Pilot study in humans on the pharmacokinetics and safety of propofol 6% SAZN.

In a pilot study on the first application of Propofol 6% SAZN in humans, the pharmacokinetics and safety of the new product seem to be similar to those of Propofol 1% SAZN and Diprivan-10 after bolus injection. The results will have to be confirmed in a larger clinical study in order to develop Propofol 6% SAZN as an alternative for Diprivan-10.

Pharmacokinetics, induction of anaesthesia and safety characteristics of propofol 6% SAZN vs propofol 1% SAZN and Diprivan-10 after bolus injection.

AIMS: In order to avoid the potential for elevated serum lipid levels as a consequence of long term sedation with propofol, a formulation of propofol 6% in Lipofundin(R) MCT/LCT 10% (Propofol 6% SAZN) has been developed. The pharmacokinetics, induction of anaesthesia and safety characteristics of this new formulation were investigated after bolus injection and were compared with the commercially available product (propofol 1% in Intralipid(R) 10%, Diprivan-10) and propofol 1% in Lipofundin(R) MCT/LCT 10% (Propofol 1% SAZN). METHODS: In a randomised double-blind study, 24 unpremedicated female patients received an induction dose of propofol of 2.5 mg kg-1 over 60 s which was followed by standardized balanced anaesthesia. The patients were randomized to receive propofol as Propofol 6% SAZN, Propofol 1% SAZN or Diprivan-10. RESULTS: For all formulations the pharmacokinetics were adequately described by a tri-exponential equation, as the propofol concentrations collected early after the injection suggested an additional initial more rapid phase. The average values for clearance (CL), volume of distribution at steady-state (Vd,ss ), elimination half-life (t1/2,z ) and distribution half-life (t1/2, lambda2) observed in the three groups were 32+/-1.5 ml kg-1 min-1, 2. 0+/-0.18 l kg-1, 95+/-5.6 min and 3.4+/-0.20 min, respectively (mean+/-s.e.mean, n=24) and no significant differences were noted between the three formulations (P >0.05). The half-life of the additional initial distribution phase (t1/2,lambda1 ) in all subjects ranged from 0.1 to 0.6 min. Anaesthesia was induced successfully and uneventfully in all cases, and the quality of induction was adequate in all 24 patients. The induction time did not vary between the three formulations and the average induction time observed in the three groups was 51+/-1.3 s which corresponded to an induction dose of propofol of 2.1+/-0.06 mg kg-1 (mean+/-s.e. mean, n=24). The percentage of patients reporting any pain on injection did not vary between the formulations and was 17% for the three groups. No postoperative phlebitis or other venous sequelae of the vein used for injection occurred in any of the patients at recovery of anaesthesia nor after 24 h. CONCLUSIONS: From the above results, we conclude that the alteration of the type of emulsion and the higher concentration of propofol in the new parenteral formulation of propofol does not affect the pharmacokinetics and induction characteristics of propofol, compared with the currently available product. Propofol 6% SAZN can be administered safely and has the advantage of a reduction of the load of fat and emulsifier which may be preferable when long term administration of propofol is required.

The influence of nitrous oxide to supplement fentanyl/low-dose propofol anesthesia on transcranial myogenic motor-evoked potentials during thoracic aortic surgery.

OBJECTIVE: Intraoperative monitoring of myogenic motor evoked potentials to transcranial electrical stimulation (tc MEPs) is a new method to assess the integrity of the motor pathways. The authors studied the effects of 50% nitrous oxide (N2O) and a low-dose propofol infusion on tc MEPs paired electrical stimulation during fentanyl anesthesia with partial neuromuscular blockade. DESIGN: Cross-over study. SETTING: St Antonius Hospital, Nieuwegein, The Netherlands. PARTICIPANTS: Ten patients scheduled to undergo surgery on the thoracoabdominal aorta were studied; 6 women aged 54 to 69 years and 4 men aged 68 to 77 years. INTERVENTIONS: After achieving a stable anesthetic state and before surgery, tc MEPs were recorded during four 15-minute periods: (I) air/oxygen (O2; F(I)O2 = 50%); propofol target blood concentration, 0.5 microg/mL; (II) N2O/O2 (F(I)O2 = 50%); propofol target blood concentration, 0.5 microg/mL; (III) N2O/O2 (F(I)O2 = 50%; propofol target blood concentration, 1.0 microg/mL; and (IV) air/O2 (F(I)O2 = 50%); propofol target blood concentration, 1.0 microg/mL. MEASUREMENTS AND MAIN RESULTS: Tc MEPs were recorded from the right extensor digitorum communis muscle and the right tibialis anterior muscle. The right thenar muscle was used for recording the level of relaxation; the T1 response was maintained at 40% to 70% of the control compound muscle action potential. There was no significant difference in onset latency among the four phases. The addition of N2O and doubling the target propofol infusion to 1.0 microg/mL resulted in a 40% to 50% reduction of tc MEP amplitude recorded in the extensor digitorum communis muscle and tibialis anterior muscle (p < 0.01). During each phase, tc MEPs could be elicited and interpreted, except in one patient, in whom no tc MEPs could be elicited in the leg because of technical problems. CONCLUSION: The data indicate that tc MEP monitoring is feasible during low-dose propofol, fentanyl/50% N2O in 02 anesthesia and partial neuromuscular blockade.

