Ian M. Schwieger

Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging.

RATIONALE AND OBJECTIVES To assess in humans the pharmacokinetics of SonoVue, a new echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles and to provide additional safety and tolerability information on the compound. METHODS The blood kinetics and pulmonary elimination of SF6 after intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg) of SonoVue were evaluated in 12 healthy subjects (7 men, 5 women). In addition, safety and tolerability were evaluated by monitoring vital signs, adverse effects, discomfort, and physical examination and laboratory parameters associated with the SonoVue injection. RESULTS The blood kinetics of SF6 was not dose dependent. SF6 was rapidly removed from the blood by the pulmonary route, with 40% to 50% of the injected dose eliminated within the first minute after administration and 80% to 90% eliminated by 11 minutes after administration; the elimination was similar in men and women and independent of dose. Both dosages were well tolerated. No adverse effects were observed immediately or during the 24-hour follow-up period. CONCLUSIONS SonoVue was shown to be rapidly removed from the blood. The route of SF6 elimination was by means of the lungs in the expired air. SonoVue appeared to be safe and well tolerated in healthy subjects.

Less than additive antinociceptive interaction between midazolam and fentanyl in enflurane-anesthetized dogs

The anesthetic interactions of midazolam and fentanyl were determined in terms of enflurane MAC reduction in dogs. In part 1, 8 animals received an intravenous (iv) loading dose of fentanyl followed by a constant infusion at 0.05 micrograms.kg-1.min-1 to produce a stable enflurane MAC reduction of approximately 20%. Midazolam was then administered in a series of three incremental loading doses and infusions (2.4, 9.6, and 28.8 micrograms.kg-1.min-1 previously determined to produce enflurane MAC reductions of approximately 30, 45, and 60%, respectively. Enflurane MAC was determined for each infusion. Then fentanyl was discontinued; naloxone 1 mg/kg was administered; and enflurane MAC was determined. In part 2, six dogs received a loading dose and a continuous infusion of fentanyl (0.2 micrograms.kg-1.min-1) designed to produce a stable enflurane MAC reduction of approximately 40%. A series of two incremental loading doses and infusions of midazolam (2.4 and 28.8 micrograms.kg-1.min-1) were added, and MAC determinations were repeated at each infusion rate. Then midazolam was discontinued; flumazenil (RO 15-1788) 1.5 mg/kg was administered; and enflurane MAC was determined. The fentanyl concentrations in plasma remained stable at 1.0 +/- 0.3 ng/ml (mean +/- standard deviation [SD], part 1) and 3.1 +/- 0.5 ng/ml (part 2) throughout the study and, in the absence of midazolam, reduced enflurane MAC by 28 +/- 11 and 44 +/- 5%, respectively. The addition of midazolam produced significant further reductions in enflurane MAC, but the reductions were less than those predicted on the basis of an additive interaction. Naloxone returned enflurane MAC reduction to that expected for midazolam alone (part 1).(ABSTRACT TRUNCATED AT 250 WORDS)

The Anesthetic Efficacy of Midazolam in the Enflurane-anesthetized Dog

This study determined the anesthetic efficacy of midazolam (MID) in terms of its ability to reduce enflurane MAC (EMAC). Control EMAC was determined by the tail-clamp method in 15 mongrel dogs. Each animal then received at least three incremental infusion rates of MID from among the following: 0.48, 2.4, 9,6, 19.2, 28.8, 48, or 151.2 μg · kg−1 · min−1. MAC was determined during each infusion rate following a 1-h observation period, during which time MID concentration in plasma ([MID]) stabilized. [MID] was measured every 15 min beginning 45 min from the start of each new infusion rate. There was a linear relationship between MID infusion rates and the resulting [MID] (r = 0.995). In the range of [MID] from 14 to 14,118 ng/ml, there was a linear relationship between the log [MID] and the percent EMAC reduction. The slope of the line was very shallow, and the [MID] required to reduce EMAC by more than 50% exceeded the [MID] likely to be employed clinically in humans (750 ng/ml). Also, the 73 ± 4% (mean ± SEM) EMAC reduction produced by [MID] = 9,763 ± 1213 ng/ml was not significantly greater than the 60 ± 3% EMAC reduction achieved by [MID] = 1,464 ± 293 ng/ml, a finding which suggests a ceiling effect to the anesthetic efficacy of midazolam. The authors conclude that, within the dose range of MID likely to be employed in humans, MID produced a concentration-dependent reduction of enflurane MAC in the dog. In doses above those likely to be employed clinically, a ceiling effect to the anesthetic efficacy of MID may become evident.

Incidence of Cell-Saver contamination during cardiopulmonary bypass

During regular bacteriological surveillance of cardiac surgical equipment and patients, the Cell Saver apparatus (CSA) was prospectively evaluated to determine if it represented an additional risk for infection. Nineteen patients were studied. After each operation, the effluent from the CSA was sterilely sealed for subsequent culture. A total of 42 aerobic and 42 anaerobic cultures were made. Postoperatively all patients were evaluated daily for four days and before discharge for clinical evidence of infection. Four patients had positive CSA cultures without evidence of postoperative clinical infection. Five patients in whom postoperative infectious complications developed had negative CSA cultures. Ten patients had negative CSA cultures and no evidence of postoperative infection. We conclude that the CSA does not appear to contribute to the risk of infection in cardiac surgical patients and that it is a safe adjunct to cardiac surgery.

The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane

AbstractThe plasma concentration vs. anesthetic effect relationships for ketamine are not well known. It is desirable to establish stable and predictable drug concentrations in plasma (and brain) in order to define such relationships. As a prelude to pharmacodynamic studies, we investigated ketamine pharmacokinetics in eight dogs anesthetized with enflurane and correlated ketamine concentration in plasma (KET) with its ability to reduce the enflurane concentration required for anesthesia (enflurane EC50: MAC-the endtidal concentration at which half the dogs moved in response to damping of the tail and half did not move). Four dogs (Group 1) received ketamine 10 mg/kg iv over 30 sec. Blood for determination of KET was collected repeatedly over the 5-h period following injection. Based on the pharmacokinetic parameters determined for Group I, four dogs in Group 2 received ketamine as a continuous infusion of 300 μg·kg−1·min−1 for 5hr accompanied by an initial loading dose (26 mg/kg administered over 20 min) designed to produce a stable KET of 20 μg/ml of plasma. Enflurane MAC and KET were determined regularly during the infusion and for 5 hr after discontinuation of the infusion. There were no significant differences in the following pharmacokinetic parameters determined for Group 1 vs. Group2:

Systemic and splanchnic oxygen supply-demand relationship with fenoldopam, dopamine and noradrenaline in sheep

t_{\mathop 2\limits^ \bot \beta }

Evaluation of sufentanil anesthesia obtained by a computer-controlled infusion for cardiac surgery

=122±9 vs. 141±40min (