Evaluating the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care: Protocol for the UK-ROX trial.

Background: In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes. Methods: The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation. Objectives: The primary clinical outcome is all cause mortality at 90 days following randomisation. Discussion: The UK-ROX trial has received ethical approval from the South Central - Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.

Is high sensitivity troponin, taken regardless of a clinical indication, associated with 1 year mortality in critical care patients?

The aim of this study was to assess whether high sensitivity troponin (hs-cTnI) is associated with 1 year mortality in critical care (CC). One year mortality data were obtained from NHS Digital for a consecutive cohort of patients admitted to general CC unit (GCCU) and neuroscience CC unit (NCCU) who had hs-cTnI tests performed throughout their CC admission, regardless of whether the test was clinically indicated. Cox proportional hazards were used to estimate the risk of 1-year mortality. A landmark analysis was undertaken to assess whether any relationship at 1 year was driven by mortality within the first 30 days. A total of 1033 consecutive patients were included. At 1 year 254 (24.6%) patients had died. The admission log(10)hs-cTnI concentration in the entire cohort (HR 1.35 (95% CI 1.05-1.75) p = 0.009 with a bootstrap of 1000 samples) was independently associated with 1 year mortality. On landmark analysis the association with 1 year mortality was driven by 30 day mortality. These results indicate that admission hs-cTnI concentration is independently associated with 1 year mortality in CC and this relationship may be driven by differences in mortality at 30 days.

The effect of conservative oxygen therapy on mortality in adult critically ill patients: A systematic review and meta-analysis of randomised controlled trials.

Background: Oxygen is the commonest intervention provided to critically ill patients requiring mechanical ventilation. Despite this, it is unclear how much oxygen should be administered to patients in order to promote the best clinical outcomes and it has been suggested that a strategy of conservative oxygen therapy (COT) may be advantageous. We therefore sought to answer the question of whether COT versus usual or liberal oxygen therapy was beneficial to adult patients receiving mechanical ventilation on an intensive care unit (ICU) by performing a systematic review and meta-analysis. Methods: Studies were included if they were randomised controlled trials comparing COT to liberal or usual oxygen therapy strategies in acutely ill adults (aged ⩾18 years) admitted to an ICU, and reported an outcome of interest. Studies were excluded if they were limited to a specific single disease diagnosis. The review was registered on PROSPERO (CRD42022308436). Risk of bias was assessed using a modified Cochrane Risk of Bias assessment tool. Effect estimates were pooled using a random effects model with the between study variance estimated using restricted maximum likelihood and standard errors calculated using the method of Hartung-Knapp/Sidik-Jonkman. Between study heterogeneity was quantified using the I2 statistic. The certainty in the body of evidence was assessed using GRADE criteria. Results: Nine eligible studies with 5727 participants fulfilled all eligibility criteria. Trials varied in their definitions of COT and liberal or usual oxygen therapy. The pooled estimate of risk ratio for 90 day mortality for COT versus comparator was 0.99 (95% confidence interval 0.88-1.12, 95% prediction interval 0.82-1.21). There was low heterogeneity among studies (I2 = 22.4%). The finding that mortality was similar for patients managed with COT or usual/liberal oxygen therapy was graded as moderate certainty. Conclusions: In critically ill adults admitted to an ICU, COT is neither beneficial nor harmful when compared to usual or liberal oxygen therapy. Trials to date have been inconsistent in defining both COT and liberal or usual oxygen therapy, which may have had an impact on the results of this meta-analysis. Future research should focus on unifying definitions and outcome measures.

Intensive care physicians' perceptions of the diagnosis & management of patients with acute hypoxic respiratory failure associated with COVID-19: A UK based survey.

Background: Whilst the management of Coronavirus disease-2019 (COVID-19) has evolved in response to the emerging data, treating such patients remains a challenge, and many treatments lack robust clinical evidence. We conducted a survey to evaluate Intensive Care Unit (ICU) management of COVID-19 patients with acute hypoxic respiratory failure and compared the results with data from a similar survey focusing on Acute Respiratory Distress Syndrome (ARDS) that was conducted in 2013. Methods: The questionnaire was refined from a previous survey of ARDS-related clinical practice using an online electronic survey engine (Survey Monkey®) and all UK intensivists were encouraged to participate. The survey was conducted between 16/05/2020 and 17/06/2020. Results: There were 137 responses from 89 UK centres. Non-invasive ventilation was commonly used in the form of CPAP. The primary ventilation strategy was the ARDSnet protocol, with 63% deviating from its PEEP recommendations. Similar to our previous ARDS survey, most allowed permissive targets for hypoxia (94%), hypercapnia (55%) and pH (94%). The routine use of antibiotics was common, and corticosteroids were frequently used, usually in the context of a clinical trial (45%). Late tracheostomy (>7 days) was preferred (92%). Routine follow-up was offered by 66% with few centres providing routine dedicated rehabilitation programmes following discharge. Compared to the ARDS survey, there is an increased use of neuromuscular agents, APRV ventilation and improved provision of rehabilitation services. Conclusions: Similar to our previous ARDS survey, this survey highlights variations in the management strategies used for patients with acute hypoxic respiratory failure due to COVID-19.

