28
ANESTH ANALG 1991;72:28-35
Cardiodynamic Effects of Propofol in Comparison With Thiopental: Assessment With a Transesophageal Echocardiographic Approach Jan P. Mulier, MD, Patrick F. Wouters, MD, Hugo Van Aken, Gery Vermaut, MD,and Eugltne Vandermeersch, MD MULIER JP, WOUTERS PF, VAN AKEN H, VERMAUT G, VANDERMEERSCH E. Cardiodynamic effects of propofol in comparison with thiopental: assessment with a transesophageal echocardiographic approach. Anesth Analg 1991;72:28-35.
In 40 patients, the cardiovascular effects of low- and high-dose propofol anesthesia (single bolus of 2.5 mglkg in group A, 2.5 mglkg in group C) were examined and conipared with those of low- and high-dose thiopental (4 mglkg in group B, 6.5 mglkg in group D ) (n = 10 patients per group). After induction of anesthesia with etomidate, all patients were ventilated with 70% nitrous oxide in oxygen. Peripheral arterial systolic blood pressure (SAP) and transesophageal echocardiographic short-axis measurements were used to calculate the end-systolic pressure-volume relationship (E) as an index of global myocardial contractility. In all groups SAP decreased significantly below baseline levels for the duration of the measurements (15 rnin after drug administration), except for the lower dose of thiopental, where SAP returned to baseline values within 10 min. Propofol at a dose of 1.5 mglkg significantly decreased cardiac output (CO) (from 5.1 t 0.25 [mean t SEMI to 4.2 0.23 Llrnin), stroke volume ( S V ) (from 64 2 3 to 56 ? 3.6 mL), and the slope of E (from 71 t 3.5 to 65 4.2 mm HgImL) until 4 min after drug administration. The higher dose of propofol significantly decreased CO (from 5.1 0.29 to 4.1 0.26 Llmin), SV (from 64 t 3
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The induction of anesthesia with propofol (2,6diisopropylphenol) is often associated with marked decreases in systemic arterial blood pressure in humans (14).Clinical investigations have identified a propofol-induced afterload reduction (1,3,4) as the most important factor in explaining propofol-induced Received from the Department of Anesthesiology, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium. Accepted for publication August 9, 1990. Address correspondence to Dr. Mulier, Department of Anesthesiology, University Hospitals, Katholieke Universiteit Leuven, Herestraat 49, 8-3000 Leuven, Belgium. 01991 by the International Anesthesia Research Society 0003-2999/91/$3.50
MD,
PhD,
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to 52 & 4.6 mL), and the slope of E (from 71 3.6 to 62 2 3.7 mm HglmL) until 20 rnin after drug administration. End-systolic volume increased significantly (from 60 2 7.6 to 68 2 5.5 mL) until the sixth minute, followed by a decrease in end-diastolic volume at 10 min (from 124 6.5 to 118 2 4.3 mL). Thiopental at a dose of 4 mglkg reduced end-diastolic volume significantly at 10 rnin (118 +- 7.2 versus 128 7.8 mL) and resulted in a significantly higher CO (4.6 0.29 versus 4.2 ? 0.23 Llmin) and the slope of E (69 t 3.9 versus 65 4.2 mm HglmL) when compared with low-dose propofol at 4 min. Thiopental at a dose of 6.5 mg/kg significantly reduced the index of afterload (SAPISV) (from 63 2 5 to 56 2 4.6 mm HglmL) and the slope of E (from 69 % 4.2 to 63 3.6 rnm HglmL), whereas heart rate increased (from 76 2 5.2 to 84 2 6.8 beatslmin) until the fourth minute after drug administration. When compared with high-dose propofol, end-systolic volume was significantly lower and SAP, SV, CO, and slope of E were significantly higher during thiopental at equipotent doses. It is concluded that propofol reduces SAP mainly through its negative inotropic properties. Furthermore, the cardiodepressant effects of propofol are more pronounced and more prolonged than those of equipotent doses of thiopental when given as a single bolus.
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Key Words: ANESTHETICS, INTRAVENOUS-thiopental, propofol. HEART, CONTRACTILITY-thiopental,
propofol.
reduction of arterial blood pressure. In contrast, a recent study demonstrated that the predominant effect of propofol was a decrease in preload (5). However, Van Aken et al. concluded from their data that propofol might also have negative inotropic properties (2). Recently, data obtained from animal studies have supported this hypothesis (6,7). In the clinical setting, less invasive monitoring techniques are required to investigate the cardiovascular properties of anesthetic drugs. The ventricular end-systolic pressure-volume relationship, introduced by Sagawa (8), provides a reliable and mini-
CARDIODYNAMIC EFFECTS OF PROPOFOL
mally invasive technique for measuring myocardial contractility. This method is relatively independent of changes in preload and incorporates afterload changes (9). Inotropic interventions have been shown to modify the slope of the ventricular end-systolic pressure-volume relationship (8,lO). This technique is applicable for clinical use provided that peak systolic arterial blood pressure and echocardiographicderived volume calculations may be substituted for ventricular end-systolic pressure and absolute endsystolic volume, respectively (11). We have used the end-systolic pressure-volume relationship to determine the effects of a single dose of propofol or thiopental on the myocardial contractility in humans. The purpose of our study was to determine the relative importance of changes in preload, afterload, and myocardial contractility in the propofol-induced decreases in arterial pressure in humans. Thiopental was chosen as the drug of reference and both drugs were used in doses recommended for clinical induction of anesthesia (12,13).
Materials and Methods Forty ASA physical status I or I1 patients scheduled to undergo elective major abdominal and orthopedic surgery were studied. The study was approved by the Institutional Ethical Committee, and informed consent was obtained from all patients. Patients did not qualify if they had a history of allergy, were obese (>120% of ideal body weight), or had signs or symptoms of hepatic, renal, hematologic, metabolic, cardiac, or central nervous system disease. All patients were premedicated 2 h before anesthesia with 2 mg oral lorazepam. On arrival in the operating room, an electrocardiograph was attached and a modified V, lead continuously displayed. Under local anesthesia, cannulae were inserted into a peripheral vein and a radial artery. A continuous intravenous (IV) infusion of lactated Ringer's solution was maintained at a rate of 2 mL.kg-l.h-' for the study period. Anesthesia was induced by the IV administration of etomidate (0.3 mg/kg over 60 s). After IV administration of vecuronium (0.1 mg/kg), laryngoscopy was performed, the pharynx and vocal cords were sprayed with 5 mL of a 2% lidocaine solution, and the trachea was intubated. Mechanical ventilation was started, and anesthesia was maintained with 70% nitrous oxide in oxygen. End-tidal was monitored using a carbon dioxide Pco, (PETCO~) analyzer and maintained between 35 and 41 mm Hg using a fixed tidal volume of 10 mL/kg and adjusting the ventilatory rate. Immediately after induction, a
ANESTH ANALG 1991;722%35
29
-/ ESV Fipure 1,. Measurement of E: maximal elastance as parameter of contractility. The baseline contractility Eo is calculated as a regression line through the points nil and mn. The change in contractility is reflected by a change in the slope (a)of the line E [SAP/(ESV Vd)] through a new point p and the same point Vd.
transesophageal echocardiograph probe (Hewlett Packard) was introduced into the esophagus to determine the left ventricular volume. The probe was positioned to achieve a cross section of the left ventricle at the midpapillary muscle level and stabilized at the mouth. The radial arterial pressure and airway pressure tracings, and the electrocardiogram, were simultaneously recorded with a two-dimensional echo view of the heart. Recordings were stored on videotape for later off -line computer analysis. Midpapillary crosssectional end-diastolic area of the left ventricle and midpapillary cross-sectional end-systolic area of the left ventricle were measured to calculate end-diastolic volume (EDV) and end-systolic volume (ESV) using the modified Simpson formula (14). Stroke volume (SV) was calculated as the difference between EDV and ESV. Cardiac output (CO) was calculated as the product of SV and heart rate (HR). The quotient of systolic arterial blood pressure (SAP) and SV was used as an index of left ventricular afterload as described by Sunagawa et al. (SAP/SV = Ea: effective arterial elastance) (15).
