B. Sangster

Etomidate-anaesthesia, with and without fentanyl, compared with urethane-anaesthesia in the rat.

1 In spontaneously breathing rats, continuous infusion of etomidate with and without fentanyl caused a slight decrease in blood pressure and heart rate. Coadministration of fentanyl and etomidate in order to obtain full anaesthesia and analgesia resulted in respiratory depression. 2 In artificially ventilated rats both etomidate as well as the anaesthetic combination caused a strong reduction in aortic flow and an increase in total peripheral resistance. A single infusion of etomidate did not change blood pressure. Etomidate combined with fentanyl reduced blood pressure. Under adjusted ventilation blood pressure, aortic flow, max(dF/dt) and heart rate were progressively reduced during a 4 h period. 3 In contrast, urethane anaesthesia reduced aortic flow to a minor extent. Total peripheral resistance and max(dF/dt) were hardly affected. The slightly reduced blood pressure and blood gas variables remained stable during the experiment. 4 From pharmacokinetic studies it was established that effective etomidate plasma levels were maintained constant during the experimental period. Pharmacokinetic interaction between etomidate and fentanyl did not occur. 5 It is concluded that for anaesthesia of longer duration during cardiovascular experiments in rats, urethane is preferable to etomidate/fentanyl because it does not cause serious changes in basal haemodynamic variables.

The use of atropine and oximes in organophosphate intoxications: a modified approach

Usually intoxications with cholinesterase inhibitors are treated with large dosages of atropine. Furthermore oxime treatment, if applicable, is generally discontinued after one to two days. Two cases of severe anticholinesterase intoxication are presented. In both cases administration of oximes were part of the treatment. The first patient showed relapse cholinergic symptoms when administration of oximes was stopped after one day. In the second patient, where oximes were administered continuously during six days, no relapse cholinergic symptoms occurred. Based on pharmacological as well as on toxicokinetic considerations, and supported by animal experimental data, a continued oxime treatment, if appropriate, can be advocated, whereas the use of atropine should be minimized.

Exposure of the Skin to Methyl Bromide: A Study of Six Cases Occupationally Exposed to High Concentrations during Fumigation

1 The effects of exposure of the skin to high concentrations of methyl bromide were studied in 6 cases, who had been unintentionally exposed. 2 Exposure to high concentrations of methyl bromide (approximately 40 g/m3) for 40 min can lead to redness and blistering of the skin. This cannot be prevented by wearing standard protective clothing. 3 Skin lesions show a preference for relatively moist skin areas. 4 Plasma bromide levels were highest immediately following exposure (mean 9.0 ± 1.4 mg/l) and fell in subsequent hours (mean 6.8 ± 2.3 mg/l 12 h after the exposure), suggesting absorption of (methyl) bromide through the skin. 5 No systemic effects were noted in this series. 6 Fumigation with methyl bromide should not be done in such a way as to require the presence of workers inside closed areas, where methyl bromide is released.

Urinary Excretion of Cadmium, Protein, Beta-2-Microglobulin and Glucose in Individuals Living in a Cadmium-Polluted Area

1 Urine was collected from 289 inhabitants of a cadmium-polluted quarter of Stadskanaal. The excretion of cadmium, protein, beta-2-microglobulin and glucose were determined. After being divided according to sex and to smoking habits, the results of the inhabitants were compared with those of 293 controls. 2 In inhabitants as well as controls, cadmium excretion was age-dependent. Cadmium excretion in females increased faster with age than in males. 3 In male-smoker controls, cadmium excretion was significantly higher (p < 0.001) than in male-non-smoker controls. 4 In male-non-smoker inhabitants, cadmium excretion (p = 0.05), protein excretion (p <0.01) and glucose excretion (p <0.01) were significantly higher than in corresponding controls. In male-smoker inhabitants, protein excretion (p < 0.01) and glucose excretion (0.01 < p < 0.05) were significantly higher than in corresponding controls. In female-non-smoker inhabitants glucose excretion was significantly higher (0.01 < p < 0.05) than in corresponding controls. 5 For some categories, living in the polluted area was associated with an increased cadmium excretion in urine and a slight difference in renal function, possibly related to a difference in cadmium body burden. It was concluded that, considering the actual values of each parameter, the observed differences were not relevant in terms of potential health hazards.

