Comparison of two intravenous ranitidine regimens in a homogeneous population of intensive care unit patients.

Primed continuous infusion and repeated intravenous injections of ranitidine (daily dose 200 mg) were compared in a homogeneous population of post-operative intensive care unit patients in a randomized fashion. Intragastric pH was measured continuously for 72-96 h with combined glass electrodes positioned in the gastric corpus. Patients whose intragastric acidity fell below pH 4.0 for 70% of a 24-h period within 48 h after the operation (baseline period) were considered 'at risk' of developing stress-related lesions. From the 26 patients screened, 18 fulfilled this criterion. Nine received the continuous infusion regimen (50 mg bolus + 0.125 mg.kg/h) and nine received repeated boluses (50 mg ranitidine every 6 h). A consistent decrease of intragastric acidity was shown in each group by a rise in 24-h median pH from 1.4 (1.3-1.7; 26th-75th percentile) during the baseline period to 4.2 (1.9-5.4, P < 0.01) for the continuous infusion and from 1.55 (1.1-2.2) to 2.65 (2.1-3.5, P < 0.02) for the repeated boluses during the final 24 h of the therapy period. During that period intragastric pH was maintained above 4 for 52% of time by continuous infusion and for 40% of time for repeated boluses compared with 10.8% (P = 0.01) and 6.2% (P = 0.008) of time, respectively, in the baseline period. In conclusion, although no statistically significant differences between the two regimens could be detected, the continuous infusion regimen tended to show slightly better results in percentages of time that pH values were above 1 to 7, and in median 24-h pH values.

The short- and long-term effect of single high-dose intra-operative electron beam irradiation of retroperitoneal structures--an experimental study in dogs.

Intra-operative electron beam radiotherapy is a new treatment modality. The abdomen is the area of greatest potential applicability of IORT and therefore its effect on retroperitoneal structures was investigated in a canine model. The retroperitoneal structures tolerate 30 to 40 Gy well, with the exception of the radiation-sensitive ureter which showed fibrosis. Twenty to 25 Gy is within the safe dose limits for the clinical application of IORT.

Effects of 4-aminopyridine in Eaton Lambert Syndrome.

The effects of 4-aminopyridine (a non-anticholinesterase antagonist of curare-like agents) on the evoked muscle action potentials (EMAP) in a patient with Eaton Lambert Syndrome are reported. On two separate occasions the i.v. administration of 0.31 mg kg(-1) and 0.62 mg kg(-1) was followed by a 300% increase of EMAP for about 2 h without serious side-effects.

Bile salts and neuromuscular blocking agents.

The influence of the primary bile salts taurocholate and chenodeoxycholate on the neuromuscular blockade of the non-depolarizing drugs Org 6368, pancuronium, Org NC 45 and hexafluorenium was studied in cats. An increase in the effects of these agents, all possessing widely varying molecular structures, was found following administration of the bile salts. The bile salt concentrations in plasma were similar to those obtained after 9-10 days of extrahepatic cholestasis in cats. The effect of Org NC 45, a new monoquaternary analogue of pancuronium, was increased more than that of pancuronium. This increase in effect is probably a result of inhibition of the hepatic uptake of the neuromuscular blocking drugs. The neuromuscular blocking effect of gallamine was not influenced significantly by the administration of bile salts.

Mechanisms underlying the prolonged duration of action of muscle relaxants caused by extrahepatic cholestasis.

The neuromuscular blocking effects of Org 6368 and Org NC 45 were studied in rats with experimental cholestasis and in controls. The effect of Org NC 45 during infusion of taurocholate was investigated. In cholestatic rats we observed a three-fold increase of the duration of action of Org 6368 and Org NC 45. The same was observed for Org NC 45 with taurocholate. In the rat phrenic nerve-hemidiaphragm preparation taurocholate potentiated the neuromuscular blockade of Org 6368, pancuronium and gallamine, but not Org NC 45. Increased bile salt concentrations caused strong inhibition of hepatic uptake and biliary excretion of Org 6368 and tubocurarine in isolated perfused livers. Taurocholate and glycocholate were more potent than cholate and chenodeoxycholate. Cholestatic livers exhibited a clearance of Org 6368 which was 50% of control. We conclude that the prolonged duration of action of certain muscle relaxants because of cholestasis results from both inhibition of hepatic uptake by the accumulated bile salts and a general deterioration of liver transport function.

Prolongation by bile salts of the duration of action of a steroidal neuromuscular blocking agent.

The influence of bile salts on the duration of action of the steroidal non-depolarizing neuromuscular blocking agent ORG 6368 was investigated in cats. The intravenous administration of ORG 6368 (100 microgram/kg body wt) caused a maximum neuromuscular blockade of 71 +/- 6% with a duration of action of 3.4 +/- 0.1 min. However, intraportal administration of the same dose caused no significant neuromuscular blockade. Following an infusion of dehydrocholate 320 mumol, lasting for 8 min, the magnitude and the duration of action of the neuromuscular blockade produced by ORG 6368 were increased markedly. This effect of the bile salt is possibly a result of inhibition of the hepatic uptake of ORG 6368, thereby retarding its disappearance from the plasma and consequently prolonging the neuromuscular blockade. The neuromuscular blocking effect of intraportally administered gallamine (1 mg/kg body wt) was not influenced significantly by the infusion of dehydrocholate.

Transducer offset by electrocautery resulting in erroneous blood pressure measurement.

