Chest wall reconstruction reduces hospital mortality following major chest wall trauma: a retrospective cohort study.

INTRODUCTION: Chest wall reconstruction was introduced for the management of patients with severe chest wall injuries. We undertook a retrospective cohort study to investigate whether the treatment was associated with improved survival compared with conservative treatment. METHODS: A retrospective single institutional cohort study compared mortality following treatment of major chest wall trauma (Abbreviated Injury Scale ≥3) by chest wall reconstruction (CWR) to conservative management (Non-CWR) between September 2014 and December 2019. Univariable and multivariable associations between demographic and comorbid characteristics and mortality were estimated using Cox proportional hazard analysis and expressed as hazard ratios (HR) and corresponding confidence intervals (CI). RESULTS: Of a cohort of 947, CWR (n=157, 16.6%) had a lower prevalence of polytrauma (35.7 vs 56.3%, p<0.001) and head injury (11.5% vs 26.7%, p<0.001). CWR-treated patients experienced a greater number of fractured ribs, (8.3 vs 5.8, p<0.001), higher incidence of flail chest (84.9% vs 48.9%, p<0.001), higher admission to Critical Care (64.3% vs 44.1%, p<0.001), greater demand for ventilation (36.9% vs 25.6%, p=0.004) and a higher New Injury Severity Scale value (36.9 vs 34.6, p=0.003). Mortality of CWR patients was significantly lower (3.8% vs 8.6%, p=0.04), with adjusted HR 0.30 (95% CI 0.12, 0.72, p=0.008). CONCLUSIONS: Chest wall reconstructive surgery, provided as a part of multidisciplinary treatment strategy for major thoracic trauma, reduces risk of mortality. The results validate the UK Government strategy, designed to reduce mortality, by centralising management of serious trauma in Major Trauma Centres.

The in vitro pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, ADL 08-0011 and methylnaltrexone.

This study characterized the pharmacology of the peripherally restricted opioid receptor antagonists, alvimopan, its metabolite, ADL 08-0011, and methylnaltrexone. The activities of the compounds were investigated with respect to human or guinea pig opioid receptor binding and function in recombinant cell lines and mechanical responsiveness of the guinea pig ileum. Alvimopan and ADL 08-0011 had higher binding affinity than methylnaltrexone at human mu opioid receptors (pK (i) values of 9.6, 9.6, and 8.0, respectively). The compounds had different selectivities for the mu receptor over human delta and guinea pig kappa opioid receptors. ADL 08-0011 had the highest mu receptor selectivity. With respect to their mu opioid receptor functional activity ([(35)S]GTPgammaS incorporation), methylnaltrexone had a positive intrinsic activity, consistent with partial agonism, unlike alvimopan and ADL 08-0011, which had negative intrinsic activities. Alvimopan, ADL 08-0011, and methylnaltrexone antagonized inhibitory responses mediated by the mu opioid agonist, endomorphin-1 (pA (2) values of 9.6, 9.4, and 7.6, respectively) and by U69593, a kappa opioid agonist (pA (2) values of 8.4, 7.2, and 6.7, respectively). In morphine-naive guinea pig ileum, methylnaltrexone reduced, while alvimopan and ADL 08-0011 increased, the amplitude of electrically evoked contractions and spontaneous mechanical activity. In tissue from morphine-dependent animals, alvimopan and ADL 08-0011 increased spontaneous activity to a greater degree than methylnaltrexone. The data suggested that alvimopan-induced contractions resulted predominantly from an interaction with kappa opioid receptors. It is concluded that alvimopan, ADL 08-0011, and methylnaltrexone differ in their in vitro pharmacological properties, particularly with respect to opioid receptor subtype selectivity and intrinsic activity. The clinical significance of the data from this study remains to be determined.