Free
Meeting Abstracts  |   February 1996
Inotropic Effects of Propofol, Thiopental, Midazolam, Etomidate, and Ketamine on Isolated Human Atrial Muscle
Author Notes
  • (Gelissen) Research Fellow, Department of Anesthesiology.
  • (Epema, Krijnen) Instructor in Anesthesiology, Department of Anesthesiology.
  • (Henning) Assistant Professor, Department of clinical Pharmacology.
  • (Hennis) Professor of Anesthesiology; Chairman, Department of Anesthesiology.
  • (den Hertog) Professor of Pharmacology; Chairman, Department of Clinical Pharmacology.
  • Received from the Departments of Anesthesiology and Clinical Pharmacology, University Hospital Groningen, University of Groningen, Groningen, The Netherlands. Submitted for publication June 16, 1995. Accepted for publication October 26, 1995. Presented in part at the annual meeting of the American Society of Anesthesiologists, Washington, D.C., October 9-13, 1993, and San Francisco, California, October 15-19, 1994.
  • Address reprint requests to Dr. Epema: Department of Anesthesiology, Groningen University Hospital, P.O. Box 30001, 9700 RB Groningen, The Netherlands.
Article Information
Meeting Abstracts   |   February 1996
Inotropic Effects of Propofol, Thiopental, Midazolam, Etomidate, and Ketamine on Isolated Human Atrial Muscle
Anesthesiology 2 1996, Vol.84, 397-403.. doi:
Anesthesiology 2 1996, Vol.84, 397-403.. doi:
Key words: Anesthetics, intravenous: etomidate; ketamine; midazolam; propofol; thiopental. Heart, atria: human; isometric contraction; inotropic effect.
INTRAVENOUS induction of general anesthesia often is associated with hypotension. [1-4] Several mechanisms have been thought responsible for the decreased blood pressure, including a direct effect on the contractility of the myocardium. Indirect factors, such as concomitant changes in preload and afterload of the heart, sympathetic activity, baroreflex activity, and central nervous system activity make the direct effects of anesthetics on contractility difficult to measure in vivo, although relative heart rate and load-independent indexes of contractility can be derived from a series of pressure-volume diagrams of the left ventricle.
Measurement of the intrinsic myocardial contractility is more accurately performed in an in vitro model. In different animal species, the in vitro effects of propofol, [5-8] thiopental, [5,9-12] etomidate [13,14] and ketamine [15-17] on the contractility of isolated cardiac tissue have been determined. The results of these studies show a variable degree of negative inotropic action in papillary or left atrial muscle. In contrast, etomidate did not induce a significant inotropic effect in papillary muscle of hamster, [18] whereas positive inotropy was demonstrated in rats [19] and ferrets [20] after ketamine administration. Midazolam has not yet been studied in isolated myocardium. To the best of our knowledge, however, there are no in vitro studies concerning the inotropic influence of intravenous anesthetics on human myocardium. The purpose of this study was to evaluate the direct inotropic effects of thiopental, propofol, midazolam, etomidate, and ketamine on isometric contractions of isolated human atrial tissue.
Materials and Methods
This study was approved by the institutional Ethical Committee, and informed consent was obtained from patients scheduled for routine coronary artery bypass surgery (CABG). Ventricular function was assessed using heart catheterization and found to be normal in all subjects (ejection fraction over 0.50 and absence of regional wall motion abnormalities). We studied atrial tissue from 16 male patients. In 15 patients, preoperative medication consisted of beta1-adrenoceptor antagonists, nitrates, and calcium channel blocking agents. One patient had only a beta blocker. All cardiac medication was continued and administered the day of surgery. All patients received similar anesthetic and surgery for coronary artery bypass graft. Anesthesia was induced using sufentanil and midazolam, with pancuronium administered to facilitate tracheal intubation, and maintained using a continuous infusion of midazolam and sufentanil. During atrial cannulation, a small sample of the atrial tissue was removed, stored in sterile buffer solution and immediately transported to the laboratory. None of the patients received inotropic support before the atrial tissue was removed.
