
Results Efectrophysiologzc and Mechanical Function Table 1 displays average effects and significance of increasing concentrations of individual induction agents on cardiac electrophysiologic and mechanical variables. Statistical comparisons among the induction agents at equimolar concentrations for each variable are summarized in Table 3. The 0.5 pM concentration of each drug produced no change in any variable compared to the initial control values. Intrinsic sinoatrial rate was unaffected by concentrations of these drugs lower than 100 pM, except for propofol, which decreased heart rate at concentrations greater than 5 pM. Etomidate (1000 pM) and propofol(500 and 1000 pM)caused sinus arrest in all hearts. Propofol depressed heart rate more than the other drugs at equimolar concentrations between 5 and 100 pM (Table 3). Atrioventricular conduction time during atrial pacing at 240 beatslmin was unaffected by each drug below 250 pM, with the exception of 50 and 100 pM propofol and 100 pM midazolam, which significantly increased AV time. Propofol (100 pM) increased AV time more than the other agents; 250 pM concentrations of each drug, except ketamine, increased AV
550
STOWE ET AL. DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
ANESTH ANALG 1992:74:547-58
Table 1. Effects of Equimolar Concentrations of Anesthetic Induction Drugs on Cardiac Rate, Conduction, and Mechanical Function
PM
Drug
HR (bea tslmin)
0.5 0.5 0.5 0.5 0.5
E tomida te Ketamine Midazolam Propofol Thiopental
210 215 201 205 204
1 1
t4
t6 t5 t 5
74 72 74 71 77
Etomidate Ketarnine Midazolam Propofol Thiopental
209 + 7 210 t 8 199 t 6 205 + 4 200 t 5
76 72 74 71 77
+4
211 f 7 207 + 8 196 t 5 196 + 5 200 + 5
76 74 71 72 77
+3
5
Etomidate Ketamine Midazolam Propofol Thiopen tal
10 10 10 10 10
Etornidate Ketarnine Midazolarn Propofol Thiopen tal
211 + 7 204 t 9 189 + 6 191 t 5" 199 + 5
50 50 50 50 50
Etomidate Ketamine Midazolam Propofol Thiopental
207 197 190 179 194
100 100 100 100 100
Etomidate Ketarnine Midazolam Propofol Thiopental
195 t 186 t 168 t 158 t 187 t
250 250 250 250 250
Etomidate Ketamine Midazolam Propofol Thiopental
162 t 7'' 173 t 9" 144 t 9" 141 f 2'' 146 t 5"
9 1 + 5" 78 + 6 97 t 4l
500 500 500 500 500
Etomidate Ketarnine Midazolam Propofol Thiopental
121 t 12" 140 t 9" 128 t 10"
93 t (Y' 89 t 4 l 123 t 7'
SA arrest 129 t 5''
AVD AVD
1000 1000 1000 1000 1000
Etornidate Ketamine Midazolam Propofol Thiopental
SA arrest 105 t 7'' 130 t 12'' SA arrest 103 t 14"
PC PC PC PC PC
Etomidate Ketarnine Midazolarn
225 205 205 178 213
1 1 1
5 5 5 5
Propofol Thiopental
t 7 t8
AV time (ms)
t 7
t9 t6 + 7" t4
7" 9" 6'' 6"
4"
t7 t8 t7 t 7'' t5
LVP
(mm Hg) 93 97 106 97 93
t8 t6 t6
92 95 105 98 92
t 7
+3 +2 +3
t7 t6
+3
97 95 97 96 89
76 75 75 73 78
t3 t3 t2 2 3 +3
85 90 89 93 86
t7 t6 t 4"
77 77 75 76 78
f
3
78 78 84 95 79
f
t4 t3 t2 t3 t t t t
3 3 2 3
f3 f2
+ 3l t3
2
t4 t 2" t4 1
t3
AVD 93 t 4"
t 0.01 t 0.02 t 0.11 t 0.09 t 0.14
1.88 1.86 2.04 1.73 1.83
2.12 2.28 2.24 2.03 2.00
t 0.15 t 0.11 t 0.15 f 0.11 + 0.18
1.86 t 0.09 1.89 f 0.08 1.95 + 0.10 1.71 t 0.10 1.68 t 0.15
2.01 2.30 1.86 1.97 1.95
?
