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

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. 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. 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. 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. 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.

Skin lesions due to exposure to methyl bromide.

Six patients were occupationally exposed to high concentrations of methyl bromide during a fumigation procedure using adequate airway protection. Within a few hours all patients developed skin lesions, consisting of sharply demarcated erythema with multiple vesicles and large bullae. There was a striking predisposition for parts of the skin that were relatively moist or subject to mechanical pressure, such as axillae, groin, and abdomen. Microscopically, early skin lesions revealed necrosis of keratinocytes, severe edema of the upper dermis, subepidermal blistering, and diffuse infiltration of neutrophils and, to a lesser degree, eosinophils. Two patients developed an urticarial rash approximately one week after the exposure. On histologic examination, these late lesions showed combined features of a spongiotic dermatitis and urticaria. No immunopathologic manifestations were observed. In all patients, the skin returned to normal after four weeks, except for some residual hyperpigmentation. Plasma bromide levels after exposure strongly suggested percutaneous absorption of methyl bromide.

The influence of sodium bromide in man: a study in human volunteers with special emphasis on the endocrine and the central nervous system.

Sodium bromide was administered orally in capsules to healthy volunteers in doses of 0, 4 or 9 mg Br-/kg/day using a double-blind design. Each treatment was given to seven males for 12 weeks and to seven non-pregnant females (not using oral contraceptives) over three full cycles. Special attention was paid to possible effects on the endocrine and central nervous systems. At the start and end of the study, a full medical history, the results of a physical examination, haematological studies and standard clinical chemistry and urine analyses were recorded for each subject. These showed no changes for individuals following treatment, except for some incidence of nausea associated with bromide-capsule ingestion. Mean plasma-bromide concentrations at the end of treatment were 0.08, 2.14 and 4.30 mmol/litre for males and 0.07, 3.05 and 4.93 mmol/litre for females of the 0-, 4- and 9-mg Br-/kg/day groups, respectively. Plasma half-life was about 10 days. In the females taking 9 mg Br-/kg/day (but in no other group) there was a significant (P less than 0.01) increase in serum thyroxine and triiodothyronine between the start and end of the study but all concentrations remained within normal limits. No changes were observed in serum concentrations of free thyroxine, thyroxine-binding globulin, cortisol, oestradiol, progesterone or testosterone, or of thyrotropin, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone before or after the administration of thyrotropin-releasing hormone and LH-releasing hormone. Analysis of neurophysiological data (EEG and visual evoked response) showed a decrease in delta 1- and delta 2-activities and increases in beta-activities and in mean frequency (Mobility parameter) in the groups on 9 mg Br-/kg/day, but all the findings were within normal limits.

Cardiorespiratory depression and haemolysis due to thioridazine overdose in the rat.

The cardiovascular and respiratory effects of an intravenous overdose of thioridazine (125 mg kg-1 h-1) were examined in either spontaneously breathing or artificially ventilated urethane-anaesthetized rats. In both groups PO2, heart rate and mean arterial pressure decreased and atrioventricular and intraventricular conduction time, as well as QT time, increased similarly. PCO2 and pH did not differ significantly except in spontaneously breathing rats where a severe acidosis occurred at the end of the experiments. Haemolysis was suspected. The same dose was administered intravenously to artificially ventilated rats. Plasma concentrations of the drug and its main metabolites, haematocrit and free plasma Hb were determined in separate groups. A severe haemolysis was observed. Thioridazine administered in the same doses intragastrically, intraduodenally or intraperitoneally resulted in lower plasma values than after intravenous administration and there was no haemolysis. Much higher oral doses produced haemolysis at 36 h, at which time plasma concentrations were not higher than those recorded after administration via the other non-intravenous routes. It is probable that the observed changes in cardiovascular and respiratory parameters are partly the result of haemolysis following thioridazine administration.

Acute nitrous oxide intoxication: clinical symptoms, pathophysiology and treatment.

Nitrogen dioxide is a representative of the group of compounds which may cause pulmonary symptoms after a symptom free interval. Even when there are no symptoms immediately following exposure to nitrogen dioxide, clinical observation is advisable, because severe pulmonary involvement can be the result. The present paper discusses the clinical symptoms which are observed in man after acute exposure to nitrogen dioxide, as well as the pathophysiological mechanisms involved. Practical therapeutic guidelines are given for dealing with the diagnostic difficulties concerning this type of intoxication.

Effects of chlorthalidone and mechanical ventilation on hydroxyprolinuria during immobilization by means of muscle relaxants.

The influence of chlorthalidone on bone resorption in immobilized patients treated with mechanical ventilation was studied. Bone resorption was measured by means of urinary excretion of hydroxyproline and calcium. Blood pH was measured because of a possible effect of mechanical ventilation on calcium metabolism. Twenty-five patients were examined, 14 receiving and 11 not receiving chlorthalidone. Patients receiving chlorthalidone over a period of at least five and a maximum of 27 days showed lower hydroxyprolinuria and a higher blood pH value than the non-users. No differences were observed concerning calcium and phosphate metabolism. It is suggested that this slight alkalosis resulting from chlorthalidone may inhibit bone resorption.

