Karel J. Kotrly

Multicenter Study of General Anesthesia. II. Results

A prospective, stratified, randomized clinical trial of the safety and efficacy of four general anesthetic agents (enflurane, fentanyl, halothane, and isoflurane) was conducted in 17,201 patients (study population). Patients were studied before, during, and after anesthesia for up to 7 days. Nineteen patients died (0.11%), and in seven of these (0.04%) the anesthetic may have been a contributing factor. The rates of death, myocardial infarction, and stroke in the study population were so low (less than 0.15%) that no conclusions regarding the relative rates of these outcomes among the four anesthetic agents could be reached. The rates of 16 of 66 types of adverse outcomes in the study population were significantly different among the four study agents. Most of these outcomes were minor. However, severe ventricular arrhythmia (P less than 10(-6)) was more common with halothane, severe hypertension (P less than 10(-6)) and severe bronchospasm (P = 0.028) were more common with fentanyl, and severe tachycardia (P = 0.001) was more common with isoflurane. Recovery from anesthesia during the first 30 min was slowest in those patients who received halothane (P less than or equal to 0.001). In addition, patients who received fentanyl experienced less pain during the first hour in the recovery room (P less than 10(-6)). In conclusion, clinically important differences do exist for some outcomes among the four study agents.

First pass uptake of fentanyl, meperidine, and morphine in the human lung

The first pass uptake of fentanyl, meperidine, and morphine in human lung was studied in patients using a double indicator dilution technique. A bolus containing one of the drugs and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia for surgery. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of drug taken up by the lung during the first pass and the instantaneous extraction of drug at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. The total uptake (mean ± SE) during the first pass through the human lung for fentanyl and meperidine was 75.2 ± 3.2% and 64.7 ± 7.8% of the injected dose, respectively. The pulmonary uptake of morphine was very small, with 96.5 ± 7.1% of the injected dose recovered in arterial blood after the first pass through the lung. The arterial blood concentration of drug and dye versus time showed a slight delay of the fentanyl and meperidine peaks compared to ICG, It was also observed that greater than 90% of these drugs were extracted from the blood in the early part of the first pass, but the extraction decreased with time during the first pass through the lung. These findings indicate that sonic of the drug taken up by the lung can diffuse back out into the blood. In spite of this back diffusion, 75% and 65% of the fentanyl and meperidine remained in the lung tissue at the end of the first pass. This high first pass pulmonary uptake of fentanyl and meperidine results in a large decrease in the amount of drug that enters the systemic circulation immediately after injection. This non-respiratory pulmonary function could play a major role in determining the plasma pharmacokinetics of these drugs immediately after intravenous administration. No such role of the lung exists for morphine.

First-pass uptake of verapamil, diazepam, and thiopental in the human lung

The first-pass uptake of verapamil, diazepam, and thiopental in the human lung was determined using multiple-indicator dilution techniques. These three drugs represent lipid-soluble agents that differ in their ionic characteristics at physiological pH. Verapamil, a basic lipophilic amine, underwent significant uptake, with 50% of the drug accumulating in lung tissue during the first pass. With diazepam, a nonbasic lipophilic amine, there was 30% uptake during the first pass through the human lung-significantly less than that observed with verapamil. With thiopental, an acidic lipophilic barbiturate, only 14% of the injected drug accumulated in the lung during the first pass. Taken together, these data are consistent with observations from animal studies, which indicate that extensive pulmonary uptake is greater with basic amine drugs that are moderately to highly lipid-soluble. Also, the relatively high first-pass uptake of verapamil in the human lung suggests a quantitatively significant role of this nonrespiratoy function of the lung in the early pharmacokinetics of intravenous verapamil.