Calculation of Ventricular Contractility With PeakSystolic Pressure to End-Systolic Volume Relationship The determination of left ventricular contractility using the principle of the peak-systolic pressure to end-systolic volume relationship (8) was performed as follows (Figure 1). The baseline contractility (Eo) was calculated once the patient was hemodynamically stable. Point ml had as its coordinates ESV on
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ANESTH ANALG 1991;72:2635
the x-axis and SAP on the y-axis. Points m2 to mn, with the same coordinates, were obtained during the rapid decrease in blood pressure that followed the IV injection of 100 pg nitroglycerin. Measurements were stopped at the moment HR changed. The line Eo was constructed using linear regression analysis of all the points ml to mn. The intercept of the line Eo with the x-axis (point Vd)was the same as the extrapolated left ventricular end-systolic volume at zero blood pressure. When the drug under investigation was then administered, a new point p with ESV on the x-axis and SAP on the y-axis was determined. The slope of a new line E , drawn through point p and the intercept on the x-axis of the previously determined Eo, point Vd, was then calculated. A change in contractility when compared with baseline was reflected by a change in the slope [SAP/(ESV- Vd)] of line E when compared with Eo. An increase in contractility was reflected by an increase of the slope of E , and a decrease in contractdity was reflected by a decrease in the slope of E.
Experimental Protocol Patients were randomly assigned to four study groups. Fifteen minutes after induction of anesthesia, baseline hemodynamic recordings were obtained and baseline contractility calculated. Group A (10 patients) received a single bolus of propofol in a dose of 1.5 mg/kg. Group B (10 patients) received 4 mg/kg of thiopental. Group C (10 patients) received 2.5 mgkg of propofol, and group D (10 patients) received 6.5 mg/kg of thiopental. The drugs were administered intravenously over 60 s. Hemodynamic measurements were repeated 2, 4, 6, 10, and 15 min after injection of the drug. Blood samples were drawn at 2, 4, 10, and 15 min after injection of the drug for later analysis of plasma concentrations of the anesthetic drugs. Data are presented as mean ? SEM. For statistical comparisons of means within a group, the Friedman test was used. For statistical comparison of means between groups A and B, and between groups C and D, the Wilcoxon-Mann-Whitney test was used (16). P < 0.05 was considered to indicate a statistically significant difference.
Results The demographic data of the patients are listed in Table 1. There were no significant differences between groups with regard to age, weight, height, or body surface area.
Table 1. Demographic Data Group A Age (yr) Weight (kg) Height (cm) BSA (m2)
Group B
Group C
60+4 6223 58 2 62 2 71 t 4 76 2 6 170 t 3 167 t 2 171 ? 1.88 t 0.12 1.77 t 0.09 1.75 2
BSA, body surface area. All values are expressed as mean
Group D
59 2 3 68 t 5 168 t 4 3 0.08 1.80 ? 0.07 4
4
2 SEM.
The hemodynamic changes associated with each drug are listed in absolute values in Table 2 for groups A and B and in Table 3 for groups C and D. The changes in SAP and E are shown in Figures 2 and 3 for each group. There were no significant differences in baseline values among the four groups. In all groups SAP decreased significantly below baseline levels. With the low dose of thiopental, SAP returned to baseline values at 10 min; in the other groups SAP remained low for the duration of the experiment (15 min). At 2 and 4 min, propofol at a dose of 1.5 mg/kg decreased SV (from 64 ? 3 to 59 2 4.1 and 56 t 3.6 mL, respectively), CO (from 5.1 ? 0.25 to 4.5 ? 0.37 and 4.2 ? 0.23 L/min, respectively), and the slope of E (from 71 t 3.5 to 66 t 3.8 and 65 ? 4.2 mm Hg/mL, respectively). The higher dose of propofol decreased SV (from 64 k 3 to 52 2 4.6 mL), CO (from 5.1 t 0.29 to 4.1 t 0.26 L/min), and the slope of E (from 71 ? 3.6 to 62 k 3.7 mm Hg/mL) for 10 min after drug administration. End-systolic volume increased for 6 min (from 60 t 7.6 to 68 t 5.5 mL) and returned to baseline at 10 min, whereas EDV decreased at 10 min (from 124 ? 6.5 to 118 ? 4.3 mL). Thiopental at a dose of 4 mg/kg reduced EDV at 10 min (118 -+ 7.2 versus 128 k 7.8 mL). At 2 and 4 min after drug administration, the higher dose of thiopental increased HR (from 76 ? 5.2 to 82 ? 4.1 and 84 ? 6.8 beatslmin, respectively), decreased the slope of E (from 69 5 4.2 to 62 2 3.8 and 63 ? 3.6 mm Hg/mL, respectively), and decreased the index of afterload (from 63 k 5 to 54 ? 3.9 and 56 -+ 4.6 mm Hg/mL, respectively). End-diastolic volume was significantly below baseline at 10 min (117 7.2 versus 125 2 8.6 mL). When compared with thiopental at a dose of 4 mg/kg, 1.5 mg/kg propofol resulted in a significantly lower CO (4.2 0.23 versus 4.6 ? 0.29 Limin) and slope of E (65 2 4.2 versus 69 k 3.9 mm Hg/mL) at 4 min after drug administration. Propofol (2.5 mg/kg) was associated with a lower SAP, CO, slope of E , and SV, and with a higher ESV, when compared with 6.5 mg/kg thiopental. Plasma concentrations of propofol and thiopental are displayed in Figure 4. Both drugs reached their highest
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CARDIODYNAMIC EFFECTS OF PROPOFOL
31
ANESTH ANALG 1991;72:2%35
Table 2. Hemodynamic Data ( n = 10 in each group) After an Induction Dose (1.5 mg/kg propofol in group A; 4 mgikg thiopental in group B) Baseline
2 min
4 min
6 min
10 min
15 min
79 t 3 112 t 5.4 123 2 5.4 59 2 6.1 64 2 3 5.1 t 0.25 71 t 3.5 60 2 3.8
76 t 3.5 95 t 6.8" 121 t 6.7 62 2 4.1 59 2 4.1" 4.5 t 0.37" 66 t 3.8" 58 t 4.5
75 t 4.4 92 t 6.6" 118 t 6.3 62 t 4.8 56 t 3.6" 4.2 2 0.23"*' 65 t 4.2"," 59 2 3.7
78 t 3.6 91 _t 6a 116 2 4.8 60 t 5.2 56 2 4.6 4.4 t 0.4 66 _t 5.8 58 t 5.4
79 t 3 91 _t 7.2" 118 t 6.1 59 f 4.5 59 2 3.7 4.7 h 0.29 67 t 4.7 57 2 4.9
80 t 3.7 95 _t 6.6" 116 t 5.1 57 t 6.6 59 2 2.8 4.7 t 0.28 69 2 3.9 58 t 4.8
75 h 4.5 113 2 6.4 128 t 7.8 65 2 3.7 63 2 3.2 4.7 t 0.3 70 t 4.7 61 2 5.2
76 t 3.8 97 2 7" 126 t 10.1 64 2 4.8 62 t 4 4.7 2 0.34 67 2 5.1 55 2 4.6
79 t 3.2 99 t 5.4" 119 t 7.8 61 t 4.1 58 t 3.9 4.6 t 0.29" 69 t 3.9' 59 t 3.5
76 t 2.7 102 t 6" 120 2 6.9 62 t 5.5 58 2 3.7 4.4 t 0.26 69 t 4.5 60 h 4.2
76 t 2.8 104 t 6.2 118 t 7.2" 60 t 4 58 2 3 4.4 t 0.2 70 t 4 61 h 5.1
75 t 2.9 107 t 7.2 121 2 8.1 62 t 3.7 59 t 2.9 4.4 f 0.27 70 2 5.2 61 t 3.8
Group A HR (beatsimin) SAP (mm Hg) EDV (mL) ESV (mL) SV (mL) CO (Limin) E:SAP/(ESV - Vd) (mm HgimL) SAPiSV (mm HgimL)
Group B HR (beatsimin) SAP (mm Hg) EDV (mL) ESV (mL) SV (mL) CO (Limin) E:SAP/(ESV - Vd) (mm HgimL) SAP/SV (mm HgimL)
HR, heart rate; SAP, systolic arterial blood pressure; EDV, end-diastolic volume; ESV, end-systolic volume; SV, stroke volume; CO, cardiac output; E:SAPI(ESV - Vd), maximal elastance: index of contractility; SAPISV, arterial elastance: index of afterload. All values are expressed as mean SEM. "P < 0.05 compared with baseline values within the group. bP < 0.05 compared with same-time value in the other group.