0.15 t 0.09" t 0.13" t 0.12 t 0.15
1.82 1.88 1.82 1.67 1.74
k 0.08 t 0.10 t 0.10 k 0.09 t 0.17
1.71 1.83 1.58 1.62 1.73
t 0.08 t 0.09
t9
1.91 + 0.15 2.16 -1- 0.10 1.86 t 0.10'' 1.85 t 0.12" 1.92 + 0.15
64 84 76 75 73
t 5" t 51' t 4" t 8" t 8"
1.35 t 0.09" 1.85 t 0.12" 1.50 t 0.10" 1.28 t 0.09" 1.55 t 0.15"
1.29 t 0.06" 1.68 t 0.08" 1.35 t 0.06" 1.28 + 0.06' 1.41 t 0.12''
41 77 49 46 62
t 4"
0.92 + 1.68 t 1.01 t 0.92 t 1.31 t
0.90 1.52 0.91 0.93 1.19
t8 t9 t6 t5 t8 t9
t5 t9 t9
2 9
t 4'' t 3" ? 6" 2 7"
11 t 2" 63 2 6" 28 2 5'' 17 t 9" 32 t 5"
5 t 2" 39 18 0 17
t 4"
t 2" t 0" 2 2"
AVD
0 t 0" 17 t 3" 5 I 2" 0 t 0" 2 t 1"
74 72 74 76 74
+4 t2 t2
t3 t3
-dLVPIdt (mm Hgis) ( X 1000)
2.07 2.20 2.28 1.98 2.05
114 t 6 '
AVD AVD AVD
+ dLVPIdt (mm Hgls) ( X 1000)
86 88 104 98 82
t7 t6
4 t 10 9 2
0.07" 0.09" 0.06" 0.09" 0.12"
t 0.09 t 0.09 t 0.15 t 0.10 + 0.13
+ 0.07b t 0.09 t 0.13
t 0.06' 0.06" t 0.06" t 0.09" t 0.10"
+
0.41 t 0.06" 1.19 + 0.13" 0.62 t 0.09" 0.29 t 0.09" 0.77 + 0.09"
0.39 t 0.05' 0.86 t 0.06" 0.57 t 0.09" 0.27 k 0.09' 0.71 ? 0.07"
0.20 0.74 0.51 0.14 0.45
t t t t t
0.03'' 0.09" 0.07" 0.02" 0.07"
0.18 0.77 0.44 0.14 0.44
0.09 0.38 0.21 0.14 0.18
?
0.05"
t 0.02" t 0.06"
0.06 t 0.03" 0.38 t 0.05" 0.17 t 0.04" 0.12 ? 0.02" 0.17 f 0.06"
1.97 t 0.17 2.12 t 0.09 2.21 t 0.12 2.00 t 0.17 1.91 t 0.17
1.71 0.12 1.80 + 0.07 1.86 t 0.09 1.62 t 0.13 1.68 t 0.17
t 0.06" t 0.07"
t 0.03" t 0.07" 2 0.06" t 0.02" f 0.07"
+
HR, intnnsic heart rate in beatsimin; AV, atrioventricular conduction; LVP, isovolumetric left ventncular pressure; +dLVP/dt, maximal positive derivative of left ventricular pressure, -dLVP/dt, maximal negative derivahve of left ventricular pressure; PC, postconmil; AVD, atrioventricular dissociation; SA, sinoatrial. Data are mean 2 S E K All data except intrinsic heart rate were obtained during atrlal pacing at 240 h e a t s h i n . ","For each variable, significance is shown hv increase ( a ) and decrease ((7) i o r changes from the lowest concentration (0.5 pM) of a given drug. See Table 3 for statistical comparisons among drugs at a given concentration.
STOWE ET AL. DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
ANESTH ANALG 1992;74:547-58
551
Table 2. Effects of Equimolar Concentrations of Anesthetic Induction Drugs on Coronary Flow a n d Oxygen Utilization PM
Drug
Cor flow (mt.min-'.g-')
Po, cs (mm Hg)
MVo, (,.&min-'.g
181 t 15 185 f 20 177 t 11 157 ? 19 179 t 14
(% )
Do,/MVo,
43 t 4 45 2 1 55 t 4 41 2 3 42 f 3
64.5 t 3.8 63.8 t 4.0 67.2 t 1.8 69.4 t 4.1 65.4 t 2.8
1.61 t 0.11 1.63 2 0 . 1 1 1.50 t 0.05 1.49 t 0.10 1.55 2 0.07
67.5 t 3.8 67.7 23.5" 64.9 t 1.9 71.2 t 3.5 69.6 f 2.0"
1.53 t 0.10 1.52 t 0.09" 1.55 t 0.05 1.43 t 0.07 1.45 t 0.04" 1.51 t 0.09 1.60 t 0.10 1.56 t 0.04 1.47 t 0.08 1.45 t 0.04"
8.2 t 0.8"
0.5 0.5 0.5 0.5 0.5
Adenosine (all groups) Etomidate Ketamine Midazolam Propofol Thiopental
4.7 5.5 5.2 4.4 4.5
1 1 1 1 1
Etomidate Ketamine Midazolam Propofol Thiopental
4.6 ? 0.5 5.2 t 0.5 5.1 t 0.4 4.1 ? 0.5 4.1 t 0.3"
167 t 165 t 189 t 148 2 158 t
14 17" 10 16 11"
42 46 50 40 40
t4 t5
5 5 5 5 5
Etomidate Ketamine Midazolam Propofol Thiopental
4.6 4.9 5.5 4.1 4.1
t 0.4
165 t 181 t 191 t 165 t 160 t
14 18 10 18 10"
42 43 53 41 40
2
10 10 10 10 10
Etomidate Ketamine Midazolam Propofol Thiopental Etomidate Ketamine Midazolam Propofol Thiopental
4.6 5.0 5.6 4.3 4.1
t 0.4
50 50 50 50 50
100 100 100 100 100 250 250 250 250 250 500 500 500 500 500 1000 1000 1000 1000 1000 PC PC PC PC
rc
0, extraction I)
t 0.5 t 0.5 ?