During a coronary artery bypass operation arterial blood pressure measured with a Bentley Trantec model 800 transducer increased erroneously while continuous electrocautery was being used. This phenomenon has recurred infrequently, with fictitious hypotension being observed in one patient. To reproduce the problem of pressure offset during electrosurgery a bench test demonstrated that with peak to peak voltage of 20 volts from the electrosurgical unit, three of seven Bentley transducers had offsets as much as +/- 50 mmHg. It is important for anaesthetists to determine if electrosurgery units are functioning before treating apparent pressure drifts.

An electroencephalographic study of 4-aminopyridine.

The electroencephalographic (EEG) effects of 4-aminopyridine (4-AP) given intravenously in therapeutic doses were studied in four conscious human volunteers. 4-AP (0.2 mg/kg) caused an increase of the occipital alpha peak frequency of 0.4 to 1.0 Hz. In the dose range of 0.2 to 0.3 mg/kg there was neither evidence for epileptic activity in the EEG nor were any clinical side effects observed. This dose of 4-AP was also found to antagonize diazepam-induced sleep in four volunteers. In addition 4-AP (0.3 mg/kg) hastened the recovery by a factor of 4 in four patients having endoscopic procedures under diazepam-nitrous oxide anesthesia.

High-performance liquid chromatographic determination of galanthamine, a long-acting anticholinesterase drug, in serum, urine and bile.

The anticholinesterase drug galanthamine is obtained from alkalinized serum by repeated liquid--liquid extraction. The resulting extract is approximately 100 times concentrated with respect to the original sample. Quantitative determination of galanthamine is performed with normal-phase liquid chromatography using a mixture of dichloromethane--n-hexane and ethanolamine as an eluent. Phenacetin is used as internal standard. The absorption of the column effluent is monitored at 235 nm. No endogenous sources of interference have been observed. A galanthamine serum level of 5 ng/ml is found as the minimum detectable concentration; the coefficient of variation at this level is 37.8% (n = 4). For the assay of galanthamine in the concentration range 10-100 ng/ml, standard deviations vary between 18.9 and 2.5% (n = 32).

Effect of experimental cholestasis on neuromuscular blocking drugs in cats.

Pancuronium, Org 6368 and gallamine were compared in control cats and in cats with experimental cholestasis. A decrease in the plasma clearance and a prolongation of neuromuscular blockade with Org 6368 and pancuronium were found in the latter; no significant difference was detected in the biotransformation pattern of Org 6368 and pancuronium compared with controls. Inhibition of hepatic uptake of Org 6368 and pancuronium in extrahepatic cholestasis might explain the significant alterations in the pharmacokinetics of the two steroid neuromuscular blocking drugs. The pharmacokinetics of gallamine were normal during cholestasis. The results suggest that, under pathological conditions involving increased plasma concentrations of bile salts, neuromuscular blocking agents that are cleared from the plasma by the liver may have an impaired hepatic uptake and consequently a prolonged duration of action.

Pharmacokinetics of galanthamine (a long-acting anticholinesterase drug) in anaesthetized patients.

The pharmacokinetics of the long-acting anticholinesterase drug, galanthamine, were investigated in eight patients. After i.v. injection of 0.3 mg kg-1, the decrease in the serum concentration of galanthamine followed a biexponential curve. The serum concentration decreased rapidly from 543 +/- 47 ng ml-1 to 128 +/- 14 ng ml-1 between 2 and 30 min with a T1/2 alpha of 6.42 +/- 2.15 min, and then declined more slowly with a T1/2 beta of 264 +/- 28 min. Total serum clearance of galanthamine amounted to 5.37 +/- 0.87 ml min-1 kg-1, and the renal clearance was 1.36 +/- 0.10 ml min-1 kg-1. The cumulative urinary excretion of galanthamine between 0 and 48 h after injection amounted to 28.0 +/- 5.4% of the administered dose. The biliary excretion of galanthamine during 24 h amounted to 0.2 +/- 0.1% of the dose. There was no evidence of glucuronide or sulphate conjugation of galanthamine.

Hepatic and renal disposition of pancuronium and gallamine in patients with extrahepatic cholestasis.

The plasma clearance of pancuronium in patients with extrahepatic cholestasis was 16% lower than in a control group (1.47 +/- 0.11 ml min-1 kg-1 v. 1.76 +/- 0.21 ml min-1 kg-1), but the difference was not significant. A significant increase in the elimination half-life T 1/2 beta of pancuronium (from 141 to 224 min) and a significant increase in the volume of the peripheral compartment (V2) was found in patients with extrahepatic cholestasis when compared with control patients. There was a significantly lower cumulative biliary excretion of pancuronium (0.3 +/- 0.3% v. 10.9 +/- 3.2% in the controls) during the 48-h period of observation. The biotransformation and cumulative urinary excretion patterns of pancuronium revealed no significant differences between the two groups of patients. The increase of T 1/2 beta pancuronium in patients with extrahepatic cholestasis was mainly a consequence of the increase in the volume of distribution. No significant differences in the plasma clearance, T 1/2 beta or in the volume of distribution were observed with gallamine in the patients with extrahepatic cholestasis when compared with the control group. The cumulative urinary excretion of gallamine during 48 h in both groups of patients was approximately 100%. We concluded that in patients with cholestasis and normal glomerular filtration, gallamine is probably more reliable than pancuronium for neuromuscular blockade.