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Table 3. Hemodynamic Data ( n = 10 in each group) After an Induction Dose (2.5 mgikg propofol in group C; 6.5 mgikg thiopental in group D) ~~~~
Group C HR (beatsimin) SAP (mm Hg) EDV (mL) ESV (mL) SV (mL) CO (Limin) E:SAP/(ESV - Vd) (mm HgimL) SAPiSV (mm HgimL)
Baseline
2 min
4 min
6 min
10 min
15 min
80 t 6.9 122 t 5.3 124 2 6.5 60 t 7.6 64 t 3 5.1 t 0.29 71 t 3.6 62 t 4.2
76 5 4.8 83 t 2.9",' 120 t 7.5 71 2 6.4"," 49 t 4"J' 3.7 t 0.34"," 57 f 3.8".' 59 2 3.6
74 t 5.7 89 t 4.3" 121 t 6.8 68 t 4.9",b 53 h 2.6",' 3.9 t 0.37",' 60 2 4.7" 59 t 5.2
78 t 6.2 88 t 4.8" 119 t 4.6 68 5.5",' 51 t 4.3a,' 4 2 0.29",' 60 t 4.2''.' 60 t 4
79 ? 4.6 93 ? 4.6' 118 & 4.3" 66 I 5.1' 52 & 4.6",' 4.1 t 0.26"," 62 t 3.7" 61 C 3.5
79 t 3.4 98 t 5.5" 121 t 7.2 66 4 6.7 55 t 3.2 4.3 t 0.24 63 t 5.3 61 t 3.6
76 t 5.2 118 t 4.7 125 t 8.6 65 t 6.2 60 t 4 4.6 t 0.37 69 t 4.2 63 t 5
82 t 4.1" 90 2 3.8",' 121 t 9.2 66 t 7.8' 55 2 2.5' 4.5 2 0.3' 62 t 3.8",' 54 t 3.9"
84 t 6.8" 89 t 4 I 119 t 8.7 64 t 5" 55 t 3' 4.6 t 0.35" 63 +- 3.6" 56 t 4.6"
82 t 5.9 92 +- 3.5" 118 t 6.8 62 2 6.5' 56 t 4b 4.6 t 0.28' 65 t 4.8' 59 t 3.9
82 ? 5 94 t 3.7" 117 & 7.2" 60 t 6.8' 57 t 3.70 4.7 t 0.4' 66 ? 5.2 59 k 4.7
79 t 5.3 98 t 3.9" 118 t 7.4 62 +- 4.9 56 +- 2 4.4 +- 0.28 66 t 5 60 t 4
Group D HR (beatsimin) SAP (mm Hg) EDV (mL) ESV (mL) SV (mL) CO (Limin) E:SAP/(ESV - Vd) (mm HgimL) SAPiSV (mm Hg/mL)
Abbreviations as in Table 2. All values are expressed as mean 5 SEM. a P < 0.05 compared with baseline values within the group. 'P < 0.05 compared with same-time value in the other group.
concentrations 2 min after injection. These data resemble the profile of redistribution and plasma clearance reported in the literature (13,17). No statistically significant correlations were found between plasma concentrations and hemodynamic variables.
Discussion Previous studies on the cardiovascular effects of an Iv induction dose of propofol in humans have all documented decreases in SAP (2,4,5,17). However, the
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MULIER ET AL.
ANESTH ANALG 1991;72:28-35
-
130
120
-4-
Group B : Thiopentai4 mgkg Group C : Propofo12.5 mg/kg
I Group
D : Thiopental6.5 mglkg
110
0
X
E
100
E 90
80
Mean f SEM 70
0
5
10
15
minutes
Figure 2 . Changes in SAP after single-bolus injections of 4 and 6.5 mgikg thiopental and 1.5 and 2.5 mg/kg propofol.
reasons proposed as causes for this decrease in blood pressure vary from investigator to investigator. Claeys et al. (4), for example, suggested that the decrease in systemic vascular resistance resulted in a decrease in SAP, while CO and SV remained unchanged. However, experimental conditions such as the presence of hypercarbia in the spontaneously breathing subjects may have accounted for their observations. Van Aken et al. (2) and Carlier et al. (18), however, ascribed the decrease in systemic arterial pressure to significant decreases in CO and SV without concomitant changes in SVR or in pulmonary capillary wedge pressure. Those authors suggested that a negative inotropic action of propofol is responsible for the decrease in CO and SAP. Lepage et al. (5) also found that the decrease in mean arterial pressure was related to a decrease in cardiac index and stroke index (SI). This decrease in cardiac index was associated with a decrease in EDV or preload. They suggested that a decrease in venous return, caused by an increase in venous capacitance, may be responsible for the decrease in CO and systemic arterial pressure. However, whereas mean arterial
pressure decreased significantly, ESV remained unaffected in that study. Therefore, a reduction of mean arterial pressure without a decrease in ESV suggests a negative inotropic effect as well. Recently published results from animal studies provide evidence along the same lines. Briissel et al. demonstrated, in an acute closed-chest dog model, that propofol reduces the rate of force development in the left ventricle (6).Also, in an open-chest acutely instrumented pig model, Coetzee et al. found a significant reversed correlation between propofol plasma concentrations and myocardial contractility (7); Puttick and Terrar found a shortening of the action potential duration by propofol, indicating a reduction in calcium entry and therefore a possible negative inotropic effect (19). Our data obtained in humans indicate that the slope of the end-systolic pressure-volume relation (E), as an index of myocardial contractility, decreased significantly during low- and high-dose propofol. End-diastolic volume, as an index of preload, remained stable. Cardiac output decreased consequently and in the presence of an unchanged SAP/ SV, as an index of afterload, caused a reduction in SAP. In agreement with previously published data, the
CARDIODYNAMIC EFFECTS OF PROPOFOL
-
80
33
ANESTH ANALG 1991:72:2%35
Group B :Thiopental4 mglkg C : Propofo12.5 mglkg Group D :Thiopental6.5 mgkg
I Group
I
=w 0
70
c
0
P)
P
-0 v)
60
O
: p < 0.05 between group A an B
Mean k SEM 50
0
5
10
15
minutes
main effect of thiopental in our study was a decrease in afterload (20). The higher dose of thiopental resulted in a decrease in the index of contractility and a delayed decrease in EDV. However, CO remained unchanged due to a compensatory increase in HR and, perhaps, a decrease in SAPISV. Comparisons with the high dose of propofol indicate that the negative inotropic effects of thiopental are less pronounced. The reflex tachycardia during thiopental does not occur with propofol in the presence of similar reductions in blood pressure. These findings might indicate more pronounced baroreflex inhibition during propofol anesthesia, as described earlier by Cullen et al. (21). The peak negative inotropic effect of propofol occurred 2 min after drug administration. However, because the plasma concentrations during non-steady state are not in equilibrium with the tissue levels after single-dose administration, we could not demonstrate a significant correlation between the plasma drug concentrations and hemodynamic measurements. It appears from our data that the hemodynamic effects outlast the hypnotic effects of propofol. Etomidate as an induction dose of 0.3 mgkg with 0.1 mgkg vecuronium was given 15 min before the start of the experiment. Furthermore, 70% nitrous oxide in oxygen was administered throughout the present ex-
Figure 3. Changes in E (rnrn HgimL) as a parameter of contractility after single-bolus injections of 4 and 6.5 mgikg thiopental and 1.5 and 2.5 mgikg propofol.