Buformin concentrations in a case of fatal lactic acidosis

SummaryA fatal case of lactic acidosis in a 84 year old diabetic woman taking buformin is reported. Buformin concentrations in serum, other body fluids and tissues were measured by gas chromatography. Serum buformin concentration at admission was 5.5 mg/1. Postmortem concentrations were: in serum 3.2mg/l; in lung 2.8mg/kg wet weight; in heart 3.0mg/kg; in pericardial fluid 3.5 mg/1; in liver 5.2 mg/kg; in bile 6.3 mg/1; and in kidney 98 mg/kg.

An evaluation of derived aortic flow parameters as indices of myocardial contractility in rats.

Potential indices of myocardial contractility derived from aortic blood flow, measured by means of electromagnetic flowmetry, were evaluated in rats under different ventricular loading conditions and were compared with the familiar contractility index dP/dt max. Aortic flow acceleration (dF/dt max) appeared to increase in a direct relationship to dP/dt max following inotropic stimulation by either dobutamine or isoprenaline. Since the former drug hardly influenced cardiac frequency, the increase in both variables could be attributed to a positive inotropic action. Also, afterload reduction by both drugs as a possible factor for increase in dF/dt max might be excluded since reduction in afterload by prazosin did not influence this variable, although dP/dt max was slightly reduced. However, dF/dt max was significantly decreased when afterload was markedly increased by methoxamine, whereas dP/dt max was slightly augmented. Therefore, this variable fails to satisfy the criterium of insensitivity to a certain level of aortic pressure rise. It is concluded that dF/dt max can serve as contractility index in rats, provided the influence of afterload conditions on this variable are taken into account.

Different Toxicological Profiles for Various Beta-Blocking Agents on Cardiac Function in Isolated Rat Hearts

Propranolol, timolol and sotalol were compared regarding their cardiotoxic properties in isolated, perfused and catecholamine depleted rat hearts. Catecholamine depletion was performed in order to exclude interference of the drugs with beta-adrenergic receptors. The results demonstrate that both in spontaneously beating and atrial- stimulated hearts propranolol (3 - 30 micrograms/ml) and timolol (30 - 300 micrograms/ml) induced a dose dependent decrease in myocardial contractility, stimulus formation and stimulus conduction. Lacking local anesthetic properties as evidenced by effects on coronary flow and threshold voltage in the heart it can be deduced that the negative inotropic effect and an impaired stimulus conduction due to timolol can neither attributed to beta-adrenoceptor antagonism nor membrane stabilising activity. In addition, both propranolol (5 micrograms/ml) and timolol (200 micrograms/ml) reduced myocardial contractility to the same extent in ventricular-paced hearts. Therefore, a direct myocardial depressive effect rather than an indirect effect due to a reduced heart rate must be responsible for the negative inotropy. The hydrophilic beta-blocker sotalol demonstrated a slight cardiodepressant activity either in the spontaneously beating and atrial-stimulated hearts (30 - 300 micrograms/ml) or ventricular-paced hearts (300 micrograms/ml). It is concluded that the toxicological profile of various beta-blocking drugs might be determined by an yet unknown pharmacological property apart from beta-adrenoceptor blockade or membrane stabilising activity. Furthermore, the degree of lipophilicity of the drug might be an important determinant for the cardiotoxic profile of this class of drugs.

Calcium interferes with the cardiodepressive effects of beta-blocker overdose in isolated rat hearts.

