Dr Ben Creagh-Brown

Background

There is a need for robust, clearly defined, patient-relevant outcome measures for use in randomised trials in perioperative medicine. Our objective was to establish standard outcome measures for postoperative pulmonary complications research.

Methods

A systematic literature search was conducted using MEDLINE, Web of Science, SciELO, and the Korean Journal Database. Definitions were extracted from included manuscripts. We then conducted a three-stage Delphi consensus process to select the optimal outcome measures in terms of methodological quality and overall suitability for perioperative trials.

Results

From 2358 records, the full texts of 81 manuscripts were retrieved, of which 45 met the inclusion criteria. We identified three main categories of outcome measure specific to perioperative pulmonary outcomes: (i) composite outcome measures of multiple pulmonary outcomes (27 definitions); (ii) pneumonia (12 definitions); and (iii) respiratory failure (six definitions). These were rated by the group according to suitability for routine use. The majority of definitions were given a low score, and many were imprecise, difficult to apply consistently, or both, in large patient populations. A small number of highly rated definitions were identified as appropriate for widespread use. The group then recommended four outcome measures for future use, including one new definition.

Conclusions

A large number of postoperative pulmonary outcome measures have been used, but most are poorly defined. Our four recommended outcome measures include a new definition of postoperative pulmonary complications, incorporating an assessment of severity. These definitions will meet the needs of most clinical effectiveness trials of treatments to improve postoperative pulmonary outcomes.

The results section of this abstract should read:

Results A total of 369 patients were referred over the 6 year period. Of these, 194 (52.6%) were admitted. The largest outcome group was total liberation from all forms of MV (45%). The remainder were shown to (1) require nocturnal non-invasive ventilation (NIV) (21%); (2) require nocturnal and intermittent daytime NIV (1%); (3) require long-term tracheostomy ventilation (19%); and (4) died in hospital (15%). Post-surgical and COPD patients had the highest rate of total liberation from mechanical ventilation at 60% and 54%, respectively. The median time from admission to tracheostomy decannulation was 18 days (9?33). NMD-CWD patients had the lowest hospital mortality (7%), whereas COPD patients had the highest hospital mortality (29%). The overall survival at 12 and 24 months was 55% and 47%, respectively. 25% of the COPD patients were alive and 59% of the NMD-CWD patients were alive at 24 months (Figure 1).

Background

The work demands of critical care can be a major cause of stress in intensive care unit (ICU) professionals and lead to poor health outcomes. In the process of recovery from work, psychological rumination is considered to be an important mediating variable in the relationship between work demands and health outcomes. This study aimed to extend our knowledge of the process by which ICU stressors and differing rumination styles are associated with burnout, depression and risk of psychiatric morbidity among ICU professionals.

Methods

Ninety-six healthcare professionals (58 doctors and 38 nurses) who work in ICUs in the UK completed a questionnaire on ICU-related stressors, burnout, work-related rumination, depression and risk of psychiatric morbidity.

Results

Significant associations between ICU stressors, affective rumination, burnout, depression and risk of psychiatric morbidity were found. Longer working hours were also related to increased ICU stressors. Affective rumination (but not problem-solving pondering or distraction detachment) mediated the relationship between ICU stressors, burnout, depression and risk of psychiatric morbidity, such that increased ICU stressors, and greater affective rumination, were associated with greater burnout, depression and risk of psychiatric morbidity. No moderating effects were observed.

Conclusions

Longer working hours were associated with increased ICU stressors, and increased ICU stressors conferred greater burnout, depression and risk of psychiatric morbidity via increased affective rumination. The importance of screening healthcare practitioners within intensive care for depression, burnout and psychiatric morbidity has been highlighted. Future research should evaluate psychological interventions which target rumination style and could be made available to those at highest risk. The efficacy and cost effectiveness of delivering these interventions should also be considered.

Background and Objective: Obesity is an important contributor to the risk of both asthma and Type 2 Diabetes (T2DM). However, it has been suggested that T2DM and asthma are also independently associated. The aim of this systematic review was to synthesize the evidence for an independent relationship between T2DM and asthma.