0.5
t 0.6 t 0.4
t3
t3 t2
4
3
67.9 t 3.7 64.7 t 3.8 64.6 t 1.6 69.7 t 3.8 69.2 f 2.0"
0.4" t 0.5" t 0.5 t 0.3"
172 2 12 168 t 16 219 t 11" 166 t 15 154 t 9"
43 t 3 43 t 4 49 2 3 40 t 4 41 f 3
66.6 t 3.1 67.3 t 3.3 59.4 t 2.4" 67.7 2 3.4 69.9 t 1.V
1.53 t 0.07 1.52 ? 0.08 1.72 t 0.08' 1.51 t 0.08 1.44 t 0.04"
5.2 t 0.5" 4.9 t 0.5'' 5.8 t 0.4" 5.6 t 0.7" 4.3 t 0.4
214 ? 20" 184 2 2 0 218 t 12z 229 t 19" 170 t 15
42 2 5 42 t 4 49 i 3 44 t 5 40 f 3
58.0 64.1 59.4 57.7 66.9
t 4.3" t 3.0
1.99 t 0.30" 1.63 t 0.11 1.71 t 0.07" 1.82 t 0.16" 1.53 t 0.07
Etomidate Ketamine Midazolam Propofol Thiopen tal
5.5 t 0.5" 4.9 t 0.5" 6.8 t 0 . F 6.7 ? 0.8z 4.3 t 0.4
279 f 21" 186 t 25 293 ? 16l 301 t 14l 167 t 14
33 40 44 38 39
t 4" t3
45.6 ? 5.2" 63.5 t 5.4 45.5 2 3.5" 42.8 t 3.2" 67.5 2 2.6
2.50 20.30' 1.71 t 0.18 2.39 2 0.29" 2.46 t 0.21" 1.51 t 0.06
Etomidate Ketamine Midazolam Propofol Thiopental
5.6 4.9 6.5 7.0 4.5
318 t 17'' 192 t 27 327 t 24l 344 t 132 209 2 2 0 "
28 40 39 35 34
t 3"
6'' 6" t 3"
39.0 60.0 40.3 34.3 59.6
4.0"
2.82 t 0.33' 1.88 f 0.20 2.90 ? 0.29' 3.14 t 0.39' 1.74 t 0.13"
Etomidate Ketamine Midazolam Propofol Thiopental Etomidate Ketamine Midazolam Propofol Thiopental Etomidate Ketamine Midazolam Propofol Thiopental
6.3 2 0.7" 5.2 t 0.6 6.7 t 0.8" 7.4 t 0.9" 4.8 t 0.5
346 t 1 2 I 239 t 2 9 355 t 22' 343 I 16' 243 t 20"
29 34 31 32 35
3'' t 3" t 3" t 5" t 4"
34.3 t 3.1'' 53.6 t 6.0" 34.1 2 4 . 2 " 33.4 t 3.9" 53.3 t 3.7"
3.23 t 0.45" 2.14 t 0.29" 3.58 20.63" 3.69 ? 0.72" 1.96 f 0.15"
6.3 ? 0.7" 5.6 f 0.7 7.2 t 1.0: 7.4 I 1.02 5.0 t 0.6
348 t 14l 281 t 29" 371 ? 20' 343 ? 16z 275 t 197
29 31 31 32 31
2
34.2 45.3 31.2 33.4 46.6
t 3.9" t 3.9"
3.25 f 0.45'' 2.81 f 0.58" 3.82 2 0.73" 3.69 t 0.72l 2.30 f 0.21"
4.2 4.5 5.1 3.7 3.9
170 t 7 147 t 14" 157 t 8" 137 t 13 146 t 9"
42 t 3 45 2 4 55 2 4 40 t 6 41 ? 4
68.9 t 1.8 71.4 t 2.5z 70.9 t 1.3 75.4 t 2.2 75.3 f 1.8"
1.46 f 0.03 1.42 f 0.05" 1.41 t 0.03 1.33 f 0.04 1.34 +- 0.03"
Adenosine (all groups)
i 0.4" ?