Cardiopulmonary exercise testing has greater prognostic value than sarcopenia in oesophago-gastric cancer patients undergoing neoadjuvant therapy and surgical resection.

BACKGROUND: Sarcopenia (low skeletal muscle mass), myosteatosis (low skeletal muscle radiation-attenuation) and fitness are independently associated with postoperative outcomes in oesophago-gastric cancer. This study aimed to investigate (1) the effect of neoadjuvant therapy (NAT) on sarcopenia, myosteatosis and cardiopulmonary exercise testing (CPET), (2) the relationship between these parameters, and (3) their association with postoperative morbidity and survival. METHODS: Body composition analysis used single slice computed tomography (CT) images from chest (superior to aortic arch) and abdominal CT scans (third lumbar vertebrae). Oxygen uptake at anaerobic threshold (VO2 at AT) and at peak exercise (VO2 Peak) were measured using CPET. Measurements were performed before and after NAT and an adjusted regression model assessed their association. RESULTS: Of the 184 patients recruited, 100 underwent surgical resection. Following NAT skeletal muscle mass, radiation-attenuation and fitness reduced significantly (p < 0.001). When adjusted for age, sex, and body mass index, only pectoralis muscle mass was associated with VO2 Peak (p = 0.001). VO2 at AT and Peak were associated with 1-year survival, while neither sarcopenia nor myosteatosis were associated with morbidity or survival. CONCLUSION: Skeletal muscle and CPET variables reduced following NAT and were positively associated with each other. Cardiorespiratory function significantly contributes to short-term survival after oesophago-gastric cancer surgery.

A feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients.

BACKGROUND: Despite oxygen being the commonest drug administered to critically ill patients we do not know which oxygen saturation (SpO2) target results in optimal survival outcomes in those receiving mechanical ventilation. We therefore conducted a feasibility randomised controlled trial in the United Kingdom (UK) to assess whether it would be possible to host a larger national multi-centre trial to evaluate oxygenation targets in mechanically ventilated patients. METHODS: We set out to recruit 60 participants across two sites into a trial in which they were randomised to receive conservative oxygenation (SpO2 88-92%) or usual care (control - SpO2 ≥96%). The primary outcome was feasibility; factors related to safety and clinical outcomes were also assessed. RESULTS: A total of 34 patients were recruited into the study until it was stopped due to time constraints. A number of key barriers to success were identified during the course of the study. The conservative oxygenation intervention was feasible and appeared to be safe in this small patient cohort and it achieved wide separation of the median time-weighted average (IQR) SpO2 at 91% (90-92%) in conservative oxygenation group versus 97% (96-97%) in control group. CONCLUSION: Whilst conservative oxygenation was a feasible and safe intervention which achieved clear group separation in oxygenation levels, the model used in this trial will require alterations to improve future participant recruitment rates in the UK.

Goal-directed haemodynamic therapy (GDHT) in surgical patients: systematic review and meta-analysis of the impact of GDHT on post-operative pulmonary complications.

BACKGROUND: Perioperative goal-directed haemodynamic therapy (GDHT), defined as the administration of fluids with or without inotropes or vasoactive agents against explicit measured goals to augment blood flow, has been evaluated in many randomised controlled trials (RCTs) over the past four decades. Reported post-operative pulmonary complications commonly include chest infection or pneumonia, atelectasis, acute respiratory distress syndrome or acute lung injury, aspiration pneumonitis, pulmonary embolism, and pulmonary oedema. Despite the substantial clinical literature in this area, it remains unclear whether their incidence is reduced by GDHT. This systematic review aims to determine the effect of GDHT on the respiratory outcomes listed above, in surgical patients. METHODS: We searched the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, EMBASE, and clinical trial registries up until January 2020. We included all RCTs reporting pulmonary outcomes. The primary outcome was post-operative pulmonary complications and secondary outcomes were specific pulmonary complications and intra-operative fluid input. Data synthesis was performed on Review Manager and heterogeneity was assessed using I 2 statistics. RESULTS: We identified 66 studies with 9548 participants reporting pulmonary complications. GDHT resulted in a significant reduction in total pulmonary complications (OR 0.74, 95% CI 0.59 to 0.92). The incidence of pulmonary infections, reported in 45 studies with 6969 participants, was significantly lower in the GDHT group (OR 0.72, CI 0.60 to 0.86). Pulmonary oedema was recorded in 23 studies with 3205 participants and was less common in the GDHT group (OR 0.47, CI 0.30 to 0.73). There were no differences in the incidences of pulmonary embolism or acute respiratory distress syndrome. Sub-group analyses demonstrated: (i) benefit from GDHT in general/abdominal/mixed and cardiothoracic surgery but not in orthopaedic or vascular surgery; and (ii) benefit from fluids with inotropes and/or vasopressors in combination but not from fluids alone. Overall, the GDHT group received more colloid (+280 ml) and less crystalloid (-375 ml) solutions than the control group. Due to clinical and statistical heterogeneity, we downgraded this evidence to moderate. CONCLUSIONS: This systematic review and meta-analysis suggests that the use of GDHT using fluids with inotropes and/or vasopressors, but not fluids alone, reduces the development of post-operative pulmonary infections and pulmonary oedema in general, abdominal and cardiothoracic surgical patients. This evidence was graded as moderate.PROSPERO registry reference: CRD42020170361.