Intraoperative Detection of Myocardial Ischemia with an St Segment Trend Monitoring System

The purpose of this study was to assess the use of a modified microcomputer-based electrocardiograph (ECG) to determine its value as an aid in the intraoperative detection of myocardial ischemia. The modification of the commercially available exercise/arrhythmia monitoring ECG permitted summing the absolute values of ST segment deviations 0 point + 60 msec) from the isoelectric line for three selected ECG leads. The system provided a trend line of ST segment changes as well as electronic storage of the ECG complexes. The authors report the use of the system during cardiovascular surgical procedures in which V5, AVF, and -V1 (on the back opposite to V1) were chosen as an orthogonal lead set. The simple trend line was found to be a sensitive indicator that alerted the anesthesiologist to subtle ST segment changes not easily recognized on conventional ECG monitors. Intraoperative ECG monitoring provides rhythm and rate information, but generally fails to diagnose adequately those episodes of myocardial ischemia that result in subtle ST segment changes. This inability is due primarily to limitations of the equipment and techniques commonly employed. Most monitors do not permit simultaneous display of multiple leads and often limit lead selection. The low-frequency response of the ECG amplifiers of many monitors designed for the operating room, or any ECG amplifier in the monitor mode, is unsuited for the accurate assessment of ST segment changes (1–3). Frequently, placement of the more sensitive V5 electrode is difficult or impossible because of the site of surgery, thus less optimal but more convenient sites are used. Even when V5 or bipolar leads such as CM5, CB5, or CS5 are observed with a diagnostic bandwidth amplifier, the limitations inherent in conventional single-lead monitoring systems often preclude diagnosis of early ischemic events (1). The technology necessary to simultaneously monitor multiple leads and provide sensitive indicators of ST segment changes has been developed for exercise stress testing, but has not been adopted for intraoperative use. This report describes our experience with a microprocessor-based prototype of a system that is capable of trending ST-segment changes.

Multicenter study of general anesthesia. I. Design and patient demography.

A prospective randomized clinical trial of enflurane, fentanyl, halothane, and isoflurane is described. The 17,201 patients were stratified into two groups (preanesthetic medication and no preanesthetic medication) and were randomized to one of four study agents: enflurane, fentanyl, halothane, and isoflurane. Fifteen university-affiliated hospitals in the United States and Canada participated. All patients were first assessed preoperatively. Data were collected during anesthesia, in the immediate recovery period, and for up to 7 days after anesthesia/surgery. The mean age of the patients was 43 yr, the mean height 167 cm, and the mean weight 68 kg. Sixty-five percent of patients were female. In this study 90.7% of patients were classified as ASA Physical Status 1 or 2, and 34.7% of patients smoked. It is concluded that pooling of data across institutions was valid and does allow determination of the efficacy and relative safety of the four study agents.

Effect of Propranolol on the First Pass Uptake of Fentanyl in the Human and Rat Lung

The first pass uptake of fentanyl in the human lung was studied in two groups of patients using a double indicator dilution technique. A bolus containing fentanyl and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of fentanyl taken up by the lung during the first pass and the instantaneous extraction of fentanyl at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. In patients who had been receiving no other drugs prior to the experiment, the total first pass uptake (mean +/- SE) of fentanyl was 82.6% +/- 1.4% of the injected dose. In patients who had been receiving 30-120 mg/day of propranolol the total first pass uptake (mean +/- SE) of fentanyl decreased to 52.8% +/- 6.3% of the injected dose. In one patient on 120 mg of propranolol per day, first pass uptake of fentanyl was only 20.3% of the injected dose. Additional studies in a rat isolated perfused lung preparation coperfused with fentanyl and propranolol also demonstrated that one basic lipophilic amine (propranolol) could inhibit the pulmonary uptake of a second basic lipophilic amine (fentanyl). The high first pass uptake of fentanyl in the human lung limits the rate of entry of this drug into the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Fentanyl-diazepam anesthesia with or without N2O does not attenuate cardiopulmonary baroreflex-mediated vasoconstrictor responses to controlled hypovolemia in humans.