Experimental Design
In the laboratory, the atrial tissue was split into three strips, measuring 7.8+/-0.9 mm long and having a cross-sectional area of 2.8+/-0.3 mm2without differences between groups (analysis of variance), and mounted in a temperature-controlled (30 degrees C) chamber for isometric contraction as described earlier. [21] Strips were superfused with an oxygenated buffer consisting of (in mM): NaCl 125, CaCl21.2, KCl 6, NaH2PO41.2, MgCl22.5, hydroxyethylpiperazineethane sulfonic acid (HEPES) 10, and glucose 11 (pH 7.40+/-0.05). They were stimulated at optimal preload at 0.5 Hz with rectangular pulses of 5 ms duration, and an intensity of 10% above threshold. The peak value of the developed force was measured using a force transducer (HBM, Hamburg, Germany). After 15 min of transport bathing and 45 min of superfusion with stabilization, the muscle strips showed a constant isometric contraction on stimulation, which remained stable for many hours. The combined effects of the transport, the bathing procedure, the superfusion, and the stabilization period before the start of the actual experiment most likely allowed for the washout of any residual effects of anesthetics and patient medication. All experiments were carried out with the initial muscle lengths set at that at which force development was maximal. The mean force generated at optimal length was 14.6+/-1.9 mN *symbol* mm sup -2 without differences between groups (analysis of variance). Thiopental, propofol solved in Intralipid (10%; Zeneca, Ridderkerk, The Netherlands), midazolam, etomidate solved in propylene glycol or ketamine were incrementally added to obtain cumulative concentrations of 10 sup -6 to 10 sup -2 M. Before the maximal contraction was recorded, muscle strips were exposed to each concentration until a steady state was reached for at least 5 min. To facilitate comparison of the anesthetics, one drug was tested on each available strip. Because most atrial strips were too small to be split into five pieces, three atrial strips per patient were prepared. To obtain a standard, the effect of one of the anesthetics (propofol) was tested in muscle strips from all patients. Thus group 1 consisted of propofol, thiopental, and midazolam, group 2 of propofol, etomidate, and ketamine. To test tissue stability, three muscle strips were stimulated in the buffer solution without addition of any drug. After equilibration, the developed force of these strips was stable within+/-3% during 2.5 h, which was the average time for each experiment.
Statistical Analysis
The baseline isometric force without anesthetic was normalized to 100%. All values are expressed as mean+/-SEM. Mean concentration-response curves were fitted using a logistic regression model (Sigmaplot 4.1, Jandel) and compared with analysis of variance.
Concentration-response curves of individual patients were fitted by a similar procedure and IC50s were compared using the Student's t-test. IC50is defined as the concentration at which 50% of the maximal effect is obtained, e.g., 50% of the maximal suppression of contractility from the baseline value. P < 0.05 was considered to be significant.
Results
A typical example of the changes in isometric force in response to a step by step increase in concentrations of propofol is shown (Figure 1). Propofol, thiopental, midazolam, ketamine, and etomidate demonstrated a concentration-dependent inhibition of atrial muscle contraction, eventually leading to the complete cessation of contractions in all strips tested. Concentrations resulting in complete inhibition of contraction ranged between 3.10 sup -4 and 3.10 sup -3 M (Figure 2(A-F)). Concentration-response curves representing inhibition of the contractile force were plotted for each set of experiments and compared to the reported clinical concentration range (Figure 2(A-E)). Thiopental, and to a lesser extent, ketamine, was found to inhibit contractility in the clinical range. The concentration-response curves for propofol obtained in both groups I and II did not differ significantly (Table 1). The concentration-response curve of all propofol experiments is depicted (Figure 2(A)).
Figure 1. Typical experiment showing the force traces of an isometric twitch of human atrial tissue during exposure to increasing concentrations of propofol (15-1,500 micro Meter).
Figure 1. Typical experiment showing the force traces of an isometric twitch of human atrial tissue during exposure to increasing concentrations of propofol (15-1,500 micro Meter).
Figure 1. Typical experiment showing the force traces of an isometric twitch of human atrial tissue during exposure to increasing concentrations of propofol (15-1,500 micro Meter).
×
Figure 2. Comparative effects of increasing concentrations of anesthetic on isometric contractions of human atrial tissue induced by field stimulation. Data are mean+/-SEM. Curves were plotted using logistic regression. Hatched squares indicate the clinical concentration range during anesthesia. Coarse hatching (left) represents the total concentration and fine hatching (right) shows the free fraction. (A) Propofol (n = 16). (B) Thiopental (n = 7). (C) Midazolam (n = 7). (D) Ketamine (n = 9). (E) Etomidate (n = 9). (F) Combined plot showing the concentration-response curve of the five anesthetics. For statistical analysis, see Table 1.