Oxygen targets in the intensive care unit during mechanical ventilation for acute respiratory distress syndrome: a rapid review.

BACKGROUND: Supplemental oxygen is frequently administered to patients with acute respiratory distress syndrome (ARDS), including ARDS secondary to viral illness such as coronavirus disease 19 (COVID-19). An up-to-date understanding of how best to target this therapy (e.g. arterial partial pressure of oxygen (PaO2) or peripheral oxygen saturation (SpO2) aim) in these patients is urgently required. OBJECTIVES: To address how oxygen therapy should be targeted in adults with ARDS (particularly ARDS secondary to COVID-19 or other respiratory viruses) and requiring mechanical ventilation in an intensive care unit, and the impact oxygen therapy has on mortality, days ventilated, days of catecholamine use, requirement for renal replacement therapy, and quality of life. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, CENTRAL, MEDLINE, and Embase from inception to 15 May 2020 for ongoing or completed randomized controlled trials (RCTs). SELECTION CRITERIA: Two review authors independently assessed all records in accordance with standard Cochrane methodology for study selection. We included RCTs comparing supplemental oxygen administration (i.e. different target PaO2 or SpO2 ranges) in adults with ARDS and receiving mechanical ventilation in an intensive care setting. We excluded studies exploring oxygen administration in patients with different underlying diagnoses or those receiving non-invasive ventilation, high-flow nasal oxygen, or oxygen via facemask. DATA COLLECTION AND ANALYSIS: One review author performed data extraction, which a second review author checked. We assessed risk of bias in included studies using the Cochrane 'Risk of bias' tool. We used the GRADE approach to judge the certainty of the evidence for the following outcomes; mortality at longest follow-up, days ventilated, days of catecholamine use, and requirement for renal replacement therapy. MAIN RESULTS: We identified one completed RCT evaluating oxygen targets in patients with ARDS receiving mechanical ventilation in an intensive care setting. The study randomized 205 mechanically ventilated patients with ARDS to either conservative (PaO2 55 to 70 mmHg, or SpO2 88% to 92%) or liberal (PaO2 90 to 105 mmHg, or SpO2 ≥ 96%) oxygen therapy for seven days. Overall risk of bias was high (due to lack of blinding, small numbers of participants, and the trial stopping prematurely), and we assessed the certainty of the evidence as very low. The available data suggested that mortality at 90 days may be higher in those participants receiving a lower oxygen target (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.03 to 3.27). There was no evidence of a difference between the lower and higher target groups in mean number of days ventilated (14.0, 95% CI 10.0 to 18.0 versus 14.5, 95% CI 11.8 to 17.1); number of days of catecholamine use (8.0, 95% CI 5.5 to 10.5 versus 7.2, 95% CI 5.9 to 8.4); or participants receiving renal replacement therapy (13.7%, 95% CI 5.8% to 21.6% versus 12.0%, 95% CI 5.0% to 19.1%). Quality of life was not reported. AUTHORS' CONCLUSIONS: We are very uncertain as to whether a higher or lower oxygen target is more beneficial in patients with ARDS and receiving mechanical ventilation in an intensive care setting. We identified only one RCT with a total of 205 participants exploring this question, and rated the risk of bias as high and the certainty of the findings as very low. Further well-conducted studies are urgently needed to increase the certainty of the findings reported here. This review should be updated when more evidence is available.

High sensitivity troponin measurement in critical care: Flattering to deceive or 'never means nothing'?