Cardiopulmonary baroreceptors located primarily on the low-pressure side of the circulation sense slight reductions in cardiac filling pressures and elicit sustained peripheral vasoconstriction. Because most inhalation and many intravenous anesthetics attenuate arterial baroreflex function, the low-pressure baroreflex may serve a major role in maintaining blood pressure during intraoperative hypovolemia. To activate the low-pressure baroreflex, progressive nonhypotensive reductions in central venous pressure were produced with graded applications of lower body negative pressure (LBNP, (−5, (−10, (−15 mm Hg) in 18 ASA class 1 patients before elective surgery. Thisproduced linear reductions in stroke volume as determined by impedance cardiography and cardiac output. Cardiopulmonary baroreflex-mediated increases in total and forearm vascular resistance assisted in maintaining stable blood pressure. After ten patients were anesthetized with fentanyl(12.5 pg/kg) and diazepam (0.25 mg/kg) and an additional eight received these agents plus supplemental N, O (70%), reflex vasoconstrictor responses to LBNP were not attenuated and, therefore, blood pressure continued to be well maintained despite substantial reductions in cardiac filling pressures. Thus, these anesthetic regimens presetved vasoconstrictor responses mediated by cardiopulmonary baroreflexes. This promoted cardiovascular stability that may be particularly beneficial in patients with cerebral, cardiovascular, or renal disease undergoing surgical procedures with potential for rapid blood loss.

Baroreceptor reflex control of heart rate during morphine sulfate, diazepam, N2O/O2 anesthesia in humans.

The effect of morphine, diazepam, N2O/O2 anesthesia on baroreflex control of heart rate in humans was investigated in this study. Group 1 subjects (n = 11) received morphine 0.5 mg/kg, diazepam 0.25 mg/kg, and 70% N2O with O2. Group 2 subjects (n = 10) received morphine 0.75 mg/kg, diazepam 0.25 mg/kg, and 70% N2O with O2. Phenylephrine (the pressor test), sodium nitroprusside (the depressor test), and graded neck suction were employed to alter the stimulation of baroreceptor sites. The pressor, the depressor, and neck suction baroreflex slopes declined significantly in both groups from awake to anesthetized. There was no significant difference in the degree of depression between the two groups for all three tests. Neck suction derived slopes compared favorably to the pressor test slopes (r = 0.70, P < 0.01). This study indicates that the depression of arterial baroreflex–heart rate responses under morphine, diazepam, N2O/O2 anesthesia is similar to that seen with potent inhalational anesthetics such as isoflurane. Furthermore, there was no difference between the two morphine doses that were studied.

Halothane Anesthesia Attenuates Cardiopulmonary Baroreflex Control of Peripheral Resistance in Humans

The effects of halothane anesthesia on cardiopulmonary (low pressure) baroreflex control of peripheral resistance were studied in 10 ASA class I young men. Graded (-5,-7.5, −10, −12.5 mmHg) lower body negative pressure (LBNP) was used to produce progressive decreases in thoracic blood volume and central venous pressure. These stimuli activate reflexes from cardiopulmonary baroreceptors. Volunteers were studied while awake and during 1 MAC (0.75%) and 1.25 MAC (0.93%) halothane anesthesia. Hetastarch (6%) in 0.9% normal saline was infused into patients before baseline recordings were initiated. Blood pressure, stroke volume, cardiac output, and systemic and forearm vascular resistance decreased and forearm blood flow increased during halothane anesthesia. In awake subjects, LBNP did not alter heart rate or blood pressure, but stroke volume and cardiac output decreased. Blood pressure was maintained by cardiopulmonary baroreflex-mediated increases in peripheral resistance. In anesthetized subjects, decreases in stroke volume and cardiac output during LBNP were similar to awake responses, however, hypotension occurred because reflex resistance increases were markedly attenuated. The authors conclude that halothane anesthesia blunts cardiopulmonary baroreflex resistance responses provoked by mild decreases in thoracic blood volume in humans.

Primary Dysfunction of the Afferent Limb of the Arterial Baroreceptor Reflex System in a Patient With Severe Supine Hypertension and Orthostatic Hypotension

A 33 year old man with a history of recurrent episodes of orthostatic dizziness since adolescence was noted to have a supine blood pressure of 200/120 mm Hg and a standing blood pressure of 90/60 mm Hg. Results of extensive laboratory studies for secondary hypertension were negative. Studies of the autonomic nervous system function revealed normal plasma catecholamines, cold pressor test and response to 4 minute 30% of maximal static handgrip contraction and an appropriate increase in heart rate on intravenous injection of atropine. In contrast, the heart rate response to phenylephrine and sodium nitroprusside infusion, carotid massage and graded neck suction with an airtight chamber was very abnormal, indicating marked dysfunction of the afferent limb of the arterial baroreceptor reflex system. Methyldopa decreased the supine hypertension and increased the standing blood pressure.