Alterations in alanine metabolism in diabetic dogs during short-term treatment with an artificial B cell

Summary The flux rates of plasma glucose and alanine were studied isotopically (6-³H-glucose and U-¹⁴C-alanine simultaneously) in resting chronically diabetic dogs during short-term treatment with an artificial B cell where the insulin was infused into a peripheral vein. Despite perfect blood glucose control and normal glucose flux rates, the concentration and rates of appearance and disappearance of alanine were significantly elevated in the diabetic animals before, during and after an exogenous glucose load. The incorporation of the carbon moiety of alanine into circulating glucose was also increased, but diminished to a near-normal extent when exogenous glucose was given. The plasma clearance rates for alanine in the diabetic dogs were normal throughout the study. It is concluded that normal blood glucose control in diabetes does not necessarily mean normalization of the entire metabolic network. On the basis of peripheral hyperinsulinaemia alanine formation from glucose and branched chain amino acids is elevated in muscle. This may explain increased flux of alanine despite normal blood glucose control.     

Palliation in cyanotic congenital heart disease. Fifteen years' experience of various shunt procedures

During the past 15 years, 143 systemic pulmonary shunt procedures have been performed in 117 patients. These have been evaluated for their clinical effectiveness, the need for a repeat operation and the mortality; particular attention was paid to the Teflon shunt. Variations were found in shunt performance, depending on the primary defect, the type of shunt that was employed and the year of operation. The overall shunt patency after three years was 77% (85% with the Teflon shunt). Although, in our total experience, mortality at 30 days was 12%, with 16% late deaths, "modified Blalock" (Teflon) shunts had only a 5% hospital mortality and a 5% late mortality within three years. Pulmonary atresia, without a ventricular septal defect, is often insufficiently palliated by a shunt alone. Ten of 82 patients with variations of the tetralogy complex died within 30 days of operation, and a further 11 died in the late follow-up period. Six of these 21 shunts were patent at autopsy. Less common defects, such as univentricular heart, transposition and double-outlet right ventricular connections, that are associated with pulmonary stenosis had no early mortality but led to four late deaths among 27 patients. Two of the four patients had patent shunts. Results in the early part of this experience were less than acceptable owing to inferior shunting techniques, postoperative management errors and, particularly, inadequate follow-up surveillance. With correction of these factors we find that the modified Blalock shunt provides very good early and late mortality results, with excellent clinical palliation and patency rates.     

Local anaesthetic adjuncts for peripheral regional anaesthesia: a narrative review

Moderate-to-severe postoperative pain persists for longer than the duration of single-shot peripheral nerve blocks and hence continues to be a problem even with the routine use of regional anaesthesia techniques. The administration of local anaesthetic adjuncts, defined as the concomitant intravenous or perineural injection of one or more pharmacological agents, is an attractive and technically simple strategy to potentially extend the benefits of peripheral nerve blockade beyond the conventional maximum of 8–14 hours. Historical local anaesthetic adjuncts include perineural adrenaline that has been demonstrated to increase the mean duration of analgesia by as little as just over 1 hour. Of the novel local anaesthetic adjuncts, dexmedetomidine and dexamethasone have best demonstrated the capacity to considerably improve the duration of blocks. Perineural dexmedetomidine and dexamethasone increase the mean duration of analgesia by up to 6 hour and 8 hour, respectively, when combined with long-acting local anaesthetics. The evidence for the safety of these local anaesthetic adjuncts continues to accumulate, although the findings of a neurotoxic effect with perineural dexmedetomidine during in-vitro studies are conflicting. Neither perineural dexmedetomidine nor dexamethasone fulfils all the criteria of the ideal local anaesthetic adjunct. Dexmedetomidine is limited by side-effects such as bradycardia, hypotension and sedation, and dexamethasone slightly increases glycaemia. In view of the concerns related to localised nerve and muscle injury and the lack of consistent evidence for the superiority of the perineural vs. systemic route of administration, we recommend the off-label use of systemic dexamethasone as a local anaesthetic adjunct in a dose of 0.1–0.2 mg.kg⁻¹ for all patients undergoing surgery associated with significant postoperative pain.     

Efficacy and safety of intrathecal morphine for analgesia after lower joint arthroplasty: a systematic review and meta-analysis with meta-regression and trial sequential analysis

Widespread adoption of intrathecal morphine into clinical practice is hampered by concerns about its potential side-effects. We undertook a systematic review, meta-analysis and trial sequential analysis with the primary objective of determining the efficacy and safety of intrathecal morphine. Our secondary objective was to determine the dose associated with greatest efficacy and safety. We also assessed the impact of intrathecal morphine on respiratory depression. We systematically searched the literature for trials comparing intrathecal morphine with a control group in patients undergoing hip or knee arthroplasty under spinal anaesthesia. Our primary efficacy outcome was rest pain score (0–10) at 8–12 hours; our primary safety outcome was the rate of postoperative nausea and vomiting within 24 hours. Twenty-nine trials including 1814 patients were identified. Rest pain score at 8–12 hours was significantly reduced in the intrathecal morphine group, with a mean difference (95%CI) of −1.7 (−2.0 to −1.3), p < 0.0001 (19 trials; 1420 patients; high-quality evidence), without sub-group differences between doses (p = 0.35). Intrathecal morphine increased postoperative nausea and vomiting, with a risk ratio (95%CI) of 1.4 (1.3–1.6), p < 0.0001 (24 trials; 1603 patients; high-quality evidence). However, a sub-group analysis by dose revealed that rates of postoperative nausea and vomiting within 24 hours were similar between groups at a dose of 100 µg, while the risk significantly increased with larger doses (p value for sub-group difference = 0.02). Patients receiving intrathecal morphine were no more likely to have respiratory depression, the risk ratio (95%CI) being 0.9 (0.5–1.7), p = 0.78 (16 trials; 1173 patients; high-quality evidence). In conclusion, there is good evidence that intrathecal morphine provides effective analgesia after lower limb arthroplasty, without an increased risk of respiratory depression, but at the expense of an increased rate of postoperative nausea and vomiting. A dose of 100 µg is a ‘ceiling’ dose for analgesia and a threshold dose for increased rate of postoperative nausea and vomiting.     