0.4
t 0.5 t 0.3" 2
i 0.5" t 0.5" t
0.67
t 0.8' 2
0.4
t 0.4 t t t t
0.4" 0.4 0.4 0.3"
t4 t4
t3 2
2
3"
t5 t4 t5 f
2
t
3"
t 3" t 3"
t 5" t 3"
t 5.9" t 4.2 t 2.5"
t 4.1'' t 5.4 t 4.3"
t 2.6" f
t 3.1''
t 6.0"
24.0"
7.5 t 0.9"
Cor, coronary; CS, coronary sinus; MVo,, myocardial oxygen consumption; Do,, oxygen delivery; PC, postcontrol. ?I = 11 hearts per anesthetic group. Data are mean t SEM. Adenosine was injected into the aortic cannula to measure maximal flow responses before and after drug treatment. All data were obtained during atrial pacing at 240 beatsimin. "."For each variable, significance is shown by increase (a) and decrease ( b ) for changes from the lowest concentration (0.5 pM) of a given drug. See Table 3 for statistical comparisons among drugs at a given concentration.
552
ANESTH ANALC 1992;74:547-58
STOWE ET AL DIRECT CARDIAC EFFECTS OF INDUCTION AGENTS
Table 3. Statistical Comparisons of Five Anesthetic Induction Drugs at Equimolar Concentrations on Cardiac Variables AV conduction time
Heart rate , E K M P E -- o o o K O - - o o M o o -- o P 0 0 0 -T o o o o
lw
T
o o
o OSpM 0
.-
E , - E- Ko M o Po K O - 0 o M o o ~- 0 P 0 0 0 -T o o o o 1 PM
E K M P T E K - - + o + oF M + o -- o o 5 p M P + o o - - + T O O ~ + - 10 ClM
-
LV pressure
E , --E oK oM aP K O - 0 o M + o -- o P 0 0 + - T o o o o lw
oT o
o O.5pM
E v
500 pM
M + + -- + + 5~ P o o + - - 0 T o o + o - IOpM
rK M P - + o o - - 0 0 o -- + + o - oMooVMo
Do, IMVo,
r-
E K M P T
E K M P T
E K M E -- o o K O --o M o o -P 0 0 0 T o oIpM o
P o o o - - 0 T l o o o o -IpM
0 .
E K M P T
E + o o o
7c O2 extraction
MVo,
E K M P T
E K M P T
P T
o o o o o o 0.5pM
--
0
o --
E K M P T
E K M P T
w
E K M P T
o o o - - 0 o o o o - postwnrml
0.5pM
0
M o o ~- o o 5 p M P 0 0 0 -- 0 T o o o o -10
E K M P T
,E K M P T -- o o o o O --o a o o o -- o o I W p M
0
E K M P T
E K M P T E - - + o + o K + -- o o o
E K M P T
To
o
Table 3. Continued
T + 0 + 250pM 0 --
,E K M P T E - - o o o o K O - - 0 0 0 M o o -- 0 o IWOpM P o o o - - 0 T o o o o - postcontrol
E K M P T
5M pM
E K M P T
,E O o O o
K M P T - + o o o - - + + + o -- o o I W O w O O - - 0 o o o - poslcontrol
10 pM
10 pM
rr-
E K M P T
E K M P T E - - o o o o K O --o o o M o o -- o o MpM P 0 0 0 -- 0 T + o +pM o - -
E K M P T
E -O o
K M o o - - 0 o --
0
0
P T + + 0 0 o o 2MpM
‘r
100 p M
100 rrM
E K M P T
E K M P T
+ .- 0
w
o o5 M+ o - -
500 pM
E K M P T
El-- o o o o K M P T
E K M P
O o o o
- - o o -o o o o
o o
o o 1000pM - 0 o -
E El-K O M o P 0 T o
K M P + o o - - + + o -- o 0 0 - o o o -
T
+ o +
1WOpM
+ -
E K M P T
rE O o
K M - o o - - + o --
P T o + + o o + LWOpM 0 0 0 -- + o opostcontrol o o - -
Each drug IS compared against the others for the change in a givcn ariable f r o m the initial control at a given concentration. The right and bottom concentrations reter to significance to the right and to the left of the diagonal ( i h l i c s ) , respectively P i 0.05 = +; P > 0.05 = o (nonsignificant). E, etomidate; K, ketamine; M, rnidazolarn; P, propofol; T, thiopental; AV, atrioventricular; LL’, left ventricular; MVo,, myocardial oxygen consumptlOI1, DO?, 10.
