The Influence of the Endothelium on the Response of Vascular Smooth Muscle

This project was carried out to examine the influence of the vascular endothelium on the responses of the underlying smooth muscle. I have examined the influence of the endothelium on sensitivity of the smooth muscle to calcium and the interaction of a Ca2+-channel activator and blocker. A further study was carried out to examine how the initial tone affects the responses to both contractile and relaxatory agents and how the size of the induced tone affects the ability of Ach to cause relaxation. I studied the changes, if any, in this relationship in certain cardiovascular diseases. These effects were studied in an isolated aortic ring from the rat and also a complete vascular bed, the perfused rat tail. The following is a summary of the results: 1) Removal of the vascular endothelium from isolated aortic rings affects the sensitivity of the tissue to various agonists. The influence on the responses is greater for some agonists than for others. The agonists influenced to the greatest extent had both the pD2 and the maximum response significantly changed by removal of the endothelium: these agonists were either alpha1-adrenoceptor partial agonists or alpha2-adrenoceptor agonists in other tissues. The agonist affected to the least extent, the thromboxane mimetic drug U46619 showed no significant change on removal of the endothelium in either the maximum response or the pD2 value. 2) The presence of the vascular endothelium had no influence on the actions at alpha1-adrenoceptors, of the selective antagonists prazosin and corynanthine, or the alpha2-adrenoceptor antagonist, Wyeth 26703. The results using Wyeth 26703 did not support the possibility of alpha2-adrenoceptor stimulation releasing EDRF, since it had the same effect on responses to NA in tissues with both an intact and disrupted endothelium. 3) Increasing the initial length in aortic ring segments caused a length-dependent increase in the resting tension. The absence of the endothelium had no significant effect on the resting tensions compared with intact tissues. The size of the contraction to Phe (1uM) and relaxation to Ach (1uM) (tone induced by Phe) were dependent on the initial length of the preparation. The optimum stretch to demonstrate the proportionate effect of Ach (1uM) did not coincide with the optimum for Phe-induced contractions. 4) The size of the induced tone against which Ach produced relaxation affected the sensitivity to this agent. The greater the size of the induced tone the less sensitive the tissue was to relaxation. Atropine did not affect the size of the tone induced by NA but inhibited the relaxation to Ach. BAY-K 8644, a calcium channel facilitator, increased the tone induced by NA and inhibited the relaxation to Ach to a greater extent than would be expected by increase in tone alone. The cx2-antagonist drug Wyeth 26703, at concentrations where it acts selectively at alpha2-adrenoceptors (in other tissues), had no effect on NA-induced tone or on Ach-induced relaxation. 5) Using a maximal concentration of NA (3uM) in rat aortic rings, with either an intact or disrupted endothelium, in both a buffered and unbuffered calcium system, the contractile response was shown to be dependent on the concentration of extracellular calcium. At concentrations of calcium greater than 1.25mM the response started to fall off. This response was not potentiated using either system in the presence of BAY-K 8644 (1uM) but was significantly inhibited in the presence of nifedipine (1muM). 6) Using a submaximal concentration of NA (30nM) in the rat aortic rings either intact or disrupted, in an unbuffered system, again the response was shown to be dependent on the concentration of extracellular calcium. In this system the responses to NA (30nM) were potentiated by BAY-K 8644 (1-100nM). The potentiation was similar regardless of the presence of the endothelium and reached a maximum at BAY-K (10nM). In the presence of this drug the drop in maximum response at high concentrations of calcium was still evident. 7) In the presence of nifedipine (0.1-1muM) the responses to NA (30nM) were inhibited to a similar extent in both intact and disrupted rings. With this drug the drop in the maximum response at high calcium concentrations was not seen

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707