periment. We therefore cannot exclude the possibility that these agents modified the hemodynamic or cardiodynamic alterations associated with propofol and thiopental. However, because baseline measurements as well as all measurements after the administration of propofol or thiopental were made under equal anesthetic conditions, it seems likely that the observed changes can be ascribed to the drug that was added. Furthermore, plasma levels of etomidate decline extremely rapidly with a distribution half-life of 2.6 min (22),and in patients without heart disease only minimal effects on the cardiovascular system are observed after IV administration of 0.3 mglkg etomidate (23). Vecuronium, used to facilitate tracheal intubafion and controlled ventilation, has minimal effects on cardiovascular function (24). In the present study all hernodynamic variables returned to baseline levels 10 min after the injection of etomidate and vecuronium. Comparisons of IV anesthetic agents require the use of equianesthetic doses. Rolly et al. (25) found the relative potency of propofol compared with thiopental to be 1:2.6 in humans (inducing sleep in patients).
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MULIER ET AL.
ANESTH ANALG 1991;72:28-35
Thiopental plasma concentrations
1 40
-
E .
-
30-
UI
%
20 -
10
-
04 5
0
15
10
minutes
l2 10
-E . 0
=.
Propofol plasma concentrations
1
I T
Ij 0
4
10
5
1.5mg/kg
15
minutes
Figure 4. Thiopental and propofol plasma concentrations in micrograms per milliliter at 2, 4, 10, and 15 min after single-bolus injections of 4 and 6.5 mgikg thiopental and 1.5 and 2.5 mg/kg propofol.
Thus, 1.5 mg/kg propofol corresponds to 4 mg/kg thiopental, and 2.5 mg/kg propofol corresponds to 6.5 mg/kg thiopen tal . Assessment of contractility changes in humans in the clinical setting is quite difficult. Although radionuclide ventriculography with a gamma camera of small size and true mobility permits semi-invasive pharmacodynamic studies, problems such as difficulty in obtaining absolute volumes (as a result of the fixed field view of the detector), probe positioning over the left ventricle, recording of background activity, and radiation safety in the operating room make the use of this technique less practical (26,27). Changes in the maximum rate of increase in left ventricular pressure (dP/dt,,,) are known to be highly sensitive to acute changes in contractility. Although measurement of left ventricular dP/dt may be used to study anesthetic drugs, provided that high-fidelity catheter-tip manometers are used, this technique is very invasive. Also, dP/dt,n,, is depen-
dent on preload, afterload, and HR. Furthermore, due to ethical considerations this method cannot be used to obtain information about the effects of anesthetics on left ventricular contractility in humans. Therefore, the less invasive method using the pressure-volume analysis was used in this study. Determination of true end-systolic pressure requires left ventricular or aortic pressure measurement. The manipulation of arterial pressure to obtain different pressure-volume points may cause reflex inotropic changes because of sympathetic activation or withdrawal. Thus, for clinical use this relationship needs simplification; this was described by Heinrich et al. (11).Several important features of our protocol have to be explained. First, cross-sectional areas of the ventricle can be measured, which provides a more accurate estimation of ventricular volume than do diameter measurements. Lunkenheimer et al. (28) showed that contraction is mainly concentric and that the long-axis measurement is relatively stable. Hence, calculations are made with one long-axis measurement using the change in cross-sectional area. Second, sympathetic stress and changes due to respiration have to be avoided throughout the experiment. Therefore, our patients were anesthetized with etomidate as induction agent and 70% nitrous oxide in oxygen as a maintenance anesthetic. Furthermore, they were paralyzed, and ventilation was controlled. Intubation, changes in respiration, and probe positioning were performed immediately after administration of etomidate. Baseline measurements were obtained 15 min after the induction of anesthesia during 70% nitrous oxide in oxygen and were immediately followed by administration of the drug under investigation. In conclusion, our end-systolic pressure-volume relationship model demonstrates that propofol has dose-dependent, negative inotropic properties in humans. Furthermore, it is shown that the negative inotropic properties of propofol outweigh those of equipotent doses of thiopental in both intensity and duration.
References 1. Grounds RM, Twigley AJ, Carli F, Whitwam JG, Morgan M.
The hemodynamic effects of intravenous induction. Anaesthesia 1985;40:73540. 2. Van Aken H, Meinshausen E, Prien T, Briissel T, Heinecke A, Lawin P. The influence of fentanyl and tracheal intubation on the hemodynamic effects of anesthesia induction with propofol/N,O in humans. Anesthesiology 1988;68:157-63.
3. Coates DP, Christopher RM, Prys-Roberts C, Turtle M. Hemodynamic effects of infusions of the emulsion formulation of
CARDIODYNAMIC EFFECTS OF PROPOFOL
propofol during nitrous oxide anesthesia in humans. Anesth Analg 1987;66:64-70. 4. Claeys MA, Gepts E, Camu F. Haemodynamic changes during anaesthesia induced and maintained with propofol. Br J Anaesth 1988;60:3-9. 5. Lepage JM, Pinaud ML, Helias JH, et a]. Left ventricular function during propofol and fentanyl anesthesia in patients with coronary artery disease: assessment with a radionuclide approach. Anesth Analg 1988;67:949-55. 6. Brussel T, Theissen JL, Vigfusson G, Lunkenheimer PP, Van Aken H, Lawin P. Hemodynamic and cardiodynamic effects of propofol and etomidate: negative inotropic properties of propofol. Anesth Analg 1989;69:3540. 7. Coetzee A, Fourie P, Coetzee J, et al. Effect of various propofol plasma concentrations on regional myocardial contractility and left ventricular afterload. Anesth Analg 1989;69:47%83. 8. Sagawa K. The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use. Circulation 1981;63:1223-7. 9. Suga H, Sagawa K, Shoukas A. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973;32:31422. 10. Grossman W, Braunwald E, Mann T, McLaurin LP, Green LH. Contractile state of the left ventricle in man as evaluated from end-systolic pressure-volume relations. Circulation 1977;56: 845-52. 11. Heinrich H, Fosel Th, Fontaine L, Spilker D, Winter H, Ahnefeld FW. Assessment of contractility changes in humans by transoesophageal echocardiography: the peak-systolic pressure end-systolic diameter relationship. Int J Clin Monit Comp 1987;4:243-8. 12. Fahy LY, van Mourik GA, Utting JE. A comparison of the induction characteristics of thiopentone and propofol. Anaesthesia 1985;40939-44. 13. White PF. Propofol: pharmacokinetics and pharmacodynamics. Semin Anesth 1988;7(Supp1):&20. 14. Gueret P, Meerbaum S, Wyatt HL, Zwehl W, Corday E. Determination of left ventricular stroke volume by crosssectional echocardiography. Circulation 1979;60:1104-13. 15. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K. Left ventricular interaction with arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:H77WO.