INTRODUCTION: Troponin elevation is central to the diagnosis of acute type 1 myocardial infarction. It is, however, elevated in a range of other conditions, including type 2 myocardial infarction, and this setting is increasingly associated with adverse clinical outcomes. Patients within intensive care frequently have at least one organ failure together with a range of co-morbidities. Interpretation of troponin assay results in this population is challenging. This clinical uncertainty is compounded by the introduction of ever more sensitive troponin assays. AREAS COVERED: The aims of this review are to (a) describe the currently available literature about the use of troponin assays in intensive care, (b) analyse the challenges presented by the introduction of increasingly sensitive troponin assays and (c) assess whether the role of troponin assays in intensive care may change in the future, dependent upon recent and ongoing research suggesting that they are predictive of outcome regardless of the underlying cause: the 'never means nothing' hypothesis.

Immunonutrition for Adults With ARDS: Results From a Cochrane Systematic Review and Meta-Analysis.

BACKGROUND: ARDS is an overwhelming systemic inflammatory process associated with significant morbidity and mortality. Several trials have evaluated the effects of pharmaconutrients, given as part of a feeding formula or as a nutritional supplement, on clinical outcomes in critical illness and ARDS. The aim of this review is to assess the effects of immunonutrition on mechanically ventilated adults with ARDS compared to the standard feeding formula. METHODS: We searched MEDLINE, EMBASE, CENTRAL, conference proceedings, and trial registries for appropriate studies up to April 2018. We performed statistical analysis according to Cochrane methodological standards. We used the GRADE approach to assess the quality of evidence for each outcome. RESULTS: We identified 10 randomized controlled trials with 1,015 participants. All of the studies compared an enteral formula or additional supplemental omega-3 fatty acids (eg, eicosapentaenoic acid, docosahexaenoic acid), γ-linolenic acid, and antioxidants. All of the studies reported mortality. For the primary outcome, there was no difference in all-cause mortality (for the longest period reported) with the use of an immunonutrition enteral formula or additional supplements of omega-3 fatty acids, γ-linolenic acid, and antioxidants (risk ratio = 0.79, 95% CI 0.59-1.07; low-quality evidence). For the secondary outcomes, we are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants improves ICU length of stay, ventilator days, and oxygenation or increases harm. CONCLUSIONS: This Cochrane meta-analysis of 10 studies of varying quality examined the effects of omega-3 fatty acids and antioxidants in adults with ARDS. This intervention may produce little or no difference in all-cause mortality between groups. We are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants improves ventilator days, ICU length of stay, or oxygenation due to the very low quality of evidence.

Effects of dietary nitrate supplementation on microvascular physiology at 4559 m altitude - A randomised controlled trial (Xtreme Alps).

Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate 'placebo'. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 µM) and at day 5 (D5) of high altitude (22.9 vs 84.3 µM, p < 0.001). Dietary nitrate supplementation also significantly increased both plasma nitrite (0.78 vs. 0.86 µM SL, 0.31 vs. 0.41 µM D5, p = 0.03) and total nitroso product (11.3 vs. 19.7 nM SL, 9.7 vs. 12.3 nM D5, p < 0.001) levels both at sea level and at 4559 m. However, plasma nitrite concentrations were more than 50% lower at 4559 m compared to sea level in both treatment groups. Despite these significant changes, dietary nitrate supplementation had no effect on any measured read-outs of sublingual or forearm blood flow, even when environmental hypoxia was experimentally reversed using supplemental oxygen. In conclusion, dietary nitrate supplementation does not improve microcirculatory function at 4559 m.

Pathway redesign: putting patients ahead of professionals.

Many perioperative clinical pathways, and therefore patient journeys, are focused around provider, rather than patient, convenience. Business process re-engineering (BPRE) offers a framework for transformative process-change with the aim of improving 'consumer experience' and efficiency and may be an effective driver for improving patient experience and value within healthcare. Involvement of patients in service and pathway design, through experience-based codesign, is increasingly prevalent and may be an effective complement to BPRE. The elective perioperative pathway offers an opportunity to rethink the patient journey with the aim of maximising opportunities for effective shared decision making and improving preparation for surgery through prehabilitation and management of long-term conditions (comorbidity/multimorbidity management). Additional opportunities include improved management of transitions of care and effective medicines management to minimise polypharmacy. Pathway mapping, deconstruction and reconstruction enables such changes and is a method of service transformation that may have relevance for a spectrum of other elective/scheduled pathways.

Perioperative Quality Initiative consensus statement on the physiology of arterial blood pressure control in perioperative medicine.