Propranolol, timolol and sotalol were compared with respect to their cardiotoxic properties in isolated, spontaneously beating rat hearts. Propranolol and timolol induced a dose-dependent decrease in myocardial contractility. A high dose of sotalol had only modest negative inotropic effects. Similar reductions in myocardial contractility were observed in isolated, ventricle-stimulated rat hearts. These observations were similar to those in a previous study in which spontaneously beating and ventricle-stimulated reserpinized rat hearts were investigated. Spontaneously beating rat hearts were perfused with a high-, a normal- and a low-Ca++ medium, each with and without propranolol, timolol and sotalol. Addition of each beta-blocker to a normal-Ca++ medium induced a decrease of myocardial contractility and of heart rate and an increase of AV-conduction time when compared with the drug-free medium. In a high-Ca++ medium containing the same concentration of each beta-blocker, a less pronounced decrease of myocardial contractility was observed. Heart rate decreased and AV-conduction time increased to the same extent as after perfusion with the drug containing normal-Ca++ medium. With respect to the corresponding drug-free medium perfusion with a low-Ca++ medium with each beta-blocker enhanced the decline in myocardial contractility, most pronounced in propranolol and timolol containing media. For propranolol and sotalol the decrease in heart rate and increase in AV-conduction time were similar to the results after administration of the same beta-blocker in a high- and a normal-Ca++ perfusion media. Timolol caused an electromechanical dissociation. It was concluded that in beta-blocker intoxication the negative-inotropic phenomena cannot be explained by an action of the drugs on the beta-receptor since the results in reserpinized and non-reserpinized rat hearts were similar. Other effects have to be responsible for the observed cardiotoxic phenomena. The present results indicate that these phenomena can be influenced by Ca++ and or can be attributed to differences in lipophilicity.

Dopamine and isoproterenol in imipramine intoxication in the dog.

Artificially ventilated anesthetized dogs were given imipramine 7.5 mg/kg/hr i.v. In the first group (n = 6) mechanical cardiac activity was no longer detectable after a cumulative dose of 20.0 +/- 6.6 mg/kg (mean +/- sd). When aortic flow had decreased to 75% of its initial value, in a second group (n = 5) of experiments dopamine 10 micrograms/kg/min and in a third group (n = 5) isoproterenol 1 microgram/kg/min were administered i.v.. The doses of dopamine and isoproterenol were doubled when aortic flow had again decreased to 75% and 100%, respectively, of the original values. Cardiac mechanical activity was not detectable after a cumulative dose of 43.8 +/- 13.3 in the dopamine and 42.5 +/- 8.0 mg imipramine/kg in the isoproterenol group. These values differed significantly from that in the reference group (both 0.01 greater than p greater than 0.001). In the first group plasma imipramine concentrations at the end of the experiments were 3.06 +/- 0.66, in the second 3.36 +/- 0.66 and in the third 3.32 +/- 1.10 mg/1. Desipramine concentrations were 0.078 +/- 0.06, 0.162 +/- 0.076 and 0.383 +/- 0.09 mg/1 respectively. Dopamine induced a hemodynamic profile of low output and high pressure and isoproterenol one of low pressure and high output. It is concluded that dopamine combined with isoproterenol might be effective in counteracting the cardiodepressant action of imipramine.

Central origin of respiratory arrest in beta-blocker intoxication in rats

Propranolol HCl (7.5 mg X kg-1), timolol maleate (7.0 mg X kg-1), and sotalol HCl (10 mg X kg-1) were administered intracerebroventricularly (icv) to spontaneously breathing (SB) rats. The respiratory rate declined until the rats all died from respiratory arrest. Artificial ventilation resulted in survival of the rats for a 3-hr observation period. Intravenous (iv) administration of the same doses of the three beta blockers to SB rats did not result in either respiratory depression or death. Except for a decrease in heart rate (HR) the hemodynamic and respiratory parameters remained almost constant during the 3-hr observation period after iv administration to SB rats. After icv administration to SB as well as to ventilated rats no significant differences could be observed in the initial decrease in HR in comparison with iv administration. In SB rats at the end of the experiments a further decrease in HR was observed which might be ascribed to hypoxia since it did not occur in ventilated rats. After icv administration of each drug to the ventilated rats, mean arterial blood pressure showed a significantly greater decrease at the end of the 3-hr observation period than after iv administration. Plasma concentrations of the three drugs were determined just before death after icv administration in SB rats. In the other two groups they were measured at mean survival time and at the end of the experimental period. The plasma concentrations showed that the route of administration rather than the concentration of the beta blocker in plasma determines the occurrence of respiratory arrest. It was concluded that an overdose of propranolol, timolol, or sotalol can cause a centrally mediated respiratory arrest. Furthermore, a central mechanism appears to be implicated in the decrease in blood pressure.