Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization.

INTRODUCTION: QT interval prolongation and Torsade de Pointes (TdP) arrhythmias are recognised as a potential risk with many drugs, most of which delay cardiac repolarization by inhibiting the rapidly activating K(+) current (I(Kr)). The objective of this study was to compare the effects of compounds on cardiac action potentials recorded from guinea-pig ventricular myocytes and dog Purkinje fibres. METHODS AND RESULTS: Effects of dofetilide, sotalol, cisapride, terfenadine, haloperidol and sparfloxacin, compounds known to cause QT prolongation (positive controls), and nifedipine and verapamil, not associated with QT prolongation (negative controls) were studied on intracellular action potentials recorded from guinea-pig isolated ventricular myocytes (VM) and dog isolated Purkinje fibres (PF). Prolongation of action potential duration (APD) by sotalol, dofetilide and sparfloxacin was concentration-dependent and of greater magnitude in dog PF compared to guinea-pig VM. The maximum prolongation of APD in guinea-pig VM at 0.5 and 1 Hz was approximately 25% and this was associated with complete inhibition of I(Kr) by dofetilide. Effects on APD of cisapride and haloperidol in both preparations, and terfenadine in guinea-pig VM, were biphasic, consistent with inhibition of multiple ion channels. There was no effect of terfenadine on APD in dog PF. Haloperidol increased APD by more than 25% in guinea-pig VM, consistent with effects on additional repolarizing currents. The negative controls shortened APD to a greater extent in guinea-pig VM compared to dog PF. In general, the positive control drugs increased action potential triangulation (APD(40-90)) to a greater extent than APD(90). CONCLUSION: Guinea-pig isolated VM may be more sensitive for detecting APD prolongation with compounds inhibiting multiple ion channels and action potential triangulation (APD(40-90)). Effects on repolarizing currents other than I(Kr) were also distinguished in guinea-pig VM.

Metoclopramide and prochlorperazine do not decrease propofol hypnotic requirements.

One hundred patients scheduled for minor surgery were given either saline, metoclopramide 0.1 mg.kg-1 or 0.2 mg.kg-1, or prochlorperazine 0.1 mg.kg-1 or 0.2 mg.kg-1 before induction of anaesthesia with a fixed rate infusion of propofol. Neither metoclopramide nor prochlorperazine reduced the induction dose of propofol. The possibility that these agents increased the induction dose could not be excluded.

The output of an 'empty' Tec 3 vaporizer.

The output of 30 Tec 3 vaporizers (halothane, enflurane and isoflurane) was studied, starting at the point where no liquid was visible in the content window. At 6 l.min-1 and 1% v/v initial output, consistent delivery was on average maintained for in excess of 90 (range 55-120) min. Thereafter, output declined rapidly. At the flows and concentrations studied there is a significant reserve in the vaporizing chamber, but it is likely that when higher flows and concentrations are used this reserve may be substantially reduced.

The characteristics of the inhibition of serum cholinesterase by metoclopramide.

The inhibition of serum cholinesterase by metoclopramide has been previously characterised in vitro at high dilution of the enzyme. We examined the effect of varying enzyme dilution over a range of 1000 fold dilution, and assay temperature at 25 degrees C and 37 degrees C on the fractional inhibition of enzyme activity by metoclopramide. Neither enzyme concentration nor reaction temperature affected this fractional inhibition. Concentrations of metoclopramide producing 50% inhibition of enzyme activity were in the range 1.0-1.9 x 10(-6) M. Lineweaver-Burk analysis of the enzyme reaction suggests that the pattern of this inhibition is competitive.

The effect of ketorolac as an adjuvant to local anaesthetic infiltration for analgesia in paediatric umbilical hernia surgery.

After umbilical hernia surgery, and wound infiltration with bupivacaine 0.5%, 17 children were given ketorolac 0.5 mg.kg-1, with 18 controls receiving only the wound infiltration. No child experienced severe pain, but moderate pain was noted in patients in both groups. Objective and subjective pain scores were not different statistically at any point up to the morning after surgery.

Sustained release metoclopramide for prophylaxis of post-operative nausea and vomiting.

Oral metoclopramide may be given as a premedicant to reduce post-operative nausea and vomiting, but there is little evidence that it is effective. We studied the anti-emetic action of a sustained release formulation of metoclopramide (Gastromax 30 mg) in 39 fit women undergoing inpatient laparoscopy under general anaesthesia with a standardized anaesthetic technique in a double-blind placebo-controlled trial. No benefit was demonstrated. (Incidences: nausea: 13 of 20 patients [placebo] and 13 of 19 [metoclopramide]; vomiting: 13 of 20 and 12 of 19.)

New drug in volatile anaesthesia--desflurane.