BACKGROUND: Perioperative arterial blood pressure management is a physiologically complex challenge influenced by multiple factors. METHODS: A multidisciplinary, international working subgroup of the Third Perioperative Quality Initiative (POQI) consensus meeting reviewed the (patho)physiology and measurement of arterial pressure as applied to perioperative medicine. We addressed predefined questions by undertaking a modified Delphi analysis, in which primary clinical research and review articles were identified using MEDLINE. Strength of recommendations, where applicable, were graded by National Institute for Health and Care Excellence (NICE) guidelines. RESULTS: Multiple physiological factors contribute to the perioperative physiological importance of arterial pressure: (i) arterial pressure is the input pressure to organ blood flow, but is not the sole determinant of perfusion pressure; (ii) blood flow is often independent of changes in perfusion pressure because of autoregulatory changes in vascular resistance; (iii) microvascular dysfunction uncouples microvascular blood flow from arterial pressure (haemodynamic incoherence). From a practical clinical perspective, we identified that: (i) ambulatory measurement is the optimal method to establish baseline arterial pressure; (ii) automated and invasive arterial pressure measurements have inherent physiological and technical limitations; (iii) individualised arterial pressure targets may change over time, especially in the perioperative period. There remains a need for research in non-invasive, continuous arterial pressure measurements, macro- and micro-circulatory control, regional perfusion pressure measurement, and the development of sensitive, specific, and continuous measures of cellular function to evaluate blood pressure management in a physiologically coherent manner. CONCLUSION: The multivariable, complex physiology contributing to dynamic changes in perioperative arterial pressure may be underappreciated clinically. The frequently unrecognised dissociation between arterial pressure, organ blood flow, and microvascular and cellular function requires further research to develop a more refined, contextualised clinical approach to this routine perioperative measurement.

Perioperative Quality Initiative consensus statement on intraoperative blood pressure, risk and outcomes for elective surgery.

BACKGROUND: Intraoperative mortality is now rare, but death within 30 days of surgery remains surprisingly common. Perioperative myocardial infarction is associated with a remarkably high mortality. There are strong associations between hypotension and myocardial injury, myocardial infarction, renal injury, and death. Perioperative arterial blood pressure management was thus the basis of a Perioperative Quality Initiative consensus-building conference held in London in July 2017. METHODS: The meeting featured a modified Delphi process in which groups addressed various aspects of perioperative arterial pressure. RESULTS: Three consensus statements on intraoperative blood pressure were established. 1) Intraoperative mean arterial pressures below 60-70 mm Hg are associated with myocardial injury, acute kidney injury, and death. Injury is a function of hypotension severity and duration. 2) For adult non-cardiac surgical patients, there is insufficient evidence to recommend a general upper limit of arterial pressure at which therapy should be initiated, although pressures above 160 mm Hg have been associated with myocardial injury and infarction. 3) During cardiac surgery, intraoperative systolic arterial pressure above 140 mm Hg is associated with increased 30 day mortality. Injury is a function of arterial pressure severity and duration. CONCLUSIONS: There is increasing evidence that even brief durations of systolic arterial pressure <100 mm Hg and mean arterial pressure <60-70 mm Hg are harmful during non-cardiac surgery.

Perioperative Quality Initiative consensus statement on postoperative blood pressure, risk and outcomes for elective surgery.

BACKGROUND: Postoperative hypotension and hypertension are frequent events associated with increased risk of adverse outcomes. However, proper assessment and management is often poorly understood. As a part of the PeriOperative Quality Improvement (POQI) 3 workgroup meeting, we developed a consensus document addressing this topic. The target population includes adult, non-cardiac surgical patients in the postoperative phase outside of the ICU. METHODS: A modified Delphi technique was used, evaluating papers published in MEDLINE examining postoperative blood pressure monitoring, management, and outcomes. Practice recommendations were developed in line with National Institute for Health and Care Excellence guidelines. RESULTS: Consensus recommendations were that (i) there is evidence of harm associated with postoperative systolic arterial pressure <90 mm Hg; (ii) for patients with preoperative hypertension, the threshold at which harm occurs may be higher than a systolic arterial pressure of 90 mm Hg; (iii) there is insufficient evidence to precisely define the level of postoperative hypertension above which harm will occur; (iv) a greater frequency of postoperative blood pressure measurement is likely to identify risk of harm and clinical deterioration earlier; and (v) there is evidence of harm from withholding beta-blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors in the postoperative period. CONCLUSIONS: Despite evidence of associations with postoperative hypotension or hypertension with worse postoperative outcome, further research is needed to define the optimal levels at which intervention is beneficial, to identify the best methods and timing of postoperative blood pressure measurement, and to refine the management of long-term antihypertensive treatment in the postoperative phase.