Methods: MEDLINE and EMBASE were searched for studies reporting the relationship between asthma and T2DM in adults. Given a potential bidirectional relationship, articles relating to T2DM as a risk factor for asthma, and asthma as a risk factor for T2DM were examined separately.

Results: Eight studies were identified for inclusion in the review (n=2,934,399 participants). Four studies examined incident diabetes in those with asthma. The pooled (random effects model) adjusted hazard ratio for incident T2DM in asthma was 1.37 (95%CI 1.12-1.69; p Â0.001) after controlling for BMI. Four studies reported prevalence or incidence rates of asthma in people with T2DM; higher rates of asthma in those with T2DM were reported in all four studies. Meta-analysis of results was not possible due to methodological heterogeneity. The quality of included studies was good, but due to small numbers, publication bias cannot be excluded.

Conclusion: The published literature suggests a bidirectional independent relationship between T2DM and asthma, although we cannot exclude publication bias.

Background

Chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2DM) are common comorbidities. COPD is a known risk factor for incident T2DM, however few studies have examined the relationship in reverse. The primary aim of this study was to compare the incidence of COPD in people with and without T2DM.

Materials and methods

We conducted a retrospective case-control study using a long-established English general practice network database (n = 894,646). We matched 29,217 cases of T2DM with controls, adjusting for age, gender, smoking status, BMI and social deprivation, to achieve 1:1 propensity matching and compared the rate of incident COPD over eight years of follow-up. We performed a secondary analysis to investigate the effect of insulin, metformin and sulphonylureas on COPD incidence.

Results

People with T2DM had a reduced risk of COPD compared to matched controls over the follow-up period (HR 0.89, 95%CI 0.79?0.93). 48.5% of those with T2DM were ex-smokers compared with 27.3% of those without T2DM. Active smoking rates were 20.4% and 23.7% respectively. Insulin, metformin and sulphonylureas were not associated with incident COPD.

Conclusions

People with T2DM are less likely to be diagnosed with COPD than matched controls. This may be due to positive lifestyle changes, such as smoking cessation in those with T2DM.

Objectives According to National Health Service England (NHSE) specialist respiratory commissioning specification for complex home ventilation, patients with weaning failure should be referred to a specialist centre. However, there are limited data reporting the clinical outcomes from such centres.

Setting Prospective observational cohort study of patients admitted to a UK specialist weaning, rehabilitation and home mechanical ventilation centre between February 2005 and July 2013.

Participants 262 patients admitted with a median age of 64.2?years (IQR 52.6?73.2?years). 59.9% were male.

Results 39.7% of patients had neuromuscular and/or chest wall disease, 21% were postsurgical, 19.5% had chronic obstructive pulmonary disease (COPD), 5.3% had obesity-related respiratory failure and 14.5% had other diagnoses. 64.1% of patients were successfully weaned, with 38.2% weaned fully from ventilation, 24% weaned to nocturnal non-invasive ventilation (NIV), 1.9% weaned to nocturnal NIV with intermittent NIV during the daytime. 21.4% of patients were discharged on long-term tracheostomy ventilation. The obesity-related respiratory failure group were most likely to wean (relative risk (RR) for weaning success=1.48, 95% CI 1.35 to 1.77; pÂ0.001), but otherwise weaning success rates did not significantly vary by diagnostic group. The median time-to-wean was 19?days (IQR 9?33) and the median duration of stay was 31?days (IQR 16?50), with no difference observed between the groups. Weaning centre mortality was 14.5%, highest in the COPD group (RR=2.15, 95% CI 1.19 to 3.91, p=0.012) and lowest in the neuromuscular and/or chest wall disease group (RR=0.34, 95% CI 0.16 to 0.75, p=0.007). Of all patients discharged alive, survival was 71.7% at 6?months and 61.8% at 12?months postdischarge.

Conclusions Following NHSE guidance, patients with weaning delay and failure should be considered for transfer to a specialist centre where available, which can demonstrate favourable short-term and long-term clinical outcomes.

