Time to achieve target mean arterial pressure during resuscitation from experimental anaphylactic shock in an animal model. A comparison of adrenaline alone or in combination with different volume expanders.

Anaphylactic shock is a rare, but potentially lethal complication, combining life-threatening circulatory failure and massive fluid shifts. Treatment guidelines rely on adrenaline and volume expansion by intravenous fluids, but there is no solid evidence for the choice of one specific type of fluid over another. Our purpose was to compare the time to achieve target mean arterial pressure upon resuscitation using adrenaline alone versus adrenaline with different resuscitation fluids in an animal model and to compare the tissue oxygen pressures (PtiO2) with the various strategies. Twenty-five ovalbumin-sensitised Brown Norway rats were allocated to five groups after anaphylactic shock induction: vehicle (CON), adrenaline alone (AD), or adrenaline with isotonic saline (AD+IS), hydroxyethyl starch (AD+HES) or hypertonic saline (AD+HS). Time to reach a target mean arterial pressure value of 75 mmHg, cardiac output, skeletal muscle PtiO2, lactate/pyruvate ratio and cumulative doses of adrenaline were recorded. Non-treated rats died within 15 minutes. The target mean arterial pressure value was reached faster with AD+HES (median: 10 minutes, range: 7.5 to 12.5 minutes) and AD+IS (median: 17.5 minutes, range: 5 to 25 minutes) versus adrenaline alone (median: 25 minutes, range: 20-30 minutes). There were also reduced adrenaline requirements in these groups. The skeletal muscle PtiO2 was restored only in the AD+HES group. Although direct extrapolation to humans should be made with caution, our results support the combined use of adrenaline and volume expansion for resuscitation from anaphylactic shock. When used with adrenaline the most effective fluid was hydroxyethyl starch, whereas hypertonic saline was the least effective.

Biphasic airway-lung response to anaphylactic shock in Brown Norway rats.

Bronchospasm may be part of the response to systemic anaphylaxis in humans. The anaphylactic shock has been characterized in allergic rats, but little data are available on the concurrent changes in airway-lung mechanics. The aim was to describe the respiratory resistance (Rrs) and reactance (Xrs) response to ovalbumin (OVA) induced systemic anaphylaxis in allergic rats. Thirty five anesthetized and mechanically ventilated Brown Norway rats were randomly allocated to OVA (n=20) or vehicle (n=15) sensitization and provocation. Rrs and Xrs were obtained by the forced oscillation technique at 20 Hz. Allergic rats showed dramatic and reproducible concurrent Rrs peak and Xrs through within 4 min of OVA injection (p<0.0001). Thereafter, Rrs returned to baseline while Xrs remained significantly more negative (p<0.0001). It is concluded that systemic anaphylaxis in allergic rats is associated with severe early acute inhomogeneous bronchoconstriction followed by pulmonary interstitial/small airspace edema. The model may be of interest to assess treatments targeting the associated bronchoconstriction and/or airway vascular leakage.

[Pharmacokinetics of sulfamerazine after a single intravenous dose in healthy calves and calves with diarrhea of different severity with consideration of the influence of an existing kidney function restriction]. / Pharmakokinetik von Sulfamerazin nach einmaliger intravenöser Applikation bei gesunden und unterschiedlich stark durchfallkranken Kälbern unter Berücksichtigung des Einflusses einer vorhandenen Nierenfunktionseinschränkung.

Blood levels of Sulfamerazine were examined in 16 calves with different severity of diarrhoea in consideration of kidney function and compared with the values of 5 clinically intact animals. Urea and creatinine levels in plasma as well as urea and creatine clearance were tested to check kidney function. A single dose of 60 mg Sulfamerazine/kg body weight was administered to all animals via catheter into the vena jugularis. Blood samples were collected for 48 hours. The mean concentration of Sulfamerazine in calves with severe diarrhoea was significantly higher 24 hours post application than in the healthy control group and in animals with low and middle intensive diarrhoea (healthy animals: 37.61 +/- 7.18 micrograms/ml; animals with severe diarrhoea: 57.3 +/- 7.5 micrograms/ml). Animals with severe diarrhoea showed significantly higher values of half life time of elimination t1/2 (healthy animals: 7.08 +/- 1.25 h; animals with severe diarrhoea: 11.39 +/- 2.11 h) and of area under the curve AUC (healthy animals: 2023.4 +/- 397.21 micrograms*h/ml; animals with severe diarrhoea: 2990.6 +/- 594.9 micrograms*h/ml) than the others. Low and middle intensive diarrhoea has no important influence on the pharmacokinetics of Sulfamerazine.