Immunonutrition for acute respiratory distress syndrome (ARDS) in adults.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an overwhelming systemic inflammatory process associated with significant morbidity and mortality. Pharmacotherapies that moderate inflammation in ARDS are lacking. Several trials have evaluated the effects of pharmaconutrients, given as part of a feeding formula or as a nutritional supplement, on clinical outcomes in critical illness and ARDS. OBJECTIVES: To systematically review and critically appraise available evidence on the effects of immunonutrition compared to standard non-immunonutrition formula feeding on mechanically ventilated adults (aged 18 years or older) with acute respiratory distress syndrome (ARDS). SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, conference proceedings, and trial registries for appropriate studies up to 25 April 2018. We checked the references from published studies and reviews on this topic for potentially eligible studies. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and quasi-randomized controlled trials comparing immunonutrition versus a control or placebo nutritional formula in adults (aged 18 years or older) with ARDS, as defined by the Berlin definition of ARDS or, for older studies, by the American-European Consensus Criteria for both ARDS and acute lung injury. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the quality of studies and extracted data from the included trials. We sought additional information from study authors. We performed statistical analysis according to Cochrane methodological standards. Our primary outcome was all-cause mortality. Secondary outcomes included intensive care unit (ICU) length of stay, ventilator days, indices of oxygenation, cardiac adverse events, gastrointestinal adverse events, and total number of adverse events. We used GRADE to assess the quality of evidence for each outcome. MAIN RESULTS: We identified 10 randomized controlled trials with 1015 participants. All studies compared an enteral formula or additional supplemental omega-3 fatty acids (i.e. eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)), gamma-linolenic acid (GLA), and antioxidants. We assessed some of the included studies as having high risk of bias due to methodological shortcomings. Studies were heterogenous in nature and varied in several ways, including type and duration of interventions given, calorific targets, and reported outcomes. All studies reported mortality. For the primary outcome, study authors reported no differences in all-cause mortality (longest period reported) with the use of an immunonutrition enteral formula or additional supplements of omega-3 fatty acids and antioxidants (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.59 to 1.07; participants = 1015; studies = 10; low-quality evidence).For secondary outcomes, we are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants reduces ICU length of stay (mean difference (MD) -3.09 days. 95% CI -5.19 to -0.99; participants = 639; studies = 8; very low-quality evidence) and ventilator days (MD -2.24 days, 95% CI -3.77 to -0.71; participants = 581; studies = 7; very low-quality evidence). We are also uncertain whether omega-3 fatty acids and antioxidants improve oxygenation, defined as ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2), at day 4 (MD 39 mmHg, 95% CI 10.75 to 67.02; participants = 676; studies = 8), or whether they increase adverse events such as cardiac events (RR 0.87, 95% CI 0.09 to 8.46; participants = 339; studies = 3; very low-quality evidence), gastrointestinal events (RR 1.11, 95% CI 0.71 to 1.75; participants = 427; studies = 4; very low-quality evidence), or total adverse events (RR 0.91, 95% CI 0.67 to 1.23; participants = 517; studies = 5; very low-quality evidence). AUTHORS' CONCLUSIONS: This meta-analysis of 10 studies of varying quality examined effects of omega-3 fatty acids and/or antioxidants in adults with ARDS. This intervention may produce little or no difference in all-cause mortality between groups. We are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants improves the duration of ventilator days and ICU length of stay or oxygenation at day 4 due to the very low quality of evidence. Adverse events associated with immunonutrition are also uncertain, as confidence intervals include the potential for increased cardiac, gastrointestinal, and total adverse events.

Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial: study protocol for a multicentre international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in older patients with comorbidities undergoing gastrointestinal surgery are a major burden on healthcare systems. Infections after surgery are common in such patients, prolonging hospitalisation and reducing postoperative short-term and long-term survival. Optimal management of perioperative intravenous fluids and inotropic drugs may reduce infection rates and improve outcomes from surgery. Previous small trials of cardiac-output-guided haemodynamic therapy algorithms suggested a modest reduction in postoperative morbidity. A large definitive trial is needed to confirm or refute this and inform widespread clinical practice. METHODS: The Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial is a multicentre, international, parallel group, open, randomised controlled trial. 2502 high-risk patients undergoing major elective gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intravenous fluid combined with low-dose inotrope infusion, or usual care. The trial intervention will be carried out during and for 4 hours after surgery. The primary outcome is postoperative infection of Clavien-Dindo grade II or higher within 30 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation; however, outcome assessors will be blinded when feasible. Participant recruitment started in January 2017 and is scheduled to last 3 years, within 50 hospitals worldwide. ETHICS/DISSEMINATION: The OPTIMISE II trial has been approved by the UK National Research Ethics Service and has been approved by responsible ethics committees in all participating countries. The findings will be disseminated through publication in a widely accessible peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: ISRCTN39653756.

Exercise interventions for people undergoing multimodal cancer treatment that includes surgery.

