John H. Eisele

Cardiovascular function during controlled hypotension induced by adenosine triphosphate or sodium nitroprusside in the anesthetized dog

The present study was undertaken to compare the hemodynamic effects of adenosine triphosphate (ATP) and sodium nitroprusside (NP) given in equieffective doses to induce hypotension during halothane anesthesia. Eight dogs, instrumented with pressure and ultrasonic dimension transducers for assessment of left ventricular (LV) performance, were given both NP and ATP. Regional blood flow was measured by radioactive microspheres. After 20 min of infusion, both drugs decreased systemic arterial pressure by 36% with minimal changes in cardiac index (CI), LV end-diastolic pressure, or heart rate. However, hypotension produced by ATP was associated with a greater CI (3.84 +/- 0.32 vs 2.97 +/- 0.35 L X min-1 X m-2) than was NP and also associated with a further decrease in systemic vascular resistance (14.4 +/- 1.4 vs 17.7 +/- 2.2 mm Hg X L-1 X min X m2). Left ventricular global function, measured by the slope of the linear regression line of the LV end-systolic pressure-diameter relation (Ees), did not change significantly after either drug. Blood flow to the coronary bed was significantly greater with ATP than with NP (231.6 +/- 30.6 vs 81.7 +/- 6.1 ml X min-1 X 100 g-1). Except for an increase in hepatic arterial blood flow with NP, neither ATP nor NP significantly altered blood flow to the brain, spinal cord, spleen, kidney, jejunum, muscle, and skin. Controlled hypotension by ATP was stable and rapidly reversible without rebound hypertension. The results of this study indicate that ATP is a rapidly acting, effective hypotensive agent that compares favorably with NP.

Cardiovascular, respiratory, and analgesic effects of fentanyl in unanesthetized rhesus monkeys

&NA; To determine the suitability of the rhesus monkey as a model for investigation of opioids, we examined the analgesic, respiratory, and cardiovascular effects of fentanyl in six adult male rhesus monkeys. Fentanyl was administered in sequential bolus injections of 2, 4, 16, 64, and 128 μg/kg, with 10 min between each dose. Arterial plasma fentanyl concentrations and blood gas tensions were measured 3 and 9 min after each dose and 1, 2, 5, 20, 60, and 120 min after the final dose. At the same time periods, mean systemic arterial, pulmonary arterial, central venous, and pulmonary capillary wedge pressures, cardiac output, heart rate, and respiratory rate were measured. Analgesia was quantified as the time required for tail withdrawal from a standardized noxious stimulus. Tail latency response time increased significantly after the 4‐μg/kg dose (plasma fentanyl concentration = 2.7 ± 0.9 ng/mL). Maximum tail latency response time was attained after the 64‐μg/kg dose (43.4 ± 26.0 ng/mL) Respiratory rate decreased significantly after the 2‐μg/kg dose, and Paco2 increased significantly after the 4‐μg/kg dose. All animals became apneic, requiring tracheal intubation and controlled ventilation, after the 64‐μg/kg dose. Also, mean arterial pressure and cardiac output decreased significantly after the 64‐μg/kg dose. There were no other significant cardiovascular changes. Peak plasma fentanyl concentration after the 128‐μg/kg dose was 117.0 ± 49.6 ng/mL. It appears that plasma concentrations of approximately 40 ng/mL are sufficient to reach the full cardiovascular, respiratory, and analgesic effects of fentanyl in the rhesus monkey. Significant respiratory and analgesic effects are evident at concentrations as low as 3 ng/mL. These effects of fentanyl are similar to those previously reported in humans.

Hemodynamic responses to alfentanil in halothane-anesthetized dogs.

Alfentanil is an opioid that has been used both as a sole anesthetic and in conjunction with other inhalation anesthetics. However, its effects on myocardial performance and regional blood flow are not clearly known. Using sonomicrometry and radioactive microsphere techniques, we examined the hemodynamic responses to alfentanil when given as a loading dose (45 μg/kg) followed by continuous infusion (3 μg·kg−1·min−1) in dogs anesthetized with halothane. Similar plasma levels of alfentanil were observed after the loading and infusion doses, and both techniques of administration produced a significant reduction in arterial pressure without change in global or regional function of the left ventricle. Although cardiac output and left ventricular end-diastolic pressure remained unchanged, heart rate and systemic vascular resistance decreased significantly after the loading dose and recovered slightly when alfentanil was infused continuously. Despite the systemic hypotension, alfentanil did not alter perfusion to the heart, brain, muscle, and skin; however, blood flow to the renal cortex and the arterial supply to the liver decreased by 25 and 60%, respectively. Reduction in blood flow to the kidneys and the liver suggests that alfentanil should be used with caution when normal function of these organs is in question.

Disposition of Intrapartum Narcotic Analgesics in Monkeys

Maternal-fetal disposition and neonatal respiratory depressant effect of narcotic analgesics were studied by administration of meperidine (2 mg/kg, IV) or alfentanil (IV infusion, 0.1 mg/kg total dose) during labor in rhesus monkeys. Fetal/maternal plasma ratios were lower for alfentanil, the more highly protein-bound drug (fetal/maternal ratio 0.20 at birth versus 0.46 for meperidine). However, elimination of alfentanil was delayed in the neonate. Indeed, plasma concentrations of alfentanil increased during the first 2 postnatal hours, indicating a compartmental shift from tissues to circulation in the neonate. As regards respiratory depression, six of ten narcotic-treated monkeys had suboptimal (less than 60 breath/min) respiratory rates at birth. Respiratory rate was negatively correlated with cord vein normeperidine and meperidine levels; the strongest correlation was with normeperidine (r = -0.84, P less than 0.01). Neonatal normeperidine elimination in the postnatal period was prolonged, as has also been observed in humans. These studies serve as a basis for comparing the neonatal neurobehavioral effects of the two analgesics and support the use of the rhesus monkey as an animal model to further understanding of the effects of narcotic analgesics on neonatal respiration.

Autotransfusor Removal of Fentanyl from Blood

The removal of narcotics from blood processed by commercially available autoinfusion devices, though not previously investigated, would be anticipated given the removal of significant quantities of serum during cell processing. Therefore, we attempted to determine if significant quantities of the narcotic fentanyl are removed from intraoperatively harvested blood during saline washing of red cells before autologous transfusion.

Vagomimetic effects of morphine and innovar in man.

EVERAL animal studies have shown the S effects of narcotics, especially morphine, on heart rate (HR), suggesting vagal stimulation.1-5 According to these studies, morphine produces a slowing in HR as a result of both vagal stimulation and sympathetic depression. The present study was undertaken to determine whether morphine or Innovar,@ a widely used mixture which includes the synthetic narcotic fentanyl, has a vagal-stimulant effect in man. If narcotics have this effect, it is reasonable to expect that more atropine would be required to achieve a desired rise in HR. One might also assume that, since atropine in small doses is reported to produce vagal stimulation,6 such small doses in patients given narcotics would further reduce the HR. Larger doses of atropine, however, would be expected to block the cardiac vagal endings and overcome any vagomimetic influence of the narcotics.