Intoxication with beta-sympathicolytics.

Based on the review of available literature, this article states the possible clinical problems with beta-blocker intoxication. Some 26% of severe cases of intoxication will die. This fact stimulated the attempt, using animal experiments, to gain an insight into the pathophysiological profile of this intoxication. The results of these animal experiments led to the following conclusion: toxic doses of beta-blockers result in a dose-dependent decrease of myocardial contractility. This negative inotropic effect is not related to the antagonizing effects of the beta-blocker at the beta-adrenergic receptor level, nor to the additional properties of this group of drugs, but is influenced by a combination of other factors. These include (1) a direct negative inotropic effect on the myocardium, probably caused by a calcium dependent mechanism; (2) a decrease in serum calcium concentration, probably caused by a decreased parathormone production; (3) a centrally mediated hypotensive action. Toxic doses of beta-blockers do not only affect the myocardium and the haemodynamic system, they can also lead to respiratory arrest. This arrest is caused by the direct effect of these drugs on the central nervous system and can, in itself, be the cause of death. Such results lead to the following therapeutic advice: patients with severe beta-blocker intoxication must be admitted to an Intensive Care Unit, as early initiation of ventilation, as well as administration of beta-antagonist can be essential; the drop in serum calcium concentration must be corrected; drugs which can improve myocardial contractility, other than via the beta-adrenergic receptor, such as phosphodiesterase inhibitors and glucagon, should be administered.

Identification of cytotoxic peptide as possible mechanism for neurotoxicity of HIV viral envelope and AIDS pathogenesis.

A major segment of acquired immunodeficiency syndrome (AIDS) patients suffer from neurological complications, including impairments in concentration and motor functions. This neuronal injury, although related to the human immunodeficiency virus (HIV), occurs even though the neurons themselves are not infected by the virus. A complex web of interactions of the immune system with noxious substances released from gp120-stimulated macrophages is hypothesized as the mechanism of the injury. This study has identified an antimicrobial peptide resident in the human small intestine as a candidate for these noxious substances. This peptide is neither cell nor tumor specific and mediates cytolysis by membrane permeabilization based on membrane potential. The identified peptide is, however, type specific against viruses, only attacking enveloped viruses. This study hypothesizes that the peptide is sequestered in the HIV viral envelope and is released in very toxic concentrations when localized membrane potential is high. The peptide is localized in the Paneth cells of the human small intestine, and a transmission pathway is identified through the abrogation of intestinal tissue occurring during receptive anal intercourse. A study of amino acid sequences between this peptide and three variants of HIV confirmed homologies. The identification of this peptide as a possible mechanism could substantially alter AIDS treatment protocols.

Gas chromatographic determination of buformin in body fluids and tissues, using a nitrogen phosphorus detector: application to a postmortem case.

A specific method is described for the quantitation of the oral hypoglycemic biguanide buformin in biological material by gas chromatography. Phenformin, another biguanide derivative, is used as internal standard. Both compounds are converted to the corresponding s-triazine derivatives by reacting with acetic anhydride prior to gas chromatography with nitrogen-specific detection. The described procedure has been applied to the quantitative assay of buformin in body fluids and tissues, obtained from a postmortem case. The results of these toxicological investigations are discussed.

No beneficial effect of N-acetylcysteine treatment on broncho-alveolar lavage fluid variables in acute nitrogen dioxide intoxicated rats.

1. In previous studies a rat inhalation model was developed to investigate the efficacy of treatment in acute NO2 intoxication. 2. N-acetylcysteine (NAC) was administered intravenously to study its effect on biochemical variables in broncho-alveolar lavage fluid in acute NO2 intoxicated rats. It was decided to start the intravenous administration of NAC 24 h before the exposure to NO2 to induce higher intracellular glutathione (GSH) levels in lung cells of NAC-treated rats compared to not NAC-treated rats. Because, on theoretical grounds, the therapeutic effect of NAC may be expected to be especially marked during the first 24 h after exposure, the rats were observed for a period of 24 h and were then killed for investigation. A loading dose of 85 mg kg-1 h-1 or 170 mg kg-1 h-1 was followed by a continuous infusion (until autopsy) with a dose of 225 mg kg-1 24 h-1 or 450 mg kg-1 24 h-1 respectively. 3. Twenty four hours after exposure to 175 ppm NO2 (1 ppm is 1.88 mg m-3) for 10 min, NAC did not reduce the increase of variables in broncho-alveolar lavage fluid which reflect the severity of lung damage. 4. The protein and albumin concentration and the activities of angiotensin converting enzyme and alkaline phosphatase in broncho-alveolar lavage fluid after NO2 exposure were even more increased in the NAC-treated than in the saline-treated rats, but none of the differences was statistically significant. 5. In sham exposed rats no effect of NAC was observed.

Desferrioxamine treatment reduces histological evidence of lung damage in rats after acute nitrogen dioxide (NO2) intoxication.