BACKGROUND: People undergoing multimodal cancer treatment are at an increased risk of adverse events. Physical fitness significantly reduces following cancer treatment, which is related to poor postoperative outcome. Exercise training can stimulate skeletal muscle adaptations, such as increased mitochondrial content and improved oxygen uptake capacity may contribute to improved physical fitness. OBJECTIVES: To determine the effects of exercise interventions for people undergoing multimodal treatment for cancer, including surgery, on physical fitness, safety, health-related quality of life (HRQoL), fatigue, and postoperative outcomes. SEARCH METHODS: We searched electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, SPORTDiscus, and trial registries up to October 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared the effects of exercise training with usual care, on physical fitness, safety, HRQoL, fatigue, and postoperative outcomes in people undergoing multimodal cancer treatment, including surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, performed the data extraction, assessed the risk of bias, and rated the quality of the studies using Grading of Recommendation Assessment, Development, and Evaluation (GRADE) criteria. We pooled data for meta-analyses, where possible, and reported these as mean differences using the random-effects model. MAIN RESULTS: Eleven RCTs were identified involving 1067 participants; 568 were randomly allocated to an exercise intervention and 499 to a usual care control group. The majority of participants received treatment for breast cancer (73%). Due to the nature of the intervention, it was not possible to blind the participants or personnel delivering the intervention. The risk of detection bias was either high or unclear in some cases, whilst most other domains were rated as low risk. The included studies were of moderate to very low-certainty evidence. Pooled data demonstrated that exercise training may have little or no difference on physical fitness (VO2 max) compared to usual care (mean difference (MD) 0.05 L/min-1, 95% confidence interval (CI) -0.03 to 0.13; I2 = 0%; 2 studies, 381 participants; low-certainty evidence). Included studies also showed in terms of adverse effects (safety), that it may be of benefit to exercise (8 studies, 507 participants; low-certainty evidence). Furthermore, exercise training probably made little or no difference on HRQoL (EORTC global health status subscale) compared to usual care (MD 2.29, 95% CI -1.06 to 5.65; I2 = 0%; 3 studies, 472 participants; moderate-certainty evidence). However, exercise training probably reduces fatigue (multidimensional fatigue inventory) compared to usual care (MD -1.05, 95% CI -1.83 to -0.28; I2 = 0%; 3 studies, 449 participants moderate-certainty evidence). No studies reported postoperative outcomes. AUTHORS' CONCLUSIONS: The findings should be interpreted with caution in view of the low number of studies, the overall low-certainty of the combined evidence, and the variation in included cancer types (mainly people with breast cancer), treatments, exercise interventions, and outcomes. Exercise training may, or may not, confer modest benefit on physical fitness and HRQoL. Limited evidence suggests that exercise training is probably not harmful and probably reduces fatigue. These findings highlight the need for more RCTs, particularly in the neoadjuvant setting.

Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures.