Objectives:

The association between hyperlactatemia and adverse outcome in patients admitted to ICUs following gastrointestinal surgery has not been reported. To explore the hypothesis that in a large cohort of gastrointestinal surgical patients, the peak serum lactate (in the first 24 hr) observed in patients admitted to ICU following surgery is associated with unadjusted and severity-adjusted acute hospital mortality and that the strength of association is greater in patients admitted following ?emergency? surgery than in patients admitted following ?elective? surgery.

Design:

A retrospective cohort study of all patients who had gastrointestinal surgery and were admitted directly to the ICU between 2008 and 2012.

Setting:

Two hundred forty-nine hospitals in the United Kingdom.

Patients:

One hundred twenty-one thousand nine hundred ninety patients.

Interventions:

None.

Measurements and Main Results:

Peak blood lactate in the first 24 hours of admission to critical care, acute hospital mortality, length of stay, and other variables routinely collected within the U.K. Intensive Care National Audit and Research Centre Case Mix Programme database. Elevated blood lactate was associated with increased risk of death and prolonged duration of stay, and the relationship was maintained once adjusted for confounding variables. The positive association between mortality and levels of blood lactate continued down into the ?normal range,? without evidence of a plateau. There was no difference in the extent to which hyperlactatemia was related to mortality between patients admitted following elective and emergency surgery.

Conclusions:

These findings have implications for our understanding of the role of lactate in critically ill patients.

Background

The Standardising Endpoints for Perioperative Medicine group was established to derive an appropriate set of endpoints for use in clinical trials related to anaesthesia and perioperative medicine. Anaesthetic or analgesic technique during cancer surgery with curative intent may influence the risk of recurrence or metastasis. However, given the current equipoise in the existing literature, prospective, randomised, controlled trials are necessary to test this hypothesis. As such, a cancer subgroup was formed to derive endpoints related to research in onco-anaesthesia based on a current evidence base, international consensus and expert guidance.

Methods

We undertook a systematic review to identify measures of oncological outcome used in the oncological, surgical, and wider literature. A multiround Delphi consensus process that included up to 89 clinician?researchers was then used to refine a recommended list of endpoints.

Results

We identified 90 studies in a literature search, which were the basis for a preliminary list of nine outcome measures and their definitions. A further two were added during the Delphi process. Response rates for Delphi rounds one, two, and three were 88% (n=9), 82% (n=73), and 100% (n=10), respectively. A final list of 10 defined endpoints was refined and developed, of which six secured approval by e70% of the group: cancer health related quality of life, days alive and out of hospital at 90 days, time to tumour progression, disease-free survival, cancer-specific survival, and overall survival (and 5-yr overall survival).

Conclusion

Standardised endpoints in clinical outcomes studies will support benchmarking and pooling (meta-analysis) of trials. It is therefore recommended that one or more of these consensus-derived endpoints should be considered for inclusion in clinical trials evaluating a causal effect of anaesthesia?analgesia technique on oncological outcomes.

Background:

Perioperative infection and sepsis are of fundamental concern to perioperative clinicians. However, standardised endpoints are either poorly defined or not routinely implemented. The Standardised Endpoints in Perioperative Medicine (StEP) initiative was established to derive a set of standardised endpoints for use in perioperative clinical trials.

Methods:

We undertook a systematic review to identify measures of infection and sepsis used in the perioperative literature. A multi-round Delphi consensus process that included more than 60 clinician researchers was then used to refine a recommended list of outcome measures.

Results:

A literature search yielded 1857 titles of which 255 met inclusion criteria for endpoint extraction. A long list of endpoints, with definitions and timescales, was generated and those potentially relevant to infection and sepsis circulated to the theme subgroup and then the wider StEP-COMPAC working group, undergoing a three-stage Delphi process. The response rates for Delphi rounds 1, 3, and 3 were 89% (n=8), 67% (n=62), and 80% (n=8), respectively. A set of 13 endpoints including fever, surgical site, and organ-specific infections as defined by the US Centres for Disease Control and Sepsis-3 are proposed for future use.

