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 nonrespiratory function of the lung in the early pharmacokinetics of intravenous verapamil.

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 I patients before elective surgery. This produced 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 micrograms/kg) and diazepam (0.25 mg/kg) and an additional eight received these agents plus supplemental N2O (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 preserved 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.

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 some of the drug taken up by the lung can diffuse back out into the blood.2+off

Myocardial ischemia during cardiovascular surgery as detected by an ST segment trend monitoring system.

The incidence of intraoperative myocardial ischemia was determined in 312 patients undergoing cardiovascular surgery using ECG recordings obtained from a prototype system that trends ST segment changes. Prior to cardiopulmonary bypass, ischemic ECG changes were observed in 11.9% of patients, the incidence being lower during coronary artery bypass grafting (CABG) procedures (8.1%) than in patients undergoing repeated CABG (23.5%), valve replacement (25.9%), or concomitant valve replacement and CABG (35.3%). The occurrence of intraoperative myocardial ischemia was statistically greater in patients with a history of hypertension, two or more previous myocardial infarctions, or kidney disease. The incidence of ischemia was also significantly greater in patients with left ventricular end-diastolic pressures of 15 mm Hg or higher at cardiac catheterization. The incidence during induction was significantly reduced by the addition of hypnotics to narcotics, and, during maintenance, by the addition of an inhalational agent. The majority of ischemic events were temporally related to some hemodynamic disturbance, and many coincided with surgical manipulation. The incidence of intraoperative myocardial ischemia was substantially less than that reported in comparable studies. Since the incidence decreased significantly following clinical acceptance of the prototype system, the authors conclude that such capability increases sensitivity to small ST segment changes. This heightened awareness and prompt remedial action reduced the incidence of ischemia during CABG to 6% during the final 2 years of the study.

Effects of fentanyl-diazepam-nitrous oxide anaesthesia on arterial baroreflex control of heart rate in man.

The effects of fentanyl 7.5 micrograms kg-1 (group I), 10.0 micrograms kg-1 (group II) and 12.5 micrograms kg-1 (group III) with diazepam 0.25 mg kg-1 and 70% nitrous oxide on baroreflex control of heart rate in humans were investigated. Phenylephrine (the pressor test), sodium nitroprusside (the depressor test) and graded neck suction provoked baroreflex responses. In group I the pressor, depressor and neck suction baroreflex slopes decreased during anaesthesia. In groups II and III the depressor test slopes were also decreased during anaesthesia. However, the slopes derived from the pressor and neck suction tests did not decrease. These data suggest that baroreflex control of heart rate is attenuated during low doses of fentanyl (7.5 micrograms kg-1). Baroreflex mediated tachycardia is decreased by higher doses of fentanyl (10.0 and 12.5 micrograms kg-1). However, baroreflex-mediated bradycardia is maintained during the higher doses of fentanyl. We suggest this effect is the result of enhanced vagal efferent activity mediated by fentanyl.

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.

Repetitive ramped neck suction: a quantitative test of human baroreceptor function.

Bolus intravenous injection of an alpha-agonist is a widely accepted method used for studying baroreceptor function. However, the method is invasive, multiple baroreceptor regions are stimulated, and there are diverse direct effects of these pharmacologic agents, e.g., direct effects on the carotid sinus region. A recently described noninvasive neck suction technique may be highly specific for assessing the carotid sinus to sinoatrial node baroreflex. We compared neck suction-derived baroslopes with those obtained from the standard, invasive phenylephrine infusion method. These techniques were applied to 15 adult volunteers while awake and during 1.34 and 2% isoflurane anesthesia. The correlation coefficients between the two methods were 0.74 (P = 0.002) in awake subjects and 0.75 (P = 0.001) overall. The neck suction method of repetitive, ramped carotid stimuli yielded results that were qualitatively and quantitatively similar to those of the standard phenylephrine method. The neck suction method is simple, noninvasive, and can be repeated at frequent intervals. This method may be highly specific for determining carotid baroreceptor-cardiac reflex physiology in humans.

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 less than 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.

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.

Baroreceptor reflex control of heart rate during isoflurane anesthesia in humans.

The effect of isoflurane alone (Group 1) and isoflurane following thiopental (Groups 2 and 3) on baroreflex control of heart rate in humans was investigated in this study. Phenylephrine (the pressor test) and sodium nitroprusside (the depressor test) were used to induce moderate changes in arterial blood pressure and to alter the stimulation of baroreceptor sites. In addition, graded neck suction was employed to examine carotid baroreflex control of heart rate. In Group 3 subjects, phenylephrine was infused continuously during anesthesia to maintain mean arterial blood pressure near control levels. The pressor- and neck-suction-derived baroreflex slopes were decreased progressively from awake to 1.0 and 1.5 MAC isoflurane. The slopes of the depressor responses were decreased at 1.0 MAC but showed little further depression at 1.5 MAC. For each method, the depression of baroreceptor slopes from control to 1.0 MAC and 1.5 MAC was similar among the three groups. Maintenance of arterial blood pressure (Group 3) and the utilization of thiopental (Group 2) did not significantly alter the depression of baroreflex responses during increasing levels of isoflurane anesthesia. Neck suction derived slopes compared favorably with the pressor test slopes (r = 0.75, P less than 0.001). This study indicates that the depression of arterial baroreflex heart rate responses under isoflurane anesthesia are less pronounced than the depression of baroreflex responses noted by other investigators for halothane or enflurane. The neck suction technique appears to be a sensitive method useful in assessing the carotid sinus reflex in awake and anesthetized humans.