Within-patient variability of myogenic motor-evoked potentials to multipulse transcranial electrical stimulation during two levels of partial neuromuscular blockade in aortic surgery.

UNLABELLED: Intraoperative recording of myogenic motor responses evoked by transcranial electrical stimulation (tcMEPs) is a method of assessing the integrity of the motor pathways during aortic surgery. To identify conditions for optimal spinal cord monitoring, we investigated the effects of manipulating the level of neuromuscular blockade (T1 response of the train-of-four (TOF) stimulation 5%-15% versus T1 response 45%-55% of baseline), as well as the number of transcranial pulses (two versus six stimuli) on the within-patient variability and amplitude of tcMEPs. Ten patients (30-76 yr) scheduled to undergo surgery on the thoracic and thoracoabdominal aorta were studied. After achieving a stable anesthetic state and before surgery, 10 tcMEPs were recorded from the right extensor digitorum communis muscle and the right tibialis anterior muscle in response to two-pulse and six-pulse transcranial electrical stimulation with an interstimulus interval of 2 ms during two levels of neuromuscular blockade. The right thenar eminence was used for recording the level of relaxation. The tcMEP amplitude using the six-pulse paradigm was larger (P < 0.01; leg and arm) compared with the amplitude evoked by two-pulse stimulation during both levels of relaxation. The within-patient variability, expressed as median coefficient of variation, was less when six-pulse stimulation was used. At a T1 response of 45%-55% of baseline, larger, less variable tcMEPs were recorded than at a T1 response of 5%-15%. Our results suggest that the best quality of tcMEP signals (tibialis anterior muscle) is obtained when the six-pulse paradigm is used with a stable level of muscle relaxation (the first twitch of the TOF-thenar eminence-at 45%-55% of baseline). IMPLICATIONS: This study shows that six-pulse (rather than two-pulse) transcranial electrical stimulation during a stable anesthetic state and a stable neuromuscular blockade aimed at 45%-55% (rather than 5%-15%) of baseline provides reliable and recordable muscle responses sufficiently robust for spinal cord monitoring in aortic surgery.

Influence of different fat emulsion-based intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol.

PURPOSE: The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. METHODS: Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%-like fat emulsion (Diprivan-10, D) or as a 1%- or 6% emulsion in Lipofundin MCT/LCT-10% (P1% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. RESULTS: Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compartmental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (Vd,ss) and terminal half-life (t1/2, lambda 2) were 107 +/- 4 ml/min/kg, 1.38 +/- 0.06 l/kg and 16 +/- 1 min, respectively (mean +/- S.E. n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 +/- 11 ml/min/kg, 5.19 +/- 0.41 l/kg and 45 +/- 3 min, respectively (mean +/- S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both Vd,ss and t1/2, lambda 2 (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t1/2,keo) was observed compared to the other propofol formulations (p < 0.05). CONCLUSIONS: The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.

Normal serum concentrations of S-100 protein and changes in cerebrospinal fluid concentrations of S-100 protein during and after thoracoabdominal aortic aneurysm surgery: Is S-100 protein a biochemical marker of clinical value in detecting spinal cord ischemia?