ANESTH ANALG i9~1;72:28-35
35
16. Siege1 S, Castellan NJ. Singapore: McGraw Hill, 1988. Nonparametric statistics for the behavioral sciences, 2nd ed. 17. Christensen JH, Andreasen F, Jansen JA. Pharmacokinetics and pharmacodynamics of thiopentone. Anaesthesia 1982;37: 39-04, 18. Carlier S, Van Aken H, Vandermeersch E, Thorniley A, Byttebier G. Does nitrous oxide affect the hemodynamic effects of anesthesia induction with propofol? Anesth Analg 1989;68: 72a33. 19. Puttick RM, Terrar DA. Effects of propofol on membrane currents and contraction in single myocytes isolated from guinea-pig ventricle. Br J Pharmacol 1989;98:742R. 20. Flickinger H, Fraimow W, Cathcart R, Nealon T. Effect of thiopental induction on cardiac output in man. Anesth Analg 1961;40:693-700, 21. Cullen I'M, Turtle M, Prys-Roberts C, Way WL, Dye J. Effects of propofol anesthesia on baroreflex activity in humans. Anesth Analg 1987;66:1115-20. 22. Van Hamme MJ, Ghoneim MM, Ambe JJ. Pharmacokinetics of etomidate, a new intravenous anesthetic. Anesthesiology 1978; 49:27&7. 23. Bruckner JB, Gethmann JW, Patschke D, Tarnow J, Weyrnar A. Untersuchungen zur Wirkung von Etomidate auf den Kreislauf des Menschen. Anaesthesist 1974;23:322-30. 24. Morris RB, Cahalan MK, Miller RD, Wilkinson PL, Quasha AL, Robinson SL. The cardiovascular effects of vecuronium (ORG NC45) and pancuronium in patients undergoing coronary artery bypass grafting. Anesthesiology 1983;58:43-0. 25. Rolly G, Versichelen L. Comparison of propofol and thiopental for induction of anaesthesia in premedicated patients. Anaesthesia. 1985;40:945-8. 26. Berger HJ, Davies RA, Batsford WP, Hoffer PB, Gottschalk A, Zaret BL. Beat to beat left ventricular performance assessed from the equilibrium cardiac blood pool using a computerized nuclear probe. Circulation 1981;63:133-41. 27. Tarnow J. Clinical possibilities and limitations of techniques assessing the effects of anaesthetics on myocardial function. Br J Anaesth 1988;60:52%7S. 28. Lunkenheimer PP, Redmann K, Whimster WF, Theissen J, Frieling G, Lunkenheimer A. The problem created by myocardial structure in assessing function. Br J Anaesth 1988;60:2% 7s.
ANESTH ANALG 1991;72:28-35
Cardiodynamic Effects of Propofol in Comparison With Thiopental: Assessment With a Transesophageal Echocardiographic Approach Jan P. Mulier, MD, Patrick F. Wouters, MD, Hugo Van Aken, Gery Vermaut, MD,and Eugltne Vandermeersch, MD MULIER JP, WOUTERS PF, VAN AKEN H, VERMAUT G, VANDERMEERSCH E. Cardiodynamic effects of propofol in comparison with thiopental: assessment with a transesophageal echocardiographic approach. Anesth Analg 1991;72:28-35.
In 40 patients, the cardiovascular effects of low- and high-dose propofol anesthesia (single bolus of 2.5 mglkg in group A, 2.5 mglkg in group C) were examined and conipared with those of low- and high-dose thiopental (4 mglkg in group B, 6.5 mglkg in group D ) (n = 10 patients per group). After induction of anesthesia with etomidate, all patients were ventilated with 70% nitrous oxide in oxygen. Peripheral arterial systolic blood pressure (SAP) and transesophageal echocardiographic short-axis measurements were used to calculate the end-systolic pressure-volume relationship (E) as an index of global myocardial contractility. In all groups SAP decreased significantly below baseline levels for the duration of the measurements (15 rnin after drug administration), except for the lower dose of thiopental, where SAP returned to baseline values within 10 min. Propofol at a dose of 1.5 mglkg significantly decreased cardiac output (CO) (from 5.1 t 0.25 [mean t SEMI to 4.2 0.23 Llrnin), stroke volume ( S V ) (from 64 2 3 to 56 ? 3.6 mL), and the slope of E (from 71 t 3.5 to 65 4.2 mm HgImL) until 4 min after drug administration. The higher dose of propofol significantly decreased CO (from 5.1 0.29 to 4.1 0.26 Llmin), SV (from 64 t 3
*
*
*
*
The induction of anesthesia with propofol (2,6diisopropylphenol) is often associated with marked decreases in systemic arterial blood pressure in humans (14).Clinical investigations have identified a propofol-induced afterload reduction (1,3,4) as the most important factor in explaining propofol-induced Received from the Department of Anesthesiology, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium. Accepted for publication August 9, 1990. Address correspondence to Dr. Mulier, Department of Anesthesiology, University Hospitals, Katholieke Universiteit Leuven, Herestraat 49, 8-3000 Leuven, Belgium. 01991 by the International Anesthesia Research Society 0003-2999/91/$3.50
MD,
PhD,
*
to 52 & 4.6 mL), and the slope of E (from 71 3.6 to 62 2 3.7 mm HglmL) until 20 rnin after drug administration. End-systolic volume increased significantly (from 60 2 7.6 to 68 2 5.5 mL) until the sixth minute, followed by a decrease in end-diastolic volume at 10 min (from 124 6.5 to 118 2 4.3 mL). Thiopental at a dose of 4 mglkg reduced end-diastolic volume significantly at 10 rnin (118 +- 7.2 versus 128 7.8 mL) and resulted in a significantly higher CO (4.6 0.29 versus 4.2 ? 0.23 Llmin) and the slope of E (69 t 3.9 versus 65 4.2 mm HglmL) when compared with low-dose propofol at 4 min. Thiopental at a dose of 6.5 mg/kg significantly reduced the index of afterload (SAPISV) (from 63 2 5 to 56 2 4.6 mm HglmL) and the slope of E (from 69 % 4.2 to 63 3.6 rnm HglmL), whereas heart rate increased (from 76 2 5.2 to 84 2 6.8 beatslmin) until the fourth minute after drug administration. When compared with high-dose propofol, end-systolic volume was significantly lower and SAP, SV, CO, and slope of E were significantly higher during thiopental at equipotent doses. It is concluded that propofol reduces SAP mainly through its negative inotropic properties. Furthermore, the cardiodepressant effects of propofol are more pronounced and more prolonged than those of equipotent doses of thiopental when given as a single bolus.
*
* *
*
*
Key Words: ANESTHETICS, INTRAVENOUS-thiopental, propofol. HEART, CONTRACTILITY-thiopental,
propofol.
reduction of arterial blood pressure. In contrast, a recent study demonstrated that the predominant effect of propofol was a decrease in preload (5). However, Van Aken et al. concluded from their data that propofol might also have negative inotropic properties (2). Recently, data obtained from animal studies have supported this hypothesis (6,7). In the clinical setting, less invasive monitoring techniques are required to investigate the cardiovascular properties of anesthetic drugs. The ventricular end-systolic pressure-volume relationship, introduced by Sagawa (8), provides a reliable and mini-
CARDIODYNAMIC EFFECTS OF PROPOFOL
mally invasive technique for measuring myocardial contractility. This method is relatively independent of changes in preload and incorporates afterload changes (9). Inotropic interventions have been shown to modify the slope of the ventricular end-systolic pressure-volume relationship (8,lO). This technique is applicable for clinical use provided that peak systolic arterial blood pressure and echocardiographicderived volume calculations may be substituted for ventricular end-systolic pressure and absolute endsystolic volume, respectively (11). We have used the end-systolic pressure-volume relationship to determine the effects of a single dose of propofol or thiopental on the myocardial contractility in humans. The purpose of our study was to determine the relative importance of changes in preload, afterload, and myocardial contractility in the propofol-induced decreases in arterial pressure in humans. Thiopental was chosen as the drug of reference and both drugs were used in doses recommended for clinical induction of anesthesia (12,13).