1. In previous studies a rat inhalation model was developed to investigate the efficacy of treatment in acute NO2 intoxication. 2. Desferrioxamine was administered intravenously to study its effect on histological alterations in lung tissue in rats after acute NO2 exposure. 3. Twenty four hours after exposure to 175 ppm NO2 for 10 minutes the lung injury observed by light microscopy in the desferrioxamine treated rats was less pronounced than in the saline treated rats. 4. Desferrioxamine appeared to provide more protection with a dose of 100 mg kg-1 24 h-1 than with 200 mg kg-1 24 h-1.

Rat model to investigate the treatment of acute nitrogen dioxide intoxication.

1. The pulmonary toxic events induced by acute nitrogen dioxide (NO)2 exposure were studied in the rat to develop an inhalation model to investigate therapeutic measures. 2. A good correlation was observed between the lung weights and severity of the atypical pneumonitis. The pulmonary effects observed, became more pronounced with increasing NO2 concentrations (0, 25, 75, 125, 175 or 200 ppm, 1 ppm NO2 = 1.88 mg m-3 NO2) and exposure times (5, 10, 20 or 30 min). 3. An adequate NO2 concentration is 175 ppm, because it can induce a severe lung injury without mortality. This makes it possible to investigate suitable therapeutic interventions for several days. 4. Following acute inhalatory NO2 intoxication, transformation of NO2 to nitrate is presumably more notable than transformation to nitrite. 5. The transformation of NO2 to nitrate in lung tissue causes a slight increase in the serum nitrite concentration, which does not induce measurable formation of methaemoglobin. 6. Presumably, methaemoglobin does not contribute to the toxicity of NO2 intoxication.

Biochemical and histological alterations in rats after acute nitrogen dioxide intoxication.

1. In previous studies a rat inhalation model was developed to investigate the treatment of acute nitrogen dioxide (NO2) intoxication. 2. Biochemical parameters, which may be important for the evaluation of lung injury and repair, were reviewed and compared with the histology. 3. After exposure to high NO2 concentrations (75 ppm, 125 ppm or 175 for 10 min) the lung injury observed by light microscope was most pronounced after 24 h and became worse with increasing concentration. 4. The most sensitive indicators for lung injury in the broncho-alveolar lavage fluid (BAL) were protein and albumin concentrations, angiotensin converting enzyme activity, beta-glucuronidase activity and the presence of neutrophil leucocytes. The changes observed in these variables were dose-dependent. Following exposure to 175 ppm the protein and albumin concentrations and the angiotensin converting enzyme activity showed a 100-fold increase, while the beta-glucuronidase activity showed a 10-fold increase. 5. Glucose-6-phosphate dehydrogenase and glutathione peroxidase in the supernatant of lung homogenate and gamma-glutamyl transferase activity in BAL are likely to be the most practical parameters for monitoring the phase of repair because their activities were maximal at the moment histological changes were reduced in intensity. 6. Repair was almost complete 7 d following exposure.

Development of a rabbit model to investigate the effects of acute nitrogen dioxide intoxication.

1. In previous studies a rat inhalation model was developed to investigate the effects of intervention after acute NO2 exposure. The object of the present study was to investigate whether acute NO2 intoxication induced comparable effects in rabbits as it does in rats. Where the effects of intervention in both species are similar, then the conclusions drawn from these studies may have more relevance for the treatment of man. 2. Biochemical variables in bronchoalveolar lavage and supernatant from lung homogenate, which may be relevant for the evaluation of lung injury and repair, were investigated and compared with histology. 3. After NO2 exposure for 10 min, the pulmonary effects observed became more pronounced with increasing NO2 concentrations (0, 125, 175, 250, 400, 600 or 800 ppm) [1 ppm NO2 is 1.88 mg m-3]. The effects in rabbits were found to be broadly comparable with those in rats. 4. To achieve severe lung injury in rabbits without mortality, enabling investigations of the effects of intervention over several days, exposure to a NO2 concentration of 600 ppm for 10 min was most appropriate, while a concentration of 175 ppm NO2 was needed to attain comparable effects in rats. 5. The repair phase starts later, namely at 3 days after exposure in rats, compared to 5 days in rabbits.

Severe extrapyramidal syndrome in a dog caused by a Haloperidol (Serenase®) intoxication.

Summary The case history of a one-year-old male mongrel dog intoxicated with 120 mg haloperidol is described. The dog showed a coma with a severe extrapyramidal syndrome and was treated with orphenadrine. Symptoms, occurrence, and therapy of the extrapyramidal syndrome are discussed. Emphasis is laid on the importance to differentiate this syndrome from epilepsy and other neurological disorders.

Severe extrapyramidal syndrome in a dog caused by a haloperidol (Serenase) intoxication.

The case history of a one-year-old male mongrel dog intoxicated with 120 mg haloperidol is described. The dog showed a coma with a severe extrapyramidal syndrome and was treated with orphenadrine. Symptoms, occurrence, and therapy of the extrapyrmidal syndrome are discussed. Emphasis is laid on the importance to differentiate this syndrome from epilepsy and other neurological disorders.