Figure 2. Comparative effects of increasing concentrations of anesthetic on isometric contractions of human atrial tissue induced by field stimulation. Data are mean+/-SEM. Curves were plotted using logistic regression. Hatched squares indicate the clinical concentration range during anesthesia. Coarse hatching (left) represents the total concentration and fine hatching (right) shows the free fraction. (A) Propofol (n = 16). (B) Thiopental (n = 7). (C) Midazolam (n = 7). (D) Ketamine (n = 9). (E) Etomidate (n = 9). (F) Combined plot showing the concentration-response curve of the five anesthetics. For statistical analysis, see Table 1.
Figure 2. Comparative effects of increasing concentrations of anesthetic on isometric contractions of human atrial tissue induced by field stimulation. Data are mean+/-SEM. Curves were plotted using logistic regression. Hatched squares indicate the clinical concentration range during anesthesia. Coarse hatching (left) represents the total concentration and fine hatching (right) shows the free fraction. (A) Propofol (n = 16). (B) Thiopental (n = 7). (C) Midazolam (n = 7). (D) Ketamine (n = 9). (E) Etomidate (n = 9). (F) Combined plot showing the concentration-response curve of the five anesthetics. For statistical analysis, see Table 1.
×
Table 1. Inhibitory Effects
Image not available
Table 1. Inhibitory Effects
×
To compare the characteristics of the inhibition of atrial contraction by the various anesthetics, the IC50of the concentration-response relationship was determined in each strip by fitting the measured data with a logistic function (Table 1). The IC50of etomidate and midazolam did not differ. Propofol and ketamine possessed a significantly greater IC50, whereas that for thiopental was significantly less, both compared to etomidate and to midazolam (Table 1). Thus, the ranking order of inhibitory effects of the anesthetic agents as judged by their IC50values was: ketamine and propofol < etomidate < midazolam < thiopental (Table 1).
Discussion
This study clearly documents a concentration-dependent negative inotropic effect of propofol, thiopental, midazolam, etomidate, and ketamine in isolated human atrial tissue. The negative inotropic potency of the intravenous anesthetics as found in this study was plotted together with those obtained in isolated myocardium of various animal species (Figure 3).
Figure 3. Plots of the potency of negative inotropic effects of anesthetics on human atrial tissue with data from animal experiments. IC sub 50 values from this study on the x-axis are plotted against comparable data from animal studies on the y-axis. Most data are from in vitro studies of isolated heart preparations and some from other forms of isolated heart experiments. Data are from various studies using different experimental conditions. The nature of the data is provided in symbols. Circle = contractility studies of isolated ventricular tissue; square = contractility studies of isolated atrial muscle; diamond = other studies of contractility in models of isolated heart preparations. Species are depicted in the symbols and abbreviated as follows: R = rabbit; G = guinea pig; F = ferret; D = dog. Data are from the following studies: propofol, references 5, 6, 8, and 11; thiopental, [5,9-11,12,28]; midazolam, [32]; etomidate, [13,14,35]; and ketamine, [15-17] .
Figure 3. Plots of the potency of negative inotropic effects of anesthetics on human atrial tissue with data from animal experiments. IC sub 50 values from this study on the x-axis are plotted against comparable data from animal studies on the y-axis. Most data are from in vitro studies of isolated heart preparations and some from other forms of isolated heart experiments. Data are from various studies using different experimental conditions. The nature of the data is provided in symbols. Circle = contractility studies of isolated ventricular tissue; square = contractility studies of isolated atrial muscle; diamond = other studies of contractility in models of isolated heart preparations. Species are depicted in the symbols and abbreviated as follows: R = rabbit; G = guinea pig; F = ferret; D = dog. Data are from the following studies: propofol, references 5, 6, 8, and 11; thiopental, [5,9-11,12,28]; midazolam, [32]; etomidate, [13,14,35]; and ketamine, [15-17].
Figure 3. Plots of the potency of negative inotropic effects of anesthetics on human atrial tissue with data from animal experiments. IC sub 50 values from this study on the x-axis are plotted against comparable data from animal studies on the y-axis. Most data are from in vitro studies of isolated heart preparations and some from other forms of isolated heart experiments. Data are from various studies using different experimental conditions. The nature of the data is provided in symbols. Circle = contractility studies of isolated ventricular tissue; square = contractility studies of isolated atrial muscle; diamond = other studies of contractility in models of isolated heart preparations. Species are depicted in the symbols and abbreviated as follows: R = rabbit; G = guinea pig; F = ferret; D = dog. Data are from the following studies: propofol, references 5, 6, 8, and 11; thiopental, [5,9-11,12,28]; midazolam, [32]; etomidate, [13,14,35]; and ketamine, [15-17] .
