Agonist Regulation of Adrenergic Receptors in the Rabbit

Acute elevations of the circulating catecholamines, adrenaline and noradrenaline are observed in physiological situations such as exercise, posture change and stress. Pathological settings such as phaeochromocytoma, heart failure and cirrhosis may be associated with chronic increases in plasma catecholamines. These high catecholamine levels have been associated with decreases in adrenergic receptor responsiveness or desensitisation. A reduction in adrenergic receptor density or down regulation has also been detected under these conditions. However, although the in vitro effects of raised concentrations of plasma catecholamines have been widely studied, similar investigations in vivo are not so well characterised. In addition, some in vivo experimental models (e.g. rat phaeochromocytoma) have produced plasma catecholamine levels vastly exceeding those found in many pathological settings. Therefore, the current investigations principally aimed to evaluate the effects of moderate increases in circulating catecholamines in vivo on adrenergic receptor function and number in a rabbit model. The first series of experiments were designed to validate the methods used and characterise the receptor populations under investigation. To begin with, experiments were carried out to determine if the pro-aggregatory response to adrenaline in rabbit platelets was mediated (like human platelets) by alpha2 adrenoceptors. The ability of the alpha adrenoceptor antagonists, idazoxan, yohimbine and prazosin to inhibit the platelet pro-aggregatory responses to adrenaline was recorded and IC50 values concentration of antagonist required to produce fifty percent inhibition of response) were calculated. The alpha2 adrenoceptor antagonists, idazoxan and yohimbine were found to be more potent than the alpha1 adrenoceptor antagonist, prazosin at inhibiting the platelet pro-aggregatory response to adrenaline. Therefore, these results demonstrated that alpha2 adrenoceptors primarily mediate the platelet pro-aggregatory response to adrenaline in the rabbit. The specificity of [3H] yohimbine binding to alpha2 adrenoceptors in rabbit platelets and kidney was also determined. Displacement assays were performed and the ability of various unlabelled alpha adrenoceptor antagonists to compete for [3H] yohimbine binding sites was examined and expressed as KI (a measure of affinity) values. Yohimbine was found to have a considerably higher potency than prazosin for displacing [3H] yohimbine binding sites on rabbit platelets. Similarly, in rabbit kidney; prazosin and phentolamine were both less potent than yohimbine at displacing [3H] yohimbine binding. These results were consistent with [3H] yohimbine binding to alpha2 receptors in rabbit platelets and kidney. Subpopulations of beta adrenoceptors were characterised in the platelets, lymphocytes, heart and lung of the rabbit. The ability of the beta1 (atenolol or metoprolol) and beta2 (ICI 118551 ) adrenoceptor selective antagonists to displace the beta adrenoceptor selective [125I](-) Iodocyanopindolol (ICYP) from its binding sites in platelets and was assessed. ICI 118551 was found to be more potent than atenolol in displacing [125I](-) ICYP specific binding in both tissues. These findings were in agreement with previous studies showing that the beta adrenoceptors in rabbit platelets and lymphocytes (like humans) were largely beta2 in type. In a separate study, the beta1 adrenoceptor selective antagonist, metoprolol had a higher affinity than the beta2 selective ICI 118551 at inhibiting [125I](-) ICYP specific binding in rabbit heart and lung. These results confirmed that both the heart and the lung of the rabbit harbour a higher proportion of beta1 adrenergic receptors in the rabbit. Interestingly, the proportion of beta1 and beta2 adrenoceptors in rabbit lung were shown to be quite the inverse of most other mammalian species. (Abstract shortened by ProQuest.)

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Benefit of anti-TNF therapy in rheumatoid arthritis patients with moderate disease activity

Objectives. Anti-TNF therapy has improved outcomes for patients with highly active RA. Less is known about its effectiveness in patients with lower disease activity. The aim of this analysis is to compare the response to anti-TNF therapy between RA patients with high (DAS28 > 5.1) and moderate (DAS28 > 3.2–5.1) disease activity. Methods. A total of 4687 anti-TNF and 344 DMARD patients with high disease activity despite treatment with two standard DMARDs (including MTX) and 224 anti-TNF- and 300 DMARD-treated patients with moderate disease activity were selected from the British Society For Rheumatology Biologics Register. Mean change in HAQ over the first 12 months of enrolment was compared first between anti-TNF-treated and untreated patients in each DAS28 group, and then between anti-TNF-treated patients in the moderate and high DAS28 groups, using doubly robust estimates, adjusting for age, gender, disease duration, baseline HAQ and DAS28 score, number of previous DMARDs and steroid use. Results. Compared with anti-TNF-untreated patients within each DAS group, treated patients were younger, had higher DAS28 and HAQ and had failed a higher number of previous DMARDs. The mean adjusted change in HAQ over 12 months was similar in anti-TNF-treated patients with moderate and high disease activity at baseline: moderate −0.26 (95% CI −0.35, −0.16), high −0.28 (95% CI −0.34, −0.23) and mean difference −0.03 (95% CI −0.14, 0.08). Conclusions. Improvement in HAQ score 12 months after start of anti-TNF therapy was not dependent on baseline DAS28 scores, suggesting that substantial benefits may also be gained by treating those with moderately active disease despite standard DMARD therapy

Kuluttajabarometri maakunnittain 2000, 2. neljännes

Suomen virallinen tilasto (SVT

Use of failure-to-rescue to identify international variation in postoperative care in low-, middle- and high-income countries: a 7-day cohort study of elective surgery

This was an investigator-initiated study funded by Nestle Health Sciences through an unrestricted research grant and by a National Institute for Health Research (UK) Professorship held by R.P. The study was sponsored by Queen Mary University of London

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London