Desflurane is a new fluorinated ether with rapid onset of and recovery from anaesthesia. Recovery characteristics are comparable with or faster than after propofol infusion or isoflurane anaesthesia. The minimum alveolar concentration (MAC) varies with age from 9.4% (infants) to 6% (adults), and is reduced by opioids and sedative premedication. Desflurane is highly stable. It is stable with soda-lime, and is minimally metabolised. Inhalational induction is associated with a high incidence of coughing and laryngospasm, especially in children. During anaesthesia, blood pressure is reduced, but cardiac output and organ perfusion is well maintained. Desflurane is a respiratory depressant, and enhances the action of neuromuscular blocking agents. Cerebrovascular autoregulation appears to be preserved, but intracranial pressure may still rise during desflurane anaesthesia. Delivery of vapour is using a new electrically heated vaporizer, the Tec 6, with internal monitoring circuitry and new safety features.

The desflurane Tec 6 vaporizer.

A late development model of the Tec 6 vaporizer for the administration of desflurane vapour has been evaluated. It is heated electrically and has both electronic monitors of vaporizer function and alarms. The new filling system is a significant improvement over previous Tec filling systems. The vaporizer requires a warm-up period before it may be used, but when activated it provides an output that is approximately linear between 1 and 18% vapour concentrations, at flow rates between 200 ml min-1 and 10 litre min-1.

A comparison between propofol and desflurane anaesthesia for minor gynaecological laparoscopic surgery.

Fifty-seven healthy female patients who underwent gynaecological laparoscopic surgery received either desflurane or propofol for induction and maintenance of anaesthesia. Inhalational induction was generally well tolerated, and consciousness was lost in approximately 2 min (mean end-tidal concentrations of desflurane were 8.3% with 60% nitrous oxide, and 7.1% with oxygen). Recovery of consciousness and orientation were more rapid in patients in whom anaesthesia was maintained with desflurane than with propofol, but there were no differences in psychomotor function test scores at 30 min. The data suggest that desflurane provides controllable anaesthesia and rapid recovery of consciousness after laparoscopic surgery.

Incidence of awareness with recall during general anaesthesia.

One thousand patients who were anaesthetised between February and April 1990 at University Hospital, Nottingham were interviewed between 20 and 36 hours after their operation. Patients under 16 years of age, those who had undergone obstetric or intracranial surgery, those who were unable to communicate and patients who were discharged from hospital before the postoperative visit were not interviewed. A standard set of questions was used to determine the incidences of recall of events and dreams during the operation. These incidences were 0.2% and 0.9% respectively, considerably lower than reported in previous comparable studies.

The requirement for intensive care support for the pregnant population.

Pregnancy-associated admissions to the Intensive Care Unit during the first 5 years of a newly established teaching hospital obstetric unit are reviewed. There were 23 such admissions; in the same period, 21,983 deliveries occurred. The most frequent cause for Intensive Care admission was hypertensive disease of pregnancy. Most patients required admission for less than 48 hours. Two patients died during the period of study.

Bremsstrahlung production by potassium-40 in muscle.

The bremsstrahlung spectrum produced when 1320 keV beta particles, emitted by the naturally occurring isotope 40K, are absorbed in muscle has been calculated. With reference to the external measurement of 239Pu in the lung using the 17 keV U L x-rays, a simple model was used to estimate the number of bremsstrahlung photons with energies between 12 and 25 keV that would emerge from the chest wall of a normal subject. This was calculated to be 3 min-1 for a detection area of 628 cm2, although internal bremsstrahlung may increase this to 4 min-1. The latter figure is a factor of approximately three lower than the counting rate observed when a pair of phoswich NaI detectors of the same total area are placed over an average subject. Possible reasons for this discrepancy are discussed.

Identification of 241Am in the axillary lymph nodes with an intrinsic germanium detector.

A routine measurement with two 200 mm-diameter phoswich detectors, placed one each side of the sternum, yielded an apparent lung content of 17 nCi 241Am for a subject. subject. Inspection of the data revealed that there were many more counts from the left side than from the right and that there was a greater number of Np L X rays observed, relative to the L gamma ray, than would be expected for a uniform lung distribution of 241Am. These observations suggested a shallow localised deposit in the left side of the chest. The subject's working history could not rule out an inhalation exposure, but he was known to have had a wound contaminated with Pu/Am in his left hand 16 yr previously. The wound had contained approx. 0.02-0.03 mu Ci 241Am initially, most of which was excised from the wound site after 50 days. Prompted by this knowledge we used a 50mm-diameter intrinsic Ge detector to examine the wound and relevant lymph node sites. The results demonstrated a localised deposit of 241Am in the axillary lymph nodes with approx. 1 nCi 241Am at the wound site. Subsequent measurements made with the phoswich detectors suggested that there was approx. 7 nCi 241Am in the lymph nodes with approx. 1 nCi 241Am in the liver, thereby accounting for most of the detectable 241Am contamination in the thorax.