×
Propofol
This study demonstrates a clear negative inotropic action of propofol on isolated human atrial tissue. The inhibitory potency of propofol on human atrial tissue contractility is in agreement with that obtained in guinea pig [6] and ferret papillary muscle [8] and close to that of guinea pig right ventricular tissue [11] and guinea pig left atrial muscle [5] (Figure 3). In contrast, propofol was devoid of substantial negative inotropic action in rat papillary muscle, [6,7] hamster papillary muscle, [22] and in situ canine heart preparations. [23] Clinical concentrations after induction with propofol range from 2 to 15 micro gram *symbol* ml sup -1. [24] Evidence suggests that only the free fraction of a drug is active. [25] As protein binding of propofol exceeds 95%, free fractions of propofol are less than 1 micro gram *symbol* ml sup -1 and far from the range of in vitro cardiac depression observed in this study. Thus, intrinsic depression of cardiac contractility seems to a lesser extent involved in the cardiovascular depression of propofol as observed in vivo. [25-27] .
Thiopental
The inhibitory potency of thiopental found in human atrial strips generally corresponds to that found in excised animal myocardial tissue (Figure 3). [5,9-11] A lower potency has been observed in right ventricular tissue of the ferret [12] and in isolated whole heart preparations in guinea pig. [28] The plasma concentration of thiopental at clinical induction of anesthesia reaches a peak of approximately 100 micro gram *symbol* ml sup -1 and returns to 10 micro gram/ml after 5 min. [29] These data on plasma concentration are supported by a more recent study of clinical anesthetic depth at different thiopental concentrations. [30] Thus, these studies suggest that the concentration of thiopental at induction varies between 10 and 100 micro gram *symbol* ml sup -1. Because about 75% of serum thiopental is bound to protein, the actual concentration of free drug at induction may range between approximately 2.5 and 25 micro gram *symbol* ml sup -1. In this concentration range, a significant inhibition of contractility was found in human atrial strips. Therefore, our results suggest that direct negative inotropic action of thiopental on human heart may be involved in the the cardiovascular depression observed after induction with this agent. [3,31] .
Midazolam
The negative inotropic effect of midazolam was between that of thiopental and propofol. No comparison can be made with data from isolated preparations of animal myocardium, because midazolam studies are not available. Midazolam, however, was one third as depressing on human heart as was observed in isolated whole rat heart. [32] The concentration range of midazolam after anesthetic induction varies between 0.5 and 1.5 micro gram *symbol* ml sup -1. [33] Protein binding of midazolam is more than 90%. Therefore, the free fraction probably does not exceed 0.1-0.2 micro gram *symbol* ml sup -1, suggesting that during clinical use, midazolam does not exhibit a negative inotropic action. This is supported by in vivo human and animal studies, in which hemodynamic effects of midazolam are attributed to changes in preload and afterload. [1,34] .
Etomidate
Etomidate showed a negative inotropic effect in human atrial strips with a potency similar to that found for midazolam. In isolated papillary muscle, perfused by a conscious donor dog, the measured potency of etomidate was similar to that found in this study. [35] In rabbits [13] and ferrets, [14] etomidate showed substantial negative effects on contractility of papillary muscle, but in a lower concentration range (Figure 3). In contrast, in rat [36] and frog, [14] etomidate produced only minimal effects on contractility. After induction of anesthesia with etomidate (0.3 mg *symbol* kg sup -1), its plasma concentration 4 min after the bolus injection was 0.3 micro gram *symbol* ml sup -1. [37] The concentration 1 min after intravenous administration is probably greater. As protein binding of etomidate is 75%, the concentration range of the free fraction of etomidate will not exceed 1 micro gram *symbol* ml sup -1. Thus, etomidate is assumed to be devoid of a negative inotropic action on human cardiac muscle during clinical use. This is supported by the observation that etomidate produces the least variation in hemodynamics of the intravenous anesthetics most often used. [38-40] .