Materials and Methods Forty ASA physical status I or I1 patients scheduled to undergo elective major abdominal and orthopedic surgery were studied. The study was approved by the Institutional Ethical Committee, and informed consent was obtained from all patients. Patients did not qualify if they had a history of allergy, were obese (>120% of ideal body weight), or had signs or symptoms of hepatic, renal, hematologic, metabolic, cardiac, or central nervous system disease. All patients were premedicated 2 h before anesthesia with 2 mg oral lorazepam. On arrival in the operating room, an electrocardiograph was attached and a modified V, lead continuously displayed. Under local anesthesia, cannulae were inserted into a peripheral vein and a radial artery. A continuous intravenous (IV) infusion of lactated Ringer's solution was maintained at a rate of 2 mL.kg-l.h-' for the study period. Anesthesia was induced by the IV administration of etomidate (0.3 mg/kg over 60 s). After IV administration of vecuronium (0.1 mg/kg), laryngoscopy was performed, the pharynx and vocal cords were sprayed with 5 mL of a 2% lidocaine solution, and the trachea was intubated. Mechanical ventilation was started, and anesthesia was maintained with 70% nitrous oxide in oxygen. End-tidal was monitored using a carbon dioxide Pco, (PETCO~) analyzer and maintained between 35 and 41 mm Hg using a fixed tidal volume of 10 mL/kg and adjusting the ventilatory rate. Immediately after induction, a
ANESTH ANALG 1991;722%35
29
-/ ESV Fipure 1,. Measurement of E: maximal elastance as parameter of contractility. The baseline contractility Eo is calculated as a regression line through the points nil and mn. The change in contractility is reflected by a change in the slope (a)of the line E [SAP/(ESV Vd)] through a new point p and the same point Vd.
transesophageal echocardiograph probe (Hewlett Packard) was introduced into the esophagus to determine the left ventricular volume. The probe was positioned to achieve a cross section of the left ventricle at the midpapillary muscle level and stabilized at the mouth. The radial arterial pressure and airway pressure tracings, and the electrocardiogram, were simultaneously recorded with a two-dimensional echo view of the heart. Recordings were stored on videotape for later off -line computer analysis. Midpapillary crosssectional end-diastolic area of the left ventricle and midpapillary cross-sectional end-systolic area of the left ventricle were measured to calculate end-diastolic volume (EDV) and end-systolic volume (ESV) using the modified Simpson formula (14). Stroke volume (SV) was calculated as the difference between EDV and ESV. Cardiac output (CO) was calculated as the product of SV and heart rate (HR). The quotient of systolic arterial blood pressure (SAP) and SV was used as an index of left ventricular afterload as described by Sunagawa et al. (SAP/SV = Ea: effective arterial elastance) (15).
Calculation of Ventricular Contractility With PeakSystolic Pressure to End-Systolic Volume Relationship The determination of left ventricular contractility using the principle of the peak-systolic pressure to end-systolic volume relationship (8) was performed as follows (Figure 1). The baseline contractility (Eo) was calculated once the patient was hemodynamically stable. Point ml had as its coordinates ESV on
30
MULlER ET AL.
ANESTH ANALG 1991;72:2635
the x-axis and SAP on the y-axis. Points m2 to mn, with the same coordinates, were obtained during the rapid decrease in blood pressure that followed the IV injection of 100 pg nitroglycerin. Measurements were stopped at the moment HR changed. The line Eo was constructed using linear regression analysis of all the points ml to mn. The intercept of the line Eo with the x-axis (point Vd)was the same as the extrapolated left ventricular end-systolic volume at zero blood pressure. When the drug under investigation was then administered, a new point p with ESV on the x-axis and SAP on the y-axis was determined. The slope of a new line E , drawn through point p and the intercept on the x-axis of the previously determined Eo, point Vd, was then calculated. A change in contractility when compared with baseline was reflected by a change in the slope [SAP/(ESV- Vd)] of line E when compared with Eo. An increase in contractility was reflected by an increase of the slope of E , and a decrease in contractdity was reflected by a decrease in the slope of E.
Experimental Protocol Patients were randomly assigned to four study groups. Fifteen minutes after induction of anesthesia, baseline hemodynamic recordings were obtained and baseline contractility calculated. Group A (10 patients) received a single bolus of propofol in a dose of 1.5 mg/kg. Group B (10 patients) received 4 mg/kg of thiopental. Group C (10 patients) received 2.5 mgkg of propofol, and group D (10 patients) received 6.5 mg/kg of thiopental. The drugs were administered intravenously over 60 s. Hemodynamic measurements were repeated 2, 4, 6, 10, and 15 min after injection of the drug. Blood samples were drawn at 2, 4, 10, and 15 min after injection of the drug for later analysis of plasma concentrations of the anesthetic drugs. Data are presented as mean ? SEM. For statistical comparisons of means within a group, the Friedman test was used. For statistical comparison of means between groups A and B, and between groups C and D, the Wilcoxon-Mann-Whitney test was used (16). P < 0.05 was considered to indicate a statistically significant difference.
Results The demographic data of the patients are listed in Table 1. There were no significant differences between groups with regard to age, weight, height, or body surface area.
Table 1. Demographic Data Group A Age (yr) Weight (kg) Height (cm) BSA (m2)
Group B
Group C
60+4 6223 58 2 62 2 71 t 4 76 2 6 170 t 3 167 t 2 171 ? 1.88 t 0.12 1.77 t 0.09 1.75 2