BACKGROUND: Perioperative fluid strategies influence clinical outcomes following major surgery. Many intravenous fluid preparations are based on simple solutions, such as normal saline, that feature an electrolyte composition that differs from that of physiological plasma. Buffered fluids have a theoretical advantage of containing a substrate that acts to maintain the body's acid-base status - typically a bicarbonate or a bicarbonate precursor such as maleate, gluconate, lactate, or acetate. Buffered fluids also provide additional electrolytes, including potassium, magnesium, and calcium, more closely matching the electrolyte balance of plasma. The putative benefits of buffered fluids have been compared with those of non-buffered fluids in the context of clinical studies conducted during the perioperative period. This review was published in 2012, and was updated in 2017. OBJECTIVES: To review effects of perioperative intravenous administration of buffered versus non-buffered fluids for plasma volume expansion or maintenance, or both, on clinical outcomes in adults undergoing all types of surgery. SEARCH METHODS: We electronically searched the Clinicaltrials.gov major trials registry, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 6) in the Cochrane Library, MEDLINE (1966 to June 2016), Embase (1980 to June 2016), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to June 2016). We handsearched conference abstracts and, when possible, contacted leaders in the field. We reran the search in May 2017. We added one potential new study of interest to the list of 'Studies awaiting classification' and will incorporate this trial into formal review findings when we prepare the review update. SELECTION CRITERIA: Only randomized controlled trials that compared buffered versus non-buffered intravenous fluids for surgical patients were eligible for inclusion. We excluded other forms of comparison such as crystalloids versus colloids and colloids versus different colloids. DATA COLLECTION AND ANALYSIS: Two review authors screened references for eligibility, extracted data, and assessed risks of bias. We resolved disagreements by discussion and consensus, in collaboration with a third review author. We contacted trial authors to request additional information when appropriate. We presented pooled estimates for dichotomous outcomes as odds ratios (ORs) and for continuous outcomes as mean differences (MDs), with 95% confidence intervals (CIs). We analysed data via Review Manager 5.3 using fixed-effect models, and when heterogeneity was high (I² > 40%), we used random-effects models. MAIN RESULTS: This review includes, in total, 19 publications of 18 randomized controlled trials with a total of 1096 participants. We incorporated five of those 19 studies (330 participants) after the June 2016 update. Outcome measures in the included studies were thematically similar, covering perioperative electrolyte status, renal function, and acid-base status; however, we found significant clinical and statistical heterogeneity among the included studies. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Trial authors variably reported outcome data at disparate time points and with heterogeneous patient groups. Consequently, many outcome measures are reported in small group sizes, reducing overall confidence in effect size, despite relatively low inherent bias in the included studies. Several studies reported orphan outcome measures. We did not include in the results of this review one large, ongoing study of saline versus Ringer's solution.We found insufficient evidence on effects of fluid therapies on mortality and postoperative organ dysfunction (defined as renal insufficiency leading to renal replacement therapy); confidence intervals were wide and included both clinically relevant benefit and harm: mortality (Peto OR 1.85, 95% CI 0.37 to 9.33; I² = 0%; 3 trials, 6 deaths, 276 participants; low-quality evidence); renal insufficiency (OR 0.82, 95% CI 0.34 to 1.98; I² = 0%; 4 trials, 22 events, 276 participants; low-quality evidence).We noted several metabolic differences, including a difference in postoperative pH measured at end of surgery of 0.05 units - lower in the non-buffered fluid group (12 studies with a total of 720 participants; 95% CI 0.04 to 0.07; I² = 61%). However, this difference was not maintained on postoperative day one. We rated the quality of evidence for this outcome as moderate. We observed a higher postoperative serum chloride level immediately after operation, with use of non-buffered fluids reported in 10 studies with a total of 530 participants (MD 6.77 mmol/L, 95% CI 3.38 to 10.17), and this difference persisted until day one postoperatively (five studies with a total of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). We rated the quality of evidence for this outcome as moderate. AUTHORS' CONCLUSIONS: Current evidence is insufficient to show effects of perioperative administration of buffered versus non-buffered crystalloid fluids on mortality and organ system function in adult patients following surgery. Benefits of buffered fluid were measurable in biochemical terms, particularly a significant reduction in postoperative hyperchloraemia and metabolic acidosis. Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Larger studies are needed to assess these relevant clinical outcomes.

Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Data from in-vitro, animal, and human lung injury models suggest that keratinocyte growth factor (KGF) might be beneficial in acute respiratory distress syndrome (ARDS). The objective of this trial was to investigate the effect of KGF in patients with ARDS. METHODS: We did a double-blind, allocation concealed, randomised, placebo-controlled phase 2 trial in two intensive care units in the UK, involving patients fulfilling the American-European Consensus Conference Definition of ARDS. Patients were randomly assigned (1:1) by computer-generated randomisation schedule with variable block size stratified by site and presence of severe sepsis requiring vasopressors to receive either recombinant human KGF (palifermin 60 µg/kg) or placebo (0·9% sodium chloride solution) daily for a maximum of 6 days. Both patients and investigators were masked to treatment. The primary endpoint was oxygenation index (OI) at day 7. Analyses were by intention to treat. The trial is registered with International Standard Randomised Controlled Trial Registry, number ISRCTN95690673. FINDINGS: Between Feb 23, 2011, and Feb 26, 2014, 368 patients were assessed for eligibility for inclusion in the trial. Of the 60 patients recruited, 29 patients were randomly assigned to receive KGF and 31 to placebo; all were included in the analysis of the primary outcome. There was no significant difference between the two groups in OI at day 7 (mean 62·3 [SD 57·8] in the KGF group, 43·1 [33·5] in the placebo group; mean difference 19·2, 95% CI -5·6 to 44·0, p=0·13). Of interest, although not defined as outcome measures a priori, the KGF group, compared with placebo, had fewer median ventilator-free days (1 day [IQR 0 to 17] in the KGF group vs 20 days [13-22] in the placebo group; difference -8 days, 95% CI -17 to -2; p=0·0002), a longer median duration of ventilation in survivors to day 90 (16 days [IQR 13-30] in the KGF group vs 11 days [8-16] in the placebo group; difference 6 days, 95% CI 2 to 14; p=0·002), and a higher mortality at 28 days (nine [31%] vs three [10%] deaths; risk ratio 3·2, 95% CI 1·0 to 10·7, p=0·054). Adverse events were more frequent in the KGF group than the placebo group (14 vs 5 events; odds ratio 4·9, 95% CI 1·3 to 20·3, p=0·008). The two adverse events assessed as related to KGF were due to pyrexia. INTERPRETATION: KGF did not improve physiological or clinical outcomes in ARDS and might be harmful to patient health. FUNDING: The Northern Ireland Public Health Agency Research and Development Division.