Ketamine
Ketamine was characterized by the lowest potency with respect to its negative inotropic action in isolated human atrial strips. Previous studies have described both negative and biphasic effects of ketamine on contractility in vitro. Results of the current study are comparable to the negative inotropic effects of ketamine on rabbit [15] and guinea pig ventricular muscle [16] and ferret papillary muscle after administration of bupranolol. [17] In contrast, inotropic effects of ketamine on hamster [41] and rat ventricle are positive. [16,19] Positive inotropic action observed in other species such as the ferret is attributed to the ketamine-induced blockade of noradrenaline reuptake. [20] In clinical studies, the concentration of ketamine reached 60 micro Meter l sup -1 at 5 min after induction. [42] Protein binding of ketamine is only 20% and thus the free fraction of ketamine after induction may reach 40-50 micro Meter L sup -1 at 5 min. However, greater plasma concentrations can be expected at 1-3 min after induction and may reach 100-150 micro Meter. Our results therefore suggest that ketamine may have a modest direct negative inotropic effect after induction. However, because ketamine does not depress the cardiovascular system in vivo on induction, [43] it seems likely that this action is counteracted by centrally mediated stimulating responses. [44] Nevertheless, in some clinical conditions the direct negative inotropic action of ketamine may produce pronounced cardiovascular depression. [45] .
The purpose of this study was to present a quantitative description of the intrinsic effects of clinically used intravenous anesthetics on myocardial contractility in humans. The drugs were tested in the same formulation used clinically. Therefore, possible effects of solvents are also present. The effects of the solvent of etomidate and propofol on contractility of myocardial tissue have been studied previously. Propylene glycol, the solvent of etomidate, did not affect the contraction of papillary muscle of rabbit [13] and ferret. [14] The solvent of propofol, Intralipid (10%) emulsion, did not cause changes in inotropy in guinea pig [6,11] and rat papillary muscle. [6] In contrast, Cook [8] reported a modest increase of contractility in ferret papillary muscle (10%), possibly due to intralipid serving as metabolic substrate. Therefore, it seems unlikely that the presence of solvents in our experiments influenced the results.
The results of this study must be interpreted in the context of the nonphysiologic conditions of the experiments. Results were obtained at 30 degrees C at a stimulus frequency of 0.5 Hz and may differ from results obtained at a temperature of 37 degrees C and frequencies of 1-2 Hz. HEPES buffer has been reported to affect intracellular bicarbonate concentrations, resulting in a relatively depolarized resting potential and prolonged action potential in guinea pig papillary muscle preparations. [46] However, this effect of HEPES was a minor factor in the current study, because control experiments remained stable for a longer period of time (more than 2 h).
In contrast to earlier studies using different animal models, our patients were receiving beta1-adrenoceptor antagonists and calcium channel blockers. The acute effects of these drugs on contractility are not expected to influence the outcome of this study in view of the extensive washing and equilibration period before performing the experiments. However, it cannot be ruled out that cellular adaptation after the long-term use of antianginal medication (beta1blockers, calcium channel blockers and nitrates) affected the inotropic response and thus influenced the results of our measurements. Additional studies are needed to elucidate the influence of long-term medication on the interaction between intravenous anesthetics and contractility.
Furthermore, it is not known whether the results from experiments on human atrial tissue experiments are comparable to those on ventricular tissue, because data on human ventricular tissue are not available. In animal studies, no systematic difference has been observed. Comparison of the data of Azari in guinea pig atrial tissue [5] with ventricular studies of this species does not show a clear relationship. Comparison of the inotropic action of thiopental suggests a slightly greater sensitivity of guinea pig ventricular tissue. [11] Conversely, propofol showed a similar potency compared to a study of Park [11] and a lower sensitivity of the guinea pig right ventricle in another study, [6] although this may be related to differences in the experimental setup.
In summary, in human atrial tissue, thiopental was the most potent inhibitor of contractile force as compared to midazolam and etomidate, whereas propofol and ketamine were the least inhibitory intravenous anesthetics. Negative inotropic effects in the clinical concentration range were demonstrated for thiopental, and to some extent for ketamine. Thus, cardiovascular depression on induction of general anesthesia with thiopental is based on a direct negative inotropic action on human myocardium. The depression of hemodynamics after induction with propofol, midazolam, or etomidate cannot be explained by a direct negative inotropic action. Finally, it is unlikely that the improved hemodynamics observed clinically with ketamine are caused by an intrinsic action on the myocardium.
REFERENCES
Al-Khudhairi D, Whitwam JG, Chakrabarti MK, Askitopoulou H, Grundy EM, Powrie S: Hemodynamic effects of midazolam and thiopentone during induction of anaesthesia for coronary artery surgery. Br J Anaesth 1982; 54:831-5.