BSA, body surface area. All values are expressed as mean
Group D
59 2 3 68 t 5 168 t 4 3 0.08 1.80 ? 0.07 4
4
2 SEM.
The hemodynamic changes associated with each drug are listed in absolute values in Table 2 for groups A and B and in Table 3 for groups C and D. The changes in SAP and E are shown in Figures 2 and 3 for each group. There were no significant differences in baseline values among the four groups. In all groups SAP decreased significantly below baseline levels. With the low dose of thiopental, SAP returned to baseline values at 10 min; in the other groups SAP remained low for the duration of the experiment (15 min). At 2 and 4 min, propofol at a dose of 1.5 mg/kg decreased SV (from 64 ? 3 to 59 2 4.1 and 56 t 3.6 mL, respectively), CO (from 5.1 ? 0.25 to 4.5 ? 0.37 and 4.2 ? 0.23 L/min, respectively), and the slope of E (from 71 t 3.5 to 66 t 3.8 and 65 ? 4.2 mm Hg/mL, respectively). The higher dose of propofol decreased SV (from 64 k 3 to 52 2 4.6 mL), CO (from 5.1 t 0.29 to 4.1 t 0.26 L/min), and the slope of E (from 71 ? 3.6 to 62 k 3.7 mm Hg/mL) for 10 min after drug administration. End-systolic volume increased for 6 min (from 60 t 7.6 to 68 t 5.5 mL) and returned to baseline at 10 min, whereas EDV decreased at 10 min (from 124 ? 6.5 to 118 ? 4.3 mL). Thiopental at a dose of 4 mg/kg reduced EDV at 10 min (118 -+ 7.2 versus 128 k 7.8 mL). At 2 and 4 min after drug administration, the higher dose of thiopental increased HR (from 76 ? 5.2 to 82 ? 4.1 and 84 ? 6.8 beatslmin, respectively), decreased the slope of E (from 69 5 4.2 to 62 2 3.8 and 63 ? 3.6 mm Hg/mL, respectively), and decreased the index of afterload (from 63 k 5 to 54 ? 3.9 and 56 -+ 4.6 mm Hg/mL, respectively). End-diastolic volume was significantly below baseline at 10 min (117 7.2 versus 125 2 8.6 mL). When compared with thiopental at a dose of 4 mg/kg, 1.5 mg/kg propofol resulted in a significantly lower CO (4.2 0.23 versus 4.6 ? 0.29 Limin) and slope of E (65 2 4.2 versus 69 k 3.9 mm Hg/mL) at 4 min after drug administration. Propofol (2.5 mg/kg) was associated with a lower SAP, CO, slope of E , and SV, and with a higher ESV, when compared with 6.5 mg/kg thiopental. Plasma concentrations of propofol and thiopental are displayed in Figure 4. Both drugs reached their highest
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CARDIODYNAMIC EFFECTS OF PROPOFOL
31
ANESTH ANALG 1991;72:2%35
Table 2. Hemodynamic Data ( n = 10 in each group) After an Induction Dose (1.5 mg/kg propofol in group A; 4 mgikg thiopental in group B) Baseline
2 min
4 min
6 min
10 min
15 min
79 t 3 112 t 5.4 123 2 5.4 59 2 6.1 64 2 3 5.1 t 0.25 71 t 3.5 60 2 3.8
76 t 3.5 95 t 6.8" 121 t 6.7 62 2 4.1 59 2 4.1" 4.5 t 0.37" 66 t 3.8" 58 t 4.5
75 t 4.4 92 t 6.6" 118 t 6.3 62 t 4.8 56 t 3.6" 4.2 2 0.23"*' 65 t 4.2"," 59 2 3.7
78 t 3.6 91 _t 6a 116 2 4.8 60 t 5.2 56 2 4.6 4.4 t 0.4 66 _t 5.8 58 t 5.4
79 t 3 91 _t 7.2" 118 t 6.1 59 f 4.5 59 2 3.7 4.7 h 0.29 67 t 4.7 57 2 4.9
80 t 3.7 95 _t 6.6" 116 t 5.1 57 t 6.6 59 2 2.8 4.7 t 0.28 69 2 3.9 58 t 4.8
75 h 4.5 113 2 6.4 128 t 7.8 65 2 3.7 63 2 3.2 4.7 t 0.3 70 t 4.7 61 2 5.2
76 t 3.8 97 2 7" 126 t 10.1 64 2 4.8 62 t 4 4.7 2 0.34 67 2 5.1 55 2 4.6
79 t 3.2 99 t 5.4" 119 t 7.8 61 t 4.1 58 t 3.9 4.6 t 0.29" 69 t 3.9' 59 t 3.5
76 t 2.7 102 t 6" 120 2 6.9 62 t 5.5 58 2 3.7 4.4 t 0.26 69 t 4.5 60 h 4.2
76 t 2.8 104 t 6.2 118 t 7.2" 60 t 4 58 2 3 4.4 t 0.2 70 t 4 61 h 5.1
75 t 2.9 107 t 7.2 121 2 8.1 62 t 3.7 59 t 2.9 4.4 f 0.27 70 2 5.2 61 t 3.8
Group A HR (beatsimin) SAP (mm Hg) EDV (mL) ESV (mL) SV (mL) CO (Limin) E:SAP/(ESV - Vd) (mm HgimL) SAPiSV (mm HgimL)
Group B HR (beatsimin) SAP (mm Hg) EDV (mL) ESV (mL) SV (mL) CO (Limin) E:SAP/(ESV - Vd) (mm HgimL) SAP/SV (mm HgimL)
HR, heart rate; SAP, systolic arterial blood pressure; EDV, end-diastolic volume; ESV, end-systolic volume; SV, stroke volume; CO, cardiac output; E:SAPI(ESV - Vd), maximal elastance: index of contractility; SAPISV, arterial elastance: index of afterload. All values are expressed as mean SEM. "P < 0.05 compared with baseline values within the group. bP < 0.05 compared with same-time value in the other group.
*
Table 3. Hemodynamic Data ( n = 10 in each group) After an Induction Dose (2.5 mgikg propofol in group C; 6.5 mgikg thiopental in group D) ~~~~
Group C HR (beatsimin) SAP (mm Hg) EDV (mL) ESV (mL) SV (mL) CO (Limin) E:SAP/(ESV - Vd) (mm HgimL) SAPiSV (mm HgimL)
Baseline
2 min
4 min
6 min
10 min
15 min
80 t 6.9 122 t 5.3 124 2 6.5 60 t 7.6 64 t 3 5.1 t 0.29 71 t 3.6 62 t 4.2
76 5 4.8 83 t 2.9",' 120 t 7.5 71 2 6.4"," 49 t 4"J' 3.7 t 0.34"," 57 f 3.8".' 59 2 3.6
74 t 5.7 89 t 4.3" 121 t 6.8 68 t 4.9",b 53 h 2.6",' 3.9 t 0.37",' 60 2 4.7" 59 t 5.2
78 t 6.2 88 t 4.8" 119 t 4.6 68 5.5",' 51 t 4.3a,' 4 2 0.29",' 60 t 4.2''.' 60 t 4
79 ? 4.6 93 ? 4.6' 118 & 4.3" 66 I 5.1' 52 & 4.6",' 4.1 t 0.26"," 62 t 3.7" 61 C 3.5
79 t 3.4 98 t 5.5" 121 t 7.2 66 4 6.7 55 t 3.2 4.3 t 0.24 63 t 5.3 61 t 3.6
76 t 5.2 118 t 4.7 125 t 8.6 65 t 6.2 60 t 4 4.6 t 0.37 69 t 4.2 63 t 5
82 t 4.1" 90 2 3.8",' 121 t 9.2 66 t 7.8' 55 2 2.5' 4.5 2 0.3' 62 t 3.8",' 54 t 3.9"
84 t 6.8" 89 t 4 I 119 t 8.7 64 t 5" 55 t 3' 4.6 t 0.35" 63 +- 3.6" 56 t 4.6"
82 t 5.9 92 +- 3.5" 118 t 6.8 62 2 6.5' 56 t 4b 4.6 t 0.28' 65 t 4.8' 59 t 3.9
82 ? 5 94 t 3.7" 117 & 7.2" 60 t 6.8' 57 t 3.70 4.7 t 0.4' 66 ? 5.2 59 k 4.7
79 t 5.3 98 t 3.9" 118 t 7.4 62 +- 4.9 56 +- 2 4.4 +- 0.28 66 t 5 60 t 4
Group D HR (beatsimin) SAP (mm Hg) EDV (mL) ESV (mL) SV (mL) CO (Limin) E:SAP/(ESV - Vd) (mm HgimL) SAPiSV (mm Hg/mL)
Abbreviations as in Table 2. All values are expressed as mean 5 SEM. a P < 0.05 compared with baseline values within the group. 'P < 0.05 compared with same-time value in the other group.
concentrations 2 min after injection. These data resemble the profile of redistribution and plasma clearance reported in the literature (13,17). No statistically significant correlations were found between plasma concentrations and hemodynamic variables.
Discussion Previous studies on the cardiovascular effects of an Iv induction dose of propofol in humans have all documented decreases in SAP (2,4,5,17). However, the
32
MULIER ET AL.