Toxicological studies on a benzofurane derivative. I. A comparative study with phenobarbital on rat liver.

The benzofurane derivative benzbromarone (BBR) previously has led to liver tumor formation after long-term treatment of rats, but no indications of genotoxicity were detected. The present studies were designed to elucidate the mechanism(s) possibly involved in liver tumor formation by BBR. Female Wistar rats were used. Phenobarbital (PB) served as a positive control. (1) Short-term treatment (7 days) with daily doses of 2 to 100 mg/kg BBR led to adaptive responses in the liver, i.e., growth (increases in DNA, RNA, and protein) and induction of monooxygenases. These changes were also observed after feeding BBR for 8, 33, 77, and 102 weeks at doses of 2, 10, and 50 mg/kg/day but tended to weaken with time. Similar effects were obtained with PB fed at 2, 10, or 50 mg/kg/day. However, unlike PB, BBR did not enhance the expression of cytochrome P450-PB as demonstrated by immunostaining of histological liver sections. (2) BBR feeding for 102 weeks, but not for 77 weeks, produced some neoplastic liver nodules and at 50 mg/kg produced one hepatocellular carcinoma (HCC). Thus, BBR was tumorigenic in the present study, but was clearly weaker than PB which had induced liver nodules and HCCs at 77 weeks and even more markedly at 102 weeks. (3) To check for tumor-initiating activity 100 mg/kg BBR was given 14 hr after a two-thirds hepatectomy followed by promotion with PB (50 mg/kg) for 15 weeks. No phenotypically altered liver foci were detected. (4) To test for tumor-promoting activity rats received a single dose of N-nitrosomorpholine (250 mg/kg), and subsequently BBR or PB at doses of 2, 10, and 50 mg/kg/day. While PB markedly enhanced the development of neoplastic nodules and HCCs, BBR had only a weak enhancing effect on the induction of HCC, which was not dose related. gamma-glutamyl transpeptidase-positive foci dramatically increased in PB-treated animals, in contrast they showed no response after 2 and 10 mg/kg BBR and even decreased after 50 mg/kg BBR. (5) With PB changes in liver growth, monooxygenase activity, foci expansion, and tumor promotion all correlating with tumorigenesis in a quantitative manner, apparent no-observed-effect-levels are somewhat below 2 mg/kg (or 10 mg/kg for liver enlargement). (6) These studies suggest that BBR belongs to a group of nongenotoxic, growth-stimulating drugs with tumorigenic potential in rat liver. Its effects on the liver are different from those of PB, but seemed to resemble those of peroxisome proliferators, a hypothesis studied in the subsequent papers.

DNA synthesis, apoptosis, and phenotypic expression as determinants of growth of altered foci in rat liver during phenobarbital promotion.

Carcinogenesis was initiated in female rat liver by a single dose of N-nitrosomorpholine; subsequently phenobarbital (PB) was administered via the diet at a daily dose of 50 mg/kg body weight for up to 49 weeks. Subgroups of rats were left untreated after 10 or 28 weeks on PB. PB produced the following changes: (a) accelerated appearance of neoplastic nodules and hepatocellular carcinoma (from 28 weeks onwards); (b) phenotypic changes in altered foci such as a shift from clear to eosinophilic appearance, enhanced expression of gamma-glutamyltranspeptidase and other markers, and more distinct borders from surrounding liver; (c) an increase in foci number; and (d) accelerated foci enlargement. The increase in foci number was found to be due to increased phenotypic expression of foci. DNA synthesis was measured by [3H]thymidine labeling at multiple time points. The rate of DNA synthesis was always approximately 10-fold higher in foci than in surrounding liver tissue. Despite this, after N-nitrosomorpholine alone foci grew little before 18-24 weeks. Continuous treatment with PB did not produce a persistent further increase of DNA synthesis in foci, although it accelerated foci growth. Furthermore, at early stages small and larger foci showed similar DNA synthesis activity. These findings indicate that the rate of cell replication as measured by DNA synthesis is not the only determinant of the growth rate of foci. Further studies showed that foci with indistinct borders (reflecting weak expression of the altered phenotype) grew much less than foci with distinct borders; this was at least in part due to an increased rate of cell death by apoptosis found in foci with indistinct borders. In conclusion, besides cell replication, apoptosis and the extent of phenotypic expression (remodeling) determine the growth rate of foci. Foci with weak phenotypic expression predominated after N-nitrosomorpholine alone; in these, a high incidence of apoptosis counterbalanced cell replication. In contrast, during PB treatment foci with strong phenotypic expression predominated; in these, apoptotic activity was lower and the high replicative activity could manifest itself. Finally, all effects of PB on foci were largely although not completely reversible upon cessation of treatment; as a result phenotypic expression declined, and "remodeling" foci with high apoptotic activity predominated again.

Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats.

Apoptosis is a form of cell death involved in the regulation of cell number in various organs and tumors. Quantitative determination of cell loss through apoptosis in histological sections requires, in addition to counts of apoptotic cells, information on the duration of the histologically visible stages of apoptosis. Here we describe a method to determine the duration of apoptosis in (i) normal and (ii) putative preneoplastic tissue of the liver. (i) Female rats were treated with high doses of the hepatomitogen cyproterone acetate (CPA) to induce liver hyperplasia. After stopping CPA treatment, the hyperplasia partially regressed and excessive hepatocytes were eliminated by apoptosis. CPA was given to block the initiation of apoptosis, and thereafter the time course of elimination of apoptotic cell residues (apoptotic bodies, ABs) from the liver was studied. The mean duration of the histological stages of apoptosis was found to be approximately 3 h. (ii) Phenotypically altered cell foci in rat liver were produced by a single dose of N-nitrosomorpholine and subsequent promotion for 39 weeks with phenobarbital (PB). PB was withdrawn to stop foci growth and to stimulate apoptosis. Then rats were retreated with PB to block initiation of apoptosis in foci. The results indicate that the majority of apoptotic bodies in foci disappeared within 4 h after PB, suggesting that the stages of apoptosis are as short in foci as in normal liver. Finally a simple formula is given to calculate the cell loss rate by apoptosis. The method presented may provide data for quantitative cancer risk assessment from mathematical models of carcinogenesis.

Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters.

Numerous drugs, hormones and environmental pollutants induce liver growth by hypertrophy and/or hyperplasia, and promote preferential growth of putative preneoplastic foci in the liver. In the present study the regression of hyperplasia after cessation of inducer/promoter treatment was studied in normal liver and in liver foci. High doses of cyproterone acetate (CPA), a synthetic sex steroid, were administered to rats and produced a doubling of liver size; after cessation of treatment liver size declined, and 27% of the total liver DNA disappeared within 6 days. In histological sections from the involuting liver no necroses, but numerous apoptotic bodies (ABs) were found; retreatment with CPA interrupted the formation of ABs. These findings suggest that elimination of excess liver DNA after cessation of CPA treatment is due to controlled cell death by apoptosis. In a further series of experiments putative preneoplastic foci were produced by a single dose of N-nitrosomorpholine and subsequently stimulated to grow by 10 or 28 weeks of phenobarbital (PB) treatment. After withdrawal of PB numerous ABs were present in normal liver and in the foci; in both, retreatment with PB decreased the appearance of ABs. It appears that inhibition of cell death by PB may contribute to tumour promotion. Under all conditions tested more ABs were found in the foci than in non-focal parts of the liver, suggesting an enhanced cell turnover in foci. The apparent sensitivity of foci to mechanisms controlling cell death might eventually provide a means for elimination of preneoplastic lesions.

[Lumbar lipomeningocele (case report)]. / Lumbale Lipomeningozele (kasuistischer Beitrag).

The authors describe a case of spinal lipomeningocele at the L2 to L4 level, detailing the properties of growth, clinical characteristics, diagnosis, and surgical therapy of such types of swelling.

[Bacteriostatic behavior of the tissue adhesive Fimomed (n-butyl-alpha-cyanoacrylate]. / Zum bakteriostatischen Verhalten des Gewebeklebers Fimomed (n-Butyl-alpha-Zyanoakrylat).

The tissue adhesive Fimomed (made in GDR), which is supplied in a non-sterilised form, was tested for its bacteriostatic behaviour. No such behaviour was found for Gram-negative bacteria, so that in view of the typical microorganisme occurring in hospitals sterilisation of the adhesive by means of gamma rays or an aseptic filling by the manufacturers is suggested.

[The value of possible skull-cap replacement surgery]. / Wertigkeit möglicher Schädeldachersatzplastiken.

After describing the valence of the various possible plastic procedures for covering defects of the skull cap, the results obtained by the authors are presented. In childhood, autografting from the inner layer of the wing of the ilium or from the ribs is given preference. In adults, the authors carry out alloplasty with hot-polymerizing methacrylate in order to prevent a second surgical intervention for obtaining autogenous material. If surgery has to be carried out in the vicinity of the paranasal sinuses, autogenous cartilaginous cubes must be inserted between the sinuses and the alloplasty because direct contact of the alloplastic material with the sinuses exposed to infection hazards must be avoided.