Grounds RM, Twigley AJ, Carli F, Whitwam JG, Morgan M: The hemodynamic effects of intravenous induction: Comparison of the effects of thiopentone and propofol. Anesthesia 1985; 40:735-40.
Todd MM, Drummond JC, Hoi Sang U: The hemodynamic consequences of high dose thiopental anesthesia. Anesth Analg 1985; 64:681-7.
Harris CE, Murray AM, Anderson JM, Grounds RM, Morgan M: Effects of thiopentone, etomidate and propofol on the hemodynamic response to tracheal intubation. Anesthesia 1988; 43:32-6.
Azari DM, Cork RC: Comparative myocardial depressive effects of propofol and thiopental. Anesth Analg 1993; 77:324-9.
Azuma M, Matsumura C, Kemmotsu O: Inotropic and electrophysiologic effects of propofol and thiamylal in isolated papillary muscles of guinea pig and the rat. Anesth Analg 1993; 77:557-63.
Riou B, Besse S, Lecarpentier Y, Viars P: In vitro effects of propofol on rat myocardium. ANESTHESIOLOGY 1992; 76:609-16.
Cook DJ, Housmans PR: Mechanism of the negative inotropic effect of propofol in isolated ferret ventricular myocardium. ANESTHESIOLOGY 1994; 80:859-71.
Frankl WS, Poole-Wilson PA: Effects of thiopental on tension development, action potential, and exchange of calcium and potassium in rabbit ventricular myocardium. J Cardiovasc Pharmacol 1981; 3:554-65.
Komai H, Rusy BF: Differences in the myocardial depressant action of thiopental and halothane. Anesth Analg 1984; 63:313-8.
Park WK, Lynch C III: Propofol and thiopental depression of myocardial contractility. Anesth Analg 1992; 74:395-405.
Housmans PR, Turkan Kudsioglu S, Bingham J: Mechanism of the negative inotropic effect of thiopental in isolated ferret ventricular myocardium. ANESTHESIOLOGY 1995; 82:436-50.
Komai H, Dewitt DE and Rusy B: Negative inotropic effects of etomidate in rabbit papillary muscle. Anesth Analg 1985; 64:400-4.
Mattheussen M, Housmans PR: Mechanism of the direct, negative inotropic effect of etomidate in isolated ferret ventricular myocardium. ANESTHESIOLOGY 1993; 79:1284-95.
Rusy BF, Amuzu JK, Bosscher HA, Redon D, Komai H: Negative inotropic effects of ketamine in rabbit ventricular muscle. Anesth Analg 1990; 71:275-8.
Endou M, Hattori Y, Nakaya H, Gotoh Y, Kanno M: Electrophysiological mechanisms responsible for inotropic responses to ketamine in guinea pig and rat myocardium. ANESTHESIOLOGY 1992; 76:409-18.
Kongsayreepong S, Cook DJ, Housmans PR: Mechanism of the direct, negative inotropic effect of ketamine in isolated ferret and frog ventricular myocardium. ANESTHESIOLOGY 1993; 79:313-22.
Riou B, Lecarpentier Y, Viars P: Effects of etomidate on the cardiac papillary muscle of normal hamsters and those with cardiomyopathy. ANESTHESIOLOGY 1993; 78:83-90.
Riou B, Lecarpentier Y, Viars P: Inotropic effect of ketamine on rat cardiac papillary muscle. ANESTHESIOLOGY 1989; 71:116-25.
Cook DJ, Carton EG, Housmans PR: Mechanism of the positive inotropic effect of ketamine in isolated ferret ventricular papillary muscle. ANESTHESIOLOGY 1991; 74:880-8.
Punt NC, Van Eekeren J, Van Amsterdam FTM, Zaagsma J, Den Hertog A: Dual action of D-cis-diltiazem on calcium entry in guinea pig papillary muscle cells. Eur J Pharmacol 1988; 151:347-8.
Riou B, Lejay M, Lecarpentier Y, Viars P: Myocardial effects of propofol in hamsters with hypertrophic cardiomyopathy. ANESTHESIOLOGY 1995; 82:566-73.
Ismail EF, Kim SJ, Salem MR, Crystal GJ: Direct effects of propofol on myocardial contractility in situ canine hearts. ANESTHESIOLOGY 1992; 77:964-72.
Shafer A, Doze VA, Shafer SL, White PF: Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. ANESTHESIOLOGY 1988; 69:348-456.
Wood M: Plasma binding and limitation of drug access to site of action (editorial). ANESTHESIOLOGY 1991; 75:721-3.