ANESTH ANALG 1991;72:28-35
-
130
120
-4-
Group B : Thiopentai4 mgkg Group C : Propofo12.5 mg/kg
I Group
D : Thiopental6.5 mglkg
110
0
X
E
100
E 90
80
Mean f SEM 70
0
5
10
15
minutes
Figure 2 . Changes in SAP after single-bolus injections of 4 and 6.5 mgikg thiopental and 1.5 and 2.5 mg/kg propofol.
reasons proposed as causes for this decrease in blood pressure vary from investigator to investigator. Claeys et al. (4), for example, suggested that the decrease in systemic vascular resistance resulted in a decrease in SAP, while CO and SV remained unchanged. However, experimental conditions such as the presence of hypercarbia in the spontaneously breathing subjects may have accounted for their observations. Van Aken et al. (2) and Carlier et al. (18), however, ascribed the decrease in systemic arterial pressure to significant decreases in CO and SV without concomitant changes in SVR or in pulmonary capillary wedge pressure. Those authors suggested that a negative inotropic action of propofol is responsible for the decrease in CO and SAP. Lepage et al. (5) also found that the decrease in mean arterial pressure was related to a decrease in cardiac index and stroke index (SI). This decrease in cardiac index was associated with a decrease in EDV or preload. They suggested that a decrease in venous return, caused by an increase in venous capacitance, may be responsible for the decrease in CO and systemic arterial pressure. However, whereas mean arterial
pressure decreased significantly, ESV remained unaffected in that study. Therefore, a reduction of mean arterial pressure without a decrease in ESV suggests a negative inotropic effect as well. Recently published results from animal studies provide evidence along the same lines. Briissel et al. demonstrated, in an acute closed-chest dog model, that propofol reduces the rate of force development in the left ventricle (6).Also, in an open-chest acutely instrumented pig model, Coetzee et al. found a significant reversed correlation between propofol plasma concentrations and myocardial contractility (7); Puttick and Terrar found a shortening of the action potential duration by propofol, indicating a reduction in calcium entry and therefore a possible negative inotropic effect (19). Our data obtained in humans indicate that the slope of the end-systolic pressure-volume relation (E), as an index of myocardial contractility, decreased significantly during low- and high-dose propofol. End-diastolic volume, as an index of preload, remained stable. Cardiac output decreased consequently and in the presence of an unchanged SAP/ SV, as an index of afterload, caused a reduction in SAP. In agreement with previously published data, the
CARDIODYNAMIC EFFECTS OF PROPOFOL
-
80
33
ANESTH ANALG 1991:72:2%35
Group B :Thiopental4 mglkg C : Propofo12.5 mglkg Group D :Thiopental6.5 mgkg
I Group
I
=w 0
70
c
0
P)
P
-0 v)
60
O
: p < 0.05 between group A an B
Mean k SEM 50
0
5
10
15
minutes
main effect of thiopental in our study was a decrease in afterload (20). The higher dose of thiopental resulted in a decrease in the index of contractility and a delayed decrease in EDV. However, CO remained unchanged due to a compensatory increase in HR and, perhaps, a decrease in SAPISV. Comparisons with the high dose of propofol indicate that the negative inotropic effects of thiopental are less pronounced. The reflex tachycardia during thiopental does not occur with propofol in the presence of similar reductions in blood pressure. These findings might indicate more pronounced baroreflex inhibition during propofol anesthesia, as described earlier by Cullen et al. (21). The peak negative inotropic effect of propofol occurred 2 min after drug administration. However, because the plasma concentrations during non-steady state are not in equilibrium with the tissue levels after single-dose administration, we could not demonstrate a significant correlation between the plasma drug concentrations and hemodynamic measurements. It appears from our data that the hemodynamic effects outlast the hypnotic effects of propofol. Etomidate as an induction dose of 0.3 mgkg with 0.1 mgkg vecuronium was given 15 min before the start of the experiment. Furthermore, 70% nitrous oxide in oxygen was administered throughout the present ex-
Figure 3. Changes in E (rnrn HgimL) as a parameter of contractility after single-bolus injections of 4 and 6.5 mgikg thiopental and 1.5 and 2.5 mgikg propofol.
periment. We therefore cannot exclude the possibility that these agents modified the hemodynamic or cardiodynamic alterations associated with propofol and thiopental. However, because baseline measurements as well as all measurements after the administration of propofol or thiopental were made under equal anesthetic conditions, it seems likely that the observed changes can be ascribed to the drug that was added. Furthermore, plasma levels of etomidate decline extremely rapidly with a distribution half-life of 2.6 min (22),and in patients without heart disease only minimal effects on the cardiovascular system are observed after IV administration of 0.3 mglkg etomidate (23). Vecuronium, used to facilitate tracheal intubafion and controlled ventilation, has minimal effects on cardiovascular function (24). In the present study all hernodynamic variables returned to baseline levels 10 min after the injection of etomidate and vecuronium. Comparisons of IV anesthetic agents require the use of equianesthetic doses. Rolly et al. (25) found the relative potency of propofol compared with thiopental to be 1:2.6 in humans (inducing sleep in patients).
34
MULIER ET AL.
ANESTH ANALG 1991;72:28-35
Thiopental plasma concentrations
1 40
-
E .
-
30-
UI
%
20 -
10
-
04 5
0
15
10
minutes
l2 10
-E . 0
=.
Propofol plasma concentrations
1
I T
Ij 0
4
10
5
1.5mg/kg
15
minutes
Figure 4. Thiopental and propofol plasma concentrations in micrograms per milliliter at 2, 4, 10, and 15 min after single-bolus injections of 4 and 6.5 mgikg thiopental and 1.5 and 2.5 mg/kg propofol.
Thus, 1.5 mg/kg propofol corresponds to 4 mg/kg thiopental, and 2.5 mg/kg propofol corresponds to 6.5 mg/kg thiopen tal . Assessment of contractility changes in humans in the clinical setting is quite difficult. Although radionuclide ventriculography with a gamma camera of small size and true mobility permits semi-invasive pharmacodynamic studies, problems such as difficulty in obtaining absolute volumes (as a result of the fixed field view of the detector), probe positioning over the left ventricle, recording of background activity, and radiation safety in the operating room make the use of this technique less practical (26,27). Changes in the maximum rate of increase in left ventricular pressure (dP/dt,,,) are known to be highly sensitive to acute changes in contractility. Although measurement of left ventricular dP/dt may be used to study anesthetic drugs, provided that high-fidelity catheter-tip manometers are used, this technique is very invasive. Also, dP/dt,n,, is depen-
dent on preload, afterload, and HR. Furthermore, due to ethical considerations this method cannot be used to obtain information about the effects of anesthetics on left ventricular contractility in humans. Therefore, the less invasive method using the pressure-volume analysis was used in this study. Determination of true end-systolic pressure requires left ventricular or aortic pressure measurement. The manipulation of arterial pressure to obtain different pressure-volume points may cause reflex inotropic changes because of sympathetic activation or withdrawal. Thus, for clinical use this relationship needs simplification; this was described by Heinrich et al. (11).Several important features of our protocol have to be explained. First, cross-sectional areas of the ventricle can be measured, which provides a more accurate estimation of ventricular volume than do diameter measurements. Lunkenheimer et al. (28) showed that contraction is mainly concentric and that the long-axis measurement is relatively stable. Hence, calculations are made with one long-axis measurement using the change in cross-sectional area. Second, sympathetic stress and changes due to respiration have to be avoided throughout the experiment. Therefore, our patients were anesthetized with etomidate as induction agent and 70% nitrous oxide in oxygen as a maintenance anesthetic. Furthermore, they were paralyzed, and ventilation was controlled. Intubation, changes in respiration, and probe positioning were performed immediately after administration of etomidate. Baseline measurements were obtained 15 min after the induction of anesthesia during 70% nitrous oxide in oxygen and were immediately followed by administration of the drug under investigation. In conclusion, our end-systolic pressure-volume relationship model demonstrates that propofol has dose-dependent, negative inotropic properties in humans. Furthermore, it is shown that the negative inotropic properties of propofol outweigh those of equipotent doses of thiopental in both intensity and duration.
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