Severity of Hypoxemia and Effect of High-Frequency Oscillatory Ventilation in Acute Respiratory Distress Syndrome.

RATIONALE: High-frequency oscillatory ventilation (HFOV) is theoretically beneficial for lung protection, but the results of clinical trials are inconsistent, with study-level meta-analyses suggesting no significant effect on mortality. OBJECTIVES: The aim of this individual patient data meta-analysis was to identify acute respiratory distress syndrome (ARDS) patient subgroups with differential outcomes from HFOV. METHODS: After a comprehensive search for trials, two reviewers independently identified randomized trials comparing HFOV with conventional ventilation for adults with ARDS. Prespecified effect modifiers were tested using multivariable hierarchical logistic regression models, adjusting for important prognostic factors and clustering effects. MEASUREMENTS AND MAIN RESULTS: Data from 1,552 patients in four trials were analyzed, applying uniform definitions for study variables and outcomes. Patients had a mean baseline PaO2/FiO2 of 114 ± 39 mm Hg; 40% had severe ARDS (PaO2/FiO2 <100 mm Hg). Mortality at 30 days was 321 of 785 (40.9%) for HFOV patients versus 288 of 767 (37.6%) for control subjects (adjusted odds ratio, 1.17; 95% confidence interval, 0.94-1.46; P = 0.16). This treatment effect varied, however, depending on baseline severity of hypoxemia (P = 0.0003), with harm increasing with PaO2/FiO2 among patients with mild-moderate ARDS, and the possibility of decreased mortality in patients with very severe ARDS. Compliance and body mass index did not modify the treatment effect. HFOV increased barotrauma risk compared with conventional ventilation (adjusted odds ratio, 1.75; 95% confidence interval, 1.04-2.96; P = 0.04). CONCLUSIONS: HFOV increases mortality for most patients with ARDS but may improve survival among patients with severe hypoxemia on conventional mechanical ventilation.

High-frequency oscillation for acute respiratory distress syndrome.

BACKGROUND: Patients with the acute respiratory distress syndrome (ARDS) require mechanical ventilation to maintain arterial oxygenation, but this treatment may produce secondary lung injury. High-frequency oscillatory ventilation (HFOV) may reduce this secondary damage. METHODS: In a multicenter study, we randomly assigned adults requiring mechanical ventilation for ARDS to undergo either HFOV with a Novalung R100 ventilator (Metran) or usual ventilatory care. All the patients had a ratio of the partial pressure of arterial oxygen (PaO) to the fraction of inspired oxygen (FiO) of 200 mm Hg (26.7 kPa) or less and an expected duration of ventilation of at least 2 days. The primary outcome was all-cause mortality 30 days after randomization. RESULTS: There was no significant between-group difference in the primary outcome, which occurred in 166 of 398 patients (41.7%) in the HFOV group and 163 of 397 patients (41.1%) in the conventional-ventilation group (P=0.85 by the chi-square test). After adjustment for study center, sex, score on the Acute Physiology and Chronic Health Evaluation (APACHE) II, and the initial PaO:FiO ratio, the odds ratio for survival in the conventional-ventilation group was 1.03 (95% confidence interval, 0.75 to 1.40; P=0.87 by logistic regression). CONCLUSIONS: The use of HFOV had no significant effect on 30-day mortality in patients undergoing mechanical ventilation for ARDS. (Funded by the National Institute for Health Research Health Technology Assessment Programme; OSCAR Current Controlled Trials number, ISRCTN10416500.).

The 'analysis of gene expression and biomarkers for point-of-care decision support in Sepsis' study; temporal clinical parameter analysis and validation of early diagnostic biomarker signatures for severe inflammation andsepsis-SIRS discrimination.

Introduction: Early diagnosis of sepsis and discrimination from SIRS is crucial for clinicians to provide appropriate care, management and treatment to critically ill patients. We describe identification of mRNA biomarkers from peripheral blood leukocytes, able to identify severe, systemic inflammation (irrespective of origin) and differentiate Sepsis from SIRS, in adult patients within a multi-center clinical study. Methods: Participants were recruited in Intensive Care Units (ICUs) from multiple UK hospitals, including fifty-nine patients with abdominal sepsis, eighty-four patients with pulmonary sepsis, forty-two SIRS patients with Out-of-Hospital Cardiac Arrest (OOHCA), sampled at four time points, in addition to thirty healthy control donors. Multiple clinical parameters were measured, including SOFA score, with many differences observed between SIRS and sepsis groups. Differential gene expression analyses were performed using microarray hybridization and data analyzed using a combination of parametric and non-parametric statistical tools. Results: Nineteen high-performance, differentially expressed mRNA biomarkers were identified between control and combined SIRS/Sepsis groups (FC>20.0, p<0.05), termed 'indicators of inflammation' (I°I), including CD177, FAM20A and OLAH. Best-performing minimal signatures e.g. FAM20A/OLAH showed good accuracy for determination of severe, systemic inflammation (AUC>0.99). Twenty entities, termed 'SIRS or Sepsis' (S°S) biomarkers, were differentially expressed between sepsis and SIRS (FC>2·0, p-value<0.05). Discussion: The best performing signature for discriminating sepsis from SIRS was CMTM5/CETP/PLA2G7/MIA/MPP3 (AUC=0.9758). The I°I and S°S signatures performed variably in other independent gene expression datasets, this may be due to technical variation in the study/assay platform.

TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2.

TLR and complement activation ensures efficient clearance of infection. Previous studies documented synergism between TLRs and the receptor for the pro-inflammatory complement peptide C5a (C5aR/CD88), and regulation of TLR-induced pro-inflammatory responses by C5aR, suggesting crosstalk between TLRs and C5aR. However, it is unclear whether and how TLRs modulate C5a-induced pro-inflammatory responses. We demonstrate a marked positive modulatory effect of TLR activation on cell sensitivity to C5a in vitro and ex vivo and identify an underlying mechanistic target. Pre-exposure of PBMCs and whole blood to diverse TLR ligands or bacteria enhanced C5a-induced pro-inflammatory responses. This effect was not observed in TLR4 signalling-deficient mice. TLR-induced hypersensitivity to C5a did not result from C5aR upregulation or modulation of C5a-induced Ca(2+) mobilization. Rather, TLRs targeted another C5a receptor, C5L2 (acting as a negative modulator of C5aR), by reducing C5L2 activity. TLR-induced hypersensitivity to C5a was mimicked by blocking C5L2 and was not observed in C5L2KO mice. Furthermore, TLR activation inhibited C5L2 expression upon C5a stimulation. These findings identify a novel pathway of crosstalk within the innate immune system that amplifies innate host defense at the TLR-complement interface. Unravelling the mutually regulated activities of TLRs and complement may reveal new therapeutic avenues to control inflammation.

Pre-admission interventions (prehabilitation) to improve outcome after major elective surgery: a systematic review and meta-analysis.

OBJECTIVE: To determine the benefits and harms of pre-admission interventions (prehabilitation) on postoperative outcomes in patients undergoing major elective surgery. DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs) (published or unpublished). We searched Medline, Embase, CENTRAL, DARE, HTA and NHS EED, The Cochrane Library, CINAHL, PsychINFO and ISI Web of Science (June 2020). SETTING: Secondary care. PARTICIPANTS: Patients (≥18 years) undergoing major elective surgery (curative or palliative). INTERVENTIONS: Any intervention administered in the preoperative period with the aim of improving postoperative outcomes. OUTCOMES AND MEASURES: Primary outcomes were 30-day mortality, hospital length of stay (LoS) and postoperative complications. Secondary outcomes included LoS in intensive care unit or high dependency unit, perioperative morbidity, hospital readmission, postoperative pain, heath-related quality of life, outcomes specific to the intervention, intervention-specific adverse events and resource use. REVIEW METHODS: Two authors independently extracted data from eligible RCTs and assessed risk of bias and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation. Random-effects meta-analyses were used to pool data across trials. RESULTS: 178 RCTs including eight types of intervention were included. Inspiratory muscle training (IMT), immunonutrition and multimodal interventions reduced hospital LoS (mean difference vs usual care: -1.81 days, 95% CI -2.31 to -1.31; -2.11 days, 95% CI -3.07 to -1.15; -1.67 days, 95% CI -2.31 to -1.03, respectively). Immunonutrition reduced infective complications (risk ratio (RR) 0.64 95% CI 0.40 to 1.01) and IMT, and exercise reduced postoperative pulmonary complications (RR 0.55, 95% CI 0.38 to 0.80, and RR 0.54, 95% CI 0.39 to 0.75, respectively). Smoking cessation interventions reduced wound infections (RR 0.28, 95% CI 0.12 to 0.64). CONCLUSIONS: Some prehabilitation interventions may reduce postoperative LoS and complications but the quality of the evidence was low. PROSPERO REGISTRATION NUMBER: CRD42015019191.

Finding a solution: Heparinised saline versus normal saline in the maintenance of invasive arterial lines in intensive care.

BACKGROUND: We assessed the impact of heparinised saline versus 0.9% normal saline on arterial line patency. Maintaining the patency of arterial lines is essential for obtaining accurate physiological measurements, enabling blood sampling and minimising line replacement. Use of heparinised saline is associated with risks such as thrombocytopenia, haemorrhage and mis-selection. Historical studies draw variable conclusions but suggest that normal saline is at least as effective at maintaining line patency, although recent evidence has questioned this. METHODS: We conducted a prospective analysis of the use of heparinised saline versus normal saline on unselected patients in the intensive care of our hospital. Data concerning duration of 471 lines insertion and reason for removal was collected. RESULTS: We found a higher risk of blockage for lines flushed with normal saline compared with heparinised saline (RR = 2.15, 95% CI 1.392-3.32, p ≤ 0.001). Of the 56 lines which blocked initially (19 heparinised saline and 37 normal saline lines), 16 were replaced with new lines; 5 heparinised saline lines and 11 normal saline lines were reinserted; 5 of these lines subsequently blocked again, 3 of which were flushed with normal saline. CONCLUSIONS: Our study demonstrates a clinically important reduction in arterial line longevity due to blockages when flushed with normal saline compared to heparinised saline. We have determined that these excess blockages have a significant clinical impact with further lines being inserted after blockage, resulting in increased risks to patients, wasted time and cost of resources. Our findings suggest that the current UK guidance favouring normal