PURPOSE: This study was performed to determine the concentration of S-100 protein in serum and in the cerebrospinal fluid (CSF) during and 24 hours after thoracoabdominal aortic aneurysm repair. METHODS: This prospective study was performed at St. Antonius Hospital in Nieuwegein, The Netherlands. Eight patients who underwent elective thoracoabdominal aortic surgery participated in the study. Arterial blood and CSF samples for analysis of S-100 protein were drawn after induction of anesthesia, during the cross-clamp period of the critical segment, after 5 minutes of reperfusion, during the closure of the skin, and 24 hours after closure of the skin. RESULTS: No increase in S-100 protein concentration could be detected in serum (< 0.2 microg/L). The S-100 protein concentration in CSF increased during the procedure in all patients (4.2 +/- 3.1 microg/L). However, in one patient, who became paraplegic, the S-100 protein concentration in CSF increased even further after 24 hours (10 microg/L). CONCLUSIONS: The preliminary results suggest that S-100 protein in CSF may be a marker of clinical value in evaluating the effects of measures to detect and reduce spinal cord ischemia.

Treatment with the platelet-activating factor antagonist TCV-309 in patients with severe systemic inflammatory response syndrome: a prospective, multi-center, double-blind, randomized phase II trial.

In a prospective randomized, double-blind, placebo-controlled clinical study, the safety and efficacy of the platelet-activating factor antagonist TCV-309 in the treatment of systemic inflammatory response syndrome was studied. In total 29 patients were treated with 1.0 mg/kg TCV-309 twice daily during 7 days or with placebo. Study parameters were as follows: adverse events, 28 and 56 day all cause mortality, multi-organ failure scores, and the inflammatory mediators tumor necrosis factor, interleukin 6, interleukin 8, and soluble E-selectin. There was no difference in number and severity of adverse events between TCV-309- and placebo-treated patients. Day 28 and day 56 mortality was similar in both groups (day 56: 7/12 TCV-309 vs. 9/16 placebo, NS). Pulmonary and hematological failure scores improved significantly in TCV-309-treated patients (p < .05). There was no difference in inflammatory mediator levels between TCV-309- and placebo-treated patients. Treatment with TCV-309 appears to be safe in patients with systemic inflammatory response syndrome and does improve organ failure significantly.

Rupture recurrence after surgical repair of postinfarction ventricular septal rupture. Influence of early thrombolysis.

OBJECTIVES: The aim of this study was to identify factors causing rupture recurrence after surgical repair of postinfarction ventricular septal rupture and to evaluate the indication for reoperation. PATIENTS: Recurrence of rupture was analysed in 25 out of a series of 109 patients who underwent surgical repair for postinfarction ventricular septal rupture between 1980 and 1992 in our institution. RESULTS: The mean interval between initial operation and recurrence was 3.6 days with a median of 2 days. Multivariate logistic regression analysis identified early thrombolysis after infarction (P = 0.0085) as a risk factor for recurrence of the rupture. Rupture recurrence occurred more in the anterior then in the posterior infarction site, although non-significant. Reoperation was indicated in 15 patients, in 13 for postrecurrent cardiac failure. The main determinant of cardiac failure was a large postrecurrent shunt (P = 0.05). The mean interval between initial operation and reoperation was 136 days with a median of 101 days. In 6 patients a combined apical ventricular septal rupture recurrence and anterior ventricular aneurysm was found, in 9 patients the recurrent rupture was proximally located, without concomitant aneurysm formation. Of 15 patients who were reoperated, one died in hospital and three after the in-hospital period. Of 10 patients treated conservatively, one died in hospital and two after the in-hospital period. One residual ventricular septal rupture closed spontaneously. CONCLUSIONS: Rupture recurrence is mainly determined by early thrombolysis. Postrecurrent cardiac failure, as the main indication for reoperation, is dependent on postrecurrent shunt size.

The widely used anesthetic agent propofol can replace alpha-tocopherol as an antioxidant.

The cell membrane is protected against lipid peroxidation through endogenous antioxidants such as the lipid soluble alpha-tocopherol. The anesthetic agent propofol (2,6-diisopropylphenol) has a chemical structure which is similar to alpha-tocopherol, since it also contains a phenolic OH-group. The transient protection of GSH against lipid peroxidation in control liver microsomes is not observed in microsomes deficient in alpha-tocopherol. Introducing propofol (2 and 5 microM) restored the protective effect of GSH. Similar to the control microsomes the GSH-protective effect did not occur in previously heated microsomes. These results suggest that propofol acts similarly to alpha-tocopherol as a chain breaking antioxidant in liver microsomal membranes.