Zur Anwendung des Rektaltemperatur-Todeszeit-Nomogramms am leichenfundort

Summary The application of the rectal temperature time of death nomogram at the scene of death by 11 authors from 6 lego-medical institutes resulted in a standard deviation of the differences between nomographic and real death time of ± 1.3 h in 46 cases (group I) with met requirements and clearly defined points of contact, nevertheless, including 9 cases with a more progressive cooling (0.5 > Q 0.2). In cases with a real death time of more than 4 h (N = 26) the standard deviation was ± 1.0 hours corresponding to permissible variation of 95% of ± 2.0 hours. Consequently, the permissible variation of 95% was much smaller than that suggested by the nomogram. The nomographic death time interval did not agree with the real one in 5 cases out of additional 30 cases with recognizably unsure points of contact (group II).     

Immunohistochemistry of intravascular papillary endothelial hyperplasia

Intravascular papillary endothelial hyperplasia is an interesting endothelial proliferation, the nature of which has aroused some controversy. Five cases were studied by light microscopy and by immunohistochemistry using antibodies to Factor VIII-related antigen (FVIII-rAg), ferritin, alpha 1-antitrypsin, alpha 1-antichymotrypsin and vimentin and were compared with conventional intravascular organizing thrombi. The results show a similar progression of the immunophenotype of the endothelial cells in both entities: they are initially positive for ferritin, then acquire vimentin positivity and only display FVIII-rAg positivity in advanced ("mature") lesions. This suggests that intravascular endothelial hyperplasia is closely related to organizing thrombi and is probably a peculiar form thereof.     

Embryotoxic/teratogenic potential of halothane

Summary The embryotoxic/teratogenic potential of halothane was evaluated on the basis of available data obtained in an extensive literature search. It was found that halothane induced ultrastructural visible changes in the offspring of rats exposed to concentrations of 10 ppm during gestation. These consisted of degenerative changes in the cerebral cortex and, in particular, the weakening of cell membranes and the vacuolisation of the Golgi-complex. Macroscopically visible morphological changes were seen in rats only after exposure to concentrations equivalent to 320-fold (1600 ppm) the MAK value (maximum concentration value at the workplace). Furthermore, behavioural disorders were seen when exposure to concentrations 10 ppm occurred during gestation and after parturition. In mice, only macroscopical investigations were performed. The first disturbances scored were only visible as retardation in the offspring, and occurred after exposure to concentrations of halothane 200-fold (1000 ppm) the MAK-value. In the rabbit, anaesthetic concentrations of 22 000 ppm. halothane did not result in an embryotoxic/teratogenic effect.The individual epidemiological findings in humans were discussed controversially. The studies are inconclusive in establishing an embryotoxic/teratogenic risk following sole exposure to halothane at the MAK level, since mixed exposures occurred and data on the concentrations of halothane in the inhaled air were missing. Therefore, the decision on whether halothane can impair intrauterine development is primarily based on the animal experimental findings. As long as a threshold value has not been established for the observed lesions, halothane should not be inhaled during pregnancy.     

Activation of benzylic alcohols to mutagens by human hepatic sulphotransferases

Four primary and five secondary benzylic alcohols derived frompolycyclic aromatic hydrocarbons were tested for mutagenicityin Salmonella typhimurium TA98 in the presence of 3'-phosphoadenosine-5'-phosphosulphate,the cofactor for sulphotransferases, and varying amounts ofhepatic cytosol from three or four different human subjects,a 3-year-old child, an adult female, an adult male and one unknown.All compounds except one, 4H-cyclopenta[def] phenanthren-4-ol,were activated to mutagens. The interindividual variation inthe activities was at most 3-fold and the individual activitiestowards the different substrates were correlated with each other.The same compounds had previously been tested in the presenceof hepatic cytosol from rats and all compounds activated inone species were also activated in the other species. However,there were marked quantitative differences, which were furthercomplicated by the observation of a substantial sex differencein the rat. Male and female rat liver cytosol showed highersulphotransferase activities towards 1-hydroxymethylpyrene,9-hydroxymethylanthracene, 7-hydroxymethyl-12-methylbenz[a]anthraceneand 4H-cyclopenta[def]chrysen-4-ol than human liver cytosol.The largest difference in activity was seen with 7-hydroxymethyl-12-methylbenz[a]anthracene,reaching a factor of