Myocardial Pharmacokinetics of Thiopental in Sheep after Short-Term Administration: Relationship to Thiopental-Induced Reductions in Myocardial Contractility RICHARD N. UPTON X ,YI FEI HUANG*, CLIFF GRANT,ELKE C. GRAY, AND GUY L. LUDBROOK Received October 25, 1995, from the Department of Anaesthesia and Intensive Care, Royal Adelaide Hospital, University of Adelaide, North Terrace, Adelaide, SA 5005, Australia. Accepted for publication April 22, 1996 X . * Current address: Cardiac Technology, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW 2065, Australia. Abstract 0 The myocardial kinetics and dynamics of thiopental (750 mg over 2 min) were examined in chronically instrumented sheep (five studies in four sheep). The myocardial kinetics were studied by simultaneous rapid sampling of arterial and coronary sinus blood for 30 min. The myocardial kinetics for four of the five studies were best described by a single flow-limited compartment with apparent volumes of between 42 and 113 mL. These volumes equated to half-lives of equilibration between blood and myocardium of between 0.49 and 1.00 min when baseline blood flow was taken into account. The remaining study was better described by a model with a slight membrane limitation (permeability/flow ratio of approximately 2). Myocardial contractility was studied as a measure of myocardial pharmacodynamics and was reduced to 53% of baseline at approximately 2.5 min after the start of the dose. Effect compartment analysis showed that there was hysteresis between the time course of these contractility changes and the time course of the arterial concentrations, with effect compartment half-lives between 0.08 and 0.87 min. There was significantly less hysteresis for the coronary sinus concentrations. It is concluded that thiopental equilibrated rapidly with a component of the myocardium, and that consequently its effects on myocardial contractility also rapidly equilibrated with both afferent and effluent myocardial blood. The barbiturate thiopental has been used for the induction of anaesthesia for over 50 years. Clinical experience has shown that in some patients thiopental administration can be associated with adverse hemodynamic effects including hypotension due to venodilatation and a reduction in myo- cardial contractility. 1 There is experimental evidence which suggests that the reduction in contractility is a direct effect of thiopental on the heart, as substantial reductions in contractility can be induced in isolated heart preparations without autonomic innervation. 2-4 In this paper, we explore the kinetics of thiopental in the heart and its relationships to the reductions in myocardial contractility caused by thiopental. For these purposes we used a chronically instrumented sheep preparation 5 in which the myocardial pharmacokinetics and pharmacodynamics of thio- pental could be measured repeatedly in conscious individuals. The former was determined from the concentrations of thio- pental in afferent and effluent blood from the myocardium, the latter by “on-line” measurements of an index of myocardial contractility, as given by the maximum rate of left ventricular pressure change (LV dP/dt max ). In a subsequent paper we propose to use this knowledge to investigate dose regimens for the induction of anesthesia with thiopental that reduce the magnitude of its adverse hemodynamic effects. Experimental Section The study protocol was approved by the institutional Animal Ethics Review Committee. Four adult merino ewes weighing approximately 50 kg were prepared as described below with chronic intravascular catheters and Doppler flow probes to allow drug administration, cardiovascular function monitoring, and the measurement of blood flow. All animals had free access to food and water and were housed in metabolic crates throughout the study period. Animal PreparationsThe sheep were prepared in two stages. Two weeks before experimentation, they were anesthetized with iv sodium thiopental (20 mg/kg) and intubated with a cuffed endotra- cheal tube. Anesthesia was maintained with 1.5% halothane in oxygen, and the end expiratory CO2 was monitored using an infrared carbon dioxide analyzer (Normocap, Datex Instrumentarium Co, Finland) and maintained between 4 and 4.5%. A left thoracotomy at the fourth intercostal space and a pericardiotomy were performed to expose the left main coronary artery, around which a Doppler flow probe was secured as described previously. 5 The leads of the probe were exteriorized through the chest incision and a subdermal tunnel. The incision was closed with silk sutures and the sheep allowed to recover from anesthesia. One week later, the sheep were anesthetized as described above for catheterization of various blood vessels using a modification of the method reported previously. 6 The right carotid artery and jugular vein were exposed via a neck incision. Using the Seldinger technique, two 7F (multipurpose A1 catheter, Cordis Corporation, Miami, FL) and a 9F (William A. Cook, Sydney, NSW, Australia) catheter were placed in the ascending aorta via the carotid artery, with their tips located approximately 2 cm above the aortic valves. Through the jugular vein, a 7F catheter (multipurpose A1 catheter, Cordis Corporation, Miami, FL) was placed in the inferior vena cava (IVC) and a 7F catheter (multipurpose B1 catheter, Cordis Corporation, Miami, FL) in the coronary sinus. The positions of these catheters were confirmed under direct vision using a fluoroscope with the injection of radio-opaque contrast (Conray 420 (70% iothalamate), May and Baker Ltd., Dagenham, U.K.) into the corresponding blood vessels. All the surgical procedures were performed using sterile techniques. Experiments were not started until 1 week later so that the sheep could recover fully from surgery, and to allow the Doppler flow probes to become firmly embedded in scar tissue: this ensured good acoustic coupling. The catheters were continuously flushed with heparinized (5 iu/mL) 0.9% saline at a rate of 3 mL/h, using a gas- powered system. 6 Cardiovascular Function and Blood Flow Measure- mentssMyocardial blood flow was determined from the Doppler frequency shift recorded from the flow probe, which was amplified using a four channel Doppler flowmeter (Bioengineering, The Uni- versity of Iowa, 56 M.R.F., Iowa City, Iowa). The output of the probe was calibrated in vitro at the termination of the studies using the beaker and stopwatch method to give flow in mL/min. 5 To measure LV dP/dtmax, immediately before an experiment a 5F Millar Mikro-Tip pressure transducer catheter (Millar Instruments Inc., Houston, TX) was introduced, using sterile techniques, into the left ventricle of the sheep via a Touhy-Borst adaptor (William A. Cook, Sydney, NSW, Australia) and the 9F catheter previously placed in the aortic arch. The left ventricular pressure measured using the Millar catheter was recorded digitally and differentiated (LV dP/dt). The positive peak value of LV dP/dt gave the maximum rate of left ventricular pressure rise (LV dP/dtmax), and this was used as an index of myocardial contractility. 7 Mean arterial blood pressure and heart rate were measured using X Abstract published in Advance ACS Abstracts, July 1, 1996. © 1996, American Chemical Society and S0022-3549(95)00461-8 CCC: $12.00 Journal of Pharmaceutical Sciences / 863 American Pharmaceutical Association Vol. 85, No. 8, August 1996 + +