Mulier JP, Wouters PF, Van Aken H, Van der Meersch E: Cardiodynamic effects of propofol in comparison with thiopental: Assessment with a transoesophagial echocardiographic approach. Anest Analg 1991; 72:28-35.
Claeys MA, Gepts E, Camu F: Hemodynamic changes during anaesthesia induced and maintained with propofol. Br J Anaesth 1988; 60:3-9.
Effendi H, Versprille A, Wise ME: The negative inotropic effect of barbiturates on the heart of newborn and adult guinea pigs. Arch Int Pharmacodyn Ther 1973; 209:127-43.
Burch PG, Stanski DR: The role of metabolism and protein binding in thiopental anesthesia. ANESTHESIOLOGY 1983; 58:146-52.
Hung OR, Varvel JR, Shafer SL, Stanski DR: Thiopental pharmacodynamics: 2. Quantitation of clinical and electroencephalographic depth of anesthesia. ANESTHESIOLOGY 1992; 77:237-44.
Seltzer JL, Gerson JI, Allen FB Comparison of the cardiovascular effects of bolus v. incremental administration of thiopetone. Br J Anaesth 1980; 52:527-30.
Reves JG, Kissin I, Fournier S: Negative inotropic effects of midazolam. ANESTHESIOLOGY 1984; 60:517-8.
Persson P, Nilsson A, Hartvig P, Tamsen A: Pharmacokinetics of midazolam in total IV anaesthesia. Br J Anaesth 1987; 59:549-56.
Schulte-Sasse U, Hess W, Tarnow J: Hemodynamic responses to induction of anaesthesia using midazolam in cardiac surgical patients. Br J Anaesth 1982; 54:1053-8.
Kissin I, Motomura S, Aultman DF, Reves JG: Inotropic and anesthetic potencies of etomidate and thiopental in dogs. Anesth Analg 1983; 62:961-5.
Riou B, Lecarpentier Y, Chemia D, Viars P: In vitro effects of etomidate on intrinsic myocardial contractility in the rat. ANESTHESIOLOGY 1990; 72:330-40.
Van Hamme MJ, Ghoneim MM, Ambre JJ: Pharmacokinetics of etomidate, a new intravenous anesthetic. ANESTHESIOLOGY 1978; 49:274-7.
Kettler D, Sonntag H, Donath U: Haemodynamics, myocardial mechanics, oxygen requirement, and oxygenation of the human heart during induction of anaesthesia with etomidate. Anaesthesist 1974; 23:116-21.
Bruckner JB, Gethman JW, Patschke D, Tarnow J, Weymar A: Investigations into the effect of etomidate on the human circulation. Anaesthesist 1974; 23:322-30.
Gooding JM, Corssen G: Effect of etomidate on the cardiovascular system. Anesth Analg 1977; 56:717-9.
Riou B, Viars P, Lecarpentier Y: Effects of ketamine on the cardiac papillary muscle of normal hamsters and those with cardiomyopathy. ANESTHESIOLOGY 1990; 73:910-8.
Idvall J, Ahlgren I, Aronsen KF, Stenberg P: Ketamine infusions: Pharmacokinetics and clinical effects. Br J Anaesth 1979; 51:1167-72.
White PF, Way WL, Trevor AJ: Ketamine--its pharmacology and therapeutic uses. ANESTHESIOLOGY 1982; 56:119-36.
Ivankovich AD, Miletich DJ, Reichmann C, Albrecht RF, Zahed B: Cardiovascular effects of centrally administered ketamine in goats. Anesth Analg 1974; 53:924-31.
Bidwal AV, Stanley TH, Graves CL: The effects of ketamine on cardiovascular dynamics during halothane and enflurane anesthesia. Anesth Analg 1975; 54:588-92.
Courtney KR: Significance of bicarbonate for antiarrhythmic drug action. J Mol Cell Cardiol 1981; 13:1031-4.
Figure 1. Typical experiment showing the force traces of an isometric twitch of human atrial tissue during exposure to increasing concentrations of propofol (15-1,500 micro Meter).
Figure 1. Typical experiment showing the force traces of an isometric twitch of human atrial tissue during exposure to increasing concentrations of propofol (15-1,500 micro Meter).
Figure 1. Typical experiment showing the force traces of an isometric twitch of human atrial tissue during exposure to increasing concentrations of propofol (15-1,500 micro Meter).