Conclusions:

We defined a consensus list of standardised endpoints related to infection and sepsis for perioperative trials using an established and rigorous approach. Each endpoint was evaluated with respect to validity, reliability, feasibility, and patient centredness. One or more of these should be considered for inclusion in future perioperative clinical trials assessing infection, sepsis, or both, thereby permitting synthesis and comparison of future results.

Background

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality in England, however estimates of its prevalence vary considerably. Routinely collected and coded primary care data can be used to monitor disease prevalence, however reliance upon diagnostic codes alone is likely to miss cases.

Methods

We devised an ontological approach to COPD case detection and implemented it in a large primary care database to identify definite and probable cases of COPD. We used this to estimate the prevalence of COPD in England.

Results

Use of this approach to detect definite COPD cases yielded a prevalence of 2.57% (95% CI 2.55?2.60) in the total population, 4.56% (95%CI 4.52?4.61) in those aged e 35 and 5.41% (95% CI 5.36?5.47) in ex or current smokers. The ontological approach identified an additional 10,543 definite cases compared with using diagnostic codes alone. Prevalence estimates were higher than the 1.9% prevalence currently reported by the UK primary care pay for performance (P4P) disease register. COPD prevalence when definite and probable cases were combined was 3.02% (95% CI 3.0?3.05) in the total population, 5.38% (95% CI 5.33?5.42) in those aged e 35 and 6.46% (95% CI 6.46-6.40-6.56) in ex or current smokers.

Conclusions

We demonstrate a robust reproducible method for COPD case detection in routinely collected primary care data. Our calculated prevalence differed significantly from current estimates based upon P4P data, suggesting that the burden of COPD in England is greater than currently predicted.

Background: The sepsis syndromes, frequently complicated by pulmonary and cardiac dysfunction, remain a major cause of death amongst the critically ill. Targeted therapies aimed at ameliorating the systemic inflammation that characterises the sepsis syndromes have largely yielded disappointing results in clinical trials. Whilst there are many potential reasons for lack of success of clinical trials, one possibility is that the pathways targeted, to date, are only modifiable very early in the course of the illness. More recent approaches have therefore attempted to identify pathways that could offer a wider therapeutic window, such as the receptor for advanced glycation end-products (RAGE) and its ligands.

Purpose: The objectives of this study were to review the evidence supporting the role of the RAGE axis in systemic inflammation and associated acute lung injury and myocardial dysfunction, to explore some of the problems and conflicts that these RAGE studies have raised and to consider strategies by which they might be resolved.

Methods: MEDLINE was searched (1990-2010) and relevant literature collected and reviewed.

Results and conclusion: RAGE is an inflammation-perpetuating receptor with a diverse range of ligands. Evidence supporting a role of the RAGE axis in the pathogenesis of systemic inflammation, ALI and myocardial dysfunction is compelling with numerous animal experiments showing the beneficial effects of inhibiting the RAGE axis. Despite a number of unanswered questions that need to be further addressed, the potential for inhibiting RAGE-mediated inflammation in humans undoubtedly exists.

Background. The receptor for advanced glycation end products (RAGE) is an inflammation-perpetuating receptor, and soluble RAGE (sRAGE) is a marker of cellular RAGE expression. This study investigated whether raised plasma levels prior to surgery of sRAGE or S100A8/A9 (a RAGE ligand) were associated with longer duration of hospital care in patients undergoing cardiac surgery necessitating cardiopulmonary bypass.

Methods. Patients (n=130) undergoing elective cardiac surgery were enrolled prospectively. Plasma sRAGE and S100A8/A9 concentrations were measured before and 2 h after surgery.

Results. Preoperative plasma sRAGE increased significantly (PÂ0.0001) from 1.06 ng/mL (IQR, 0.72-1.76) to 1.93 ng/mL (IQR, 1.14-2.63) 2 h postoperatively. Plasma S100A8/9 was also significantly (PÂ0.0001) higher 2 h postoperatively (2.37 g/mL, IQR, 1.81-3.05) compared to pre-operative levels (0.41 g/mL, IQR, 0.2-0.65). Preoperative sRAGE, but not S100A8/A9, was positively and significantly correlated with duration of critical illness (r=0.3, P=0.0007) and length of hospital stay (LOS; r=0.31, PÂ0.0005). Multivariate binary logistic regression showed preoperative sRAGE to be, statistically, an independent predictor of greater than median duration of critical illness (odds ratio 16.6, P=0.014) and to be, statistically, the strongest independent predictor of hospital LOS.

