The influence of cryogenic brain injury on the pharmacodynamics of pentobarbital. Evidence for a serotonergic mechanism.

To study of the influence of brain injury on the pharmacodynamics of pentobarbital, the authors examined the effect of a focal cortical freezing lesion in rats on the brain concentration of pentobarbital associated with lack of response to tail clamp. The freezing lesion was made with a probe (-50 degrees C) applied through a craniotomy to the intact dura over the left parietal cortex. Three days after injury the rats were anesthetized with a continuous intravenous infusion of pentobarbital until they first did not respond to tail clamp stimulation. The brains were then removed for determination of pentobarbital by high-performance liquid chromatography. The brain pentobarbital concentration required to prevent response to tail clamp (EC50) was reduced from 209 +/- 39 nmol/g (mean +/- standard deviation) in rats without brain injury to 149 +/- 28 nmol/g in the injured animals (P = 0.005). The cortical serotonin (5-HT) concentration was increased from 1904 +/- 358 pmol/g in uninjured rats to 2513 +/- 598 pmol/g (P less than 0.01) in injured animals ipsilateral to the lesion. Pretreatment of the rats with p-chlorophenylalanine (PCPA, 200 mg/kg by intraperitoneal injection) to inhibit 5-HT synthesis abolished both the increase in 5-HT concentration associated with the injury (left cortex, 708 +/- 389 pmol/g; right cortex, 911 +/- 979 pmol/g) and the effect of the lesion on EC50 (uninjured, EC50 = 186 +/- 24 nmol/g; injured, EC50 = 179 +/- 47 nmol/g). Prevention of the decrease in EC50 by inhibition of 5-HT synthesis provides support for a functional role for 5-HT in the influence of cold injury on the pharmacodynamics of pentobarbital.

Analgesia and serum concentrations of extradural, subdural and intraperitoneal fentanyl in a rat model.

The effects of epidural, subdural and intraperitoneal fentanyl were determined on the tail flick response of the rat using the response latency as a measure of analgesia. Dose-time-response curves were generated for incremental doses of fentanyl administered at constant injection volumes. Serum concentrations at varying doses were determined using a radioimmunoassay technique. It was found that serum concentrations for extradural, subdural and intraperitoneal fentanyl were similar at the low doses, but differed significantly at higher doses suggesting that pharmacokinetic differences may be concentration dependent. Extradural administration of naloxone (0.004 mg) was able to antagonize extradural fentanyl (8.0 micrograms), a dose eight-fold greater than the lowest maximally effective dose. The relationship between serum fentanyl concentrations and administered doses suggest that the analgesic properties of extradural and subdural fentanyl are in part dependent on centrally mediated actions.

Pharmacokinetics of sufentanil in patients undergoing abdominal aortic surgery.

The authors determined the pharmacokinetics of sufentanil, 12.5 micrograms.kg-1 iv in patients undergoing elective abdominal aortic surgery. The mean age (+/- SD) of the ten patients was 68.4 +/- 7.9 yr; their mean weight was 74.4 +/- 19.1 kg. Six patients underwent aortobifemoral grafting and four had abdominal aortic aneurysm repair. Serum sufentanil concentrations were determined in samples drawn at increasing intervals over a 24-h period. A three-compartment pharmacokinetic model was fit to the concentration versus time data. Total drug clearance was 15.0 +/- 3.2 ml.min-1.kg-1. The volume of distribution at steady-state (Vdss) was 8.7 +/- 4.5 l.kg-1. The elimination half-time were positively correlated with patient age. There were no significant correlations between the pharmacokinetic variables and the duration of aortic cross-clamping, the duration of surgery, or the rate or total volume of iv fluids given intraoperatively. In general surgical patients, the mean elimination half-time of sufentanil has been reported to be 2.7 h. When sufentanil is used in large doses as the primary anesthetic agent for patients undergoing abdominal aortic surgery, the long elimination half-time observed implies that recovery will take much longer than would have been anticipated from previously published pharmacokinetic data.

The pharmacokinetics of alfentanil in children.

The pharmacokinetics of alfentanil were studied in 18 children (3 months to 14 yr of age) undergoing surgery. Alfentanil was administered as a 30-s infusion of either 50 or 120 micrograms.kg-1. Pharmacokinetic values were independent of dose. There was no correlation between Vdss (Volume of distribution at a steady state, measured as l.kg-1) and age or weight, and there was a weak correlation between clearance and age (r = 0.51, P less than 0.05). Vdss and elimination t1/2 were not different in infants less than 1 yr of age when compared to older children. The mean value of Vdss was 0.419 (SE .028) l.kg-1) for the whole group, and elimination t1/2 was 76.3 (SE 6.5) min. The clearance rate [TBC = 7.9 (SE 0.41) ml.kg-1.min-1] was within the range of values previously determined in adult studies. From these data, it would appear that, although there may be differences in the disposition kinetics between children aged 3 months to 14 yr and those measured in adults in some studies by other investigators, age-related differences within this group were not demonstrable.

Modern infusion pumps: are they accurate?

This study examined the volumetric accuracy of six infusion pumps currently available in Canada. Volumes delivered by all pumps over a range of 20-200 ml an hour were within five per cent of their indicated values. The pumps proved to be consistent and unaffected by the height of the infusion bag above the pump or by differing cannulae sizes. A discussion of some of the infusion methods for obtaining clinical accuracy is included.

Measurement of plasma fentanyl concentration: comparison of three methods.

The measurement of plasma fentanyl concentration by radioimmunoassay (RIA) and gas liquid chromatography (GLC) using either a flame ionization detector (FID) or nitrogen/phosphorus detector (NPD) has been compared. RIA is a satisfactory but expensive method of measuring plasma fentanyl concentration. GLC using an FID is not as satisfactory as RIA, but when an NPD is used the results are equal to those of RIA. In addition, other analgesics which are chemically similar to fentanyl, such as alfentanil, may also be measured by the GLC/NPD combination using the same set of operating conditions. By contrast, an RIA method is usually specific for only one compound, and measurement of additional drugs would almost certainly necessitate the development of new assay kits for each one.