×
Figure 2. Comparative effects of increasing concentrations of anesthetic on isometric contractions of human atrial tissue induced by field stimulation. Data are mean+/-SEM. Curves were plotted using logistic regression. Hatched squares indicate the clinical concentration range during anesthesia. Coarse hatching (left) represents the total concentration and fine hatching (right) shows the free fraction. (A) Propofol (n = 16). (B) Thiopental (n = 7). (C) Midazolam (n = 7). (D) Ketamine (n = 9). (E) Etomidate (n = 9). (F) Combined plot showing the concentration-response curve of the five anesthetics. For statistical analysis, see Table 1.
Figure 2. Comparative effects of increasing concentrations of anesthetic on isometric contractions of human atrial tissue induced by field stimulation. Data are mean+/-SEM. Curves were plotted using logistic regression. Hatched squares indicate the clinical concentration range during anesthesia. Coarse hatching (left) represents the total concentration and fine hatching (right) shows the free fraction. (A) Propofol (n = 16). (B) Thiopental (n = 7). (C) Midazolam (n = 7). (D) Ketamine (n = 9). (E) Etomidate (n = 9). (F) Combined plot showing the concentration-response curve of the five anesthetics. For statistical analysis, see Table 1.
Figure 2. Comparative effects of increasing concentrations of anesthetic on isometric contractions of human atrial tissue induced by field stimulation. Data are mean+/-SEM. Curves were plotted using logistic regression. Hatched squares indicate the clinical concentration range during anesthesia. Coarse hatching (left) represents the total concentration and fine hatching (right) shows the free fraction. (A) Propofol (n = 16). (B) Thiopental (n = 7). (C) Midazolam (n = 7). (D) Ketamine (n = 9). (E) Etomidate (n = 9). (F) Combined plot showing the concentration-response curve of the five anesthetics. For statistical analysis, see Table 1.
×
Figure 3. Plots of the potency of negative inotropic effects of anesthetics on human atrial tissue with data from animal experiments. IC sub 50 values from this study on the x-axis are plotted against comparable data from animal studies on the y-axis. Most data are from in vitro studies of isolated heart preparations and some from other forms of isolated heart experiments. Data are from various studies using different experimental conditions. The nature of the data is provided in symbols. Circle = contractility studies of isolated ventricular tissue; square = contractility studies of isolated atrial muscle; diamond = other studies of contractility in models of isolated heart preparations. Species are depicted in the symbols and abbreviated as follows: R = rabbit; G = guinea pig; F = ferret; D = dog. Data are from the following studies: propofol, references 5, 6, 8, and 11; thiopental, [5,9-11,12,28]; midazolam, [32]; etomidate, [13,14,35]; and ketamine, [15-17] .
Figure 3. Plots of the potency of negative inotropic effects of anesthetics on human atrial tissue with data from animal experiments. IC sub 50 values from this study on the x-axis are plotted against comparable data from animal studies on the y-axis. Most data are from in vitro studies of isolated heart preparations and some from other forms of isolated heart experiments. Data are from various studies using different experimental conditions. The nature of the data is provided in symbols. Circle = contractility studies of isolated ventricular tissue; square = contractility studies of isolated atrial muscle; diamond = other studies of contractility in models of isolated heart preparations. Species are depicted in the symbols and abbreviated as follows: R = rabbit; G = guinea pig; F = ferret; D = dog. Data are from the following studies: propofol, references 5, 6, 8, and 11; thiopental, [5,9-11,12,28]; midazolam, [32]; etomidate, [13,14,35]; and ketamine, [15-17].
Figure 3. Plots of the potency of negative inotropic effects of anesthetics on human atrial tissue with data from animal experiments. IC sub 50 values from this study on the x-axis are plotted against comparable data from animal studies on the y-axis. Most data are from in vitro studies of isolated heart preparations and some from other forms of isolated heart experiments. Data are from various studies using different experimental conditions. The nature of the data is provided in symbols. Circle = contractility studies of isolated ventricular tissue; square = contractility studies of isolated atrial muscle; diamond = other studies of contractility in models of isolated heart preparations. Species are depicted in the symbols and abbreviated as follows: R = rabbit; G = guinea pig; F = ferret; D = dog. Data are from the following studies: propofol, references 5, 6, 8, and 11; thiopental, [5,9-11,12,28]; midazolam, [32]; etomidate, [13,14,35]; and ketamine, [15-17] .
×
Table 1. Inhibitory Effects
Image not available
Table 1. Inhibitory Effects
×