Conclusion. Higher preoperative plasma sRAGE levels were associated with prolonged duration of care in adults undergoing cardiac surgery requiring cardiopulmonary bypass.

Background

Forty per cent of critically ill patients are affected by intensive care unit-acquired weakness (ICU-AW), to which skeletal muscle wasting makes a substantial contribution. This can impair outcomes in hospital, and can cause long-term physical disability after hospital discharge. No effective mitigating strategies have yet been identified.

Application of a repetitive vascular occlusion stimulus (RVOS) a limb pressure cuff inducing brief repeated cycles of ischaemia and reperfusion, can limit disuse muscle atrophy in both healthy controls and bed-bound patients recovering from knee surgery. We wish to determine whether RVOS might be effective in mitigating against muscle wasting in the ICU. Given that RVOS can also improve vascular function in healthy controls, we also wish to assess such effects in the critically ill. We here describe a pilot study to assess whether RVOS application is safe, tolerable, feasible and acceptable for ICU patients.

Methods

This is a randomised interventional feasibility trial. Thirty-two ventilated adult ICU patients with multiorgan failure will be recruited within 48 h of admission and randomised to either the intervention arm or the control arm. Intervention participants will receive RVOS twice daily (except only once on day 1) for up to 10 days or until ICU discharge.

Serious adverse events and tolerability (pain score) will be recorded; feasibility of trial procedures will be assessed against pre-specified criteria and acceptability by semi-structured interview. Together with vascular function, muscle mass and quality will be assessed using ultrasound and measures of physical function at baseline, on days 6 and 11 of study enrolment, and at ICU and hospital discharge. Blood and urine biomarkers of muscle metabolism, vascular function, inflammation and DNA damage/repair mechanism will also be analysed. The Health questionnaire will be completed 3 months after hospital discharge.

Discussion

If this study demonstrates feasibility, the derived data will be used to inform the design (and sample size) of an appropriately-powered prospective trial to clarify whether RVOS can help preserve muscle mass/improve vascular function in critically ill patients.

Background:

Sepsis is life-threatening organ dysfunction because of a dysregulated host response to infection. Disturbed microvascular blood flow is associated with excess mortality and is a potential future target for interventions. This review addresses the evidence for pharmacological manipulation of the microcirculation in sepsis assessed by techniques that evaluate the sublingual microvasculature.

Methods:

Systematic review using a published protocol. Eligibility criteria were studies of septic patients published from January 2000 to February 2018. Interventions were drugs aimed at improving perfusion. Outcome was improvement in microvascular flow using orthogonal polarization spectral, sidestream dark field, or incident dark field imaging (Grades of Recommendation, Assessment, Development, and Evaluation criteria used).

Results:

Two thousand six hundred and six articles were screened and 22 included. (6 randomized controlled trials, 12 interventional, 3 observational, and 1 pilot, n = 572 participants). Multiple measurement techniques were described, including: automated analyses, subjective, and composite scoring systems. Norepinephrine was not found to improve microvascular flow (low-grade evidence, n = 6 studies); except in chronic hypertension (low, n = 1 study). Addition of arginine vasopressin or terlipressin to norepinephrine maintained flow while decreasing norepinephrine requirements (high, n = 2 studies). Neither dobutamine nor glyceryl trinitrate consistently improved flow (low, n = 6 studies). A single study (n = 40 participants) demonstrated improved flow with levosimendan (high). In a risk of bias assessment 16/16 interventional, pilot and observational studies were found to be high risk.

Conclusions:

There is no robust evidence to date that any one agent can reproducibly lead to improved microvascular flow. Furthermore, no study demonstrated outcome benefit of one therapeutic agent over another. Updated consensus guidelines could improve comparable reporting of measurements and reduce bias, to enable meaningful comparisons around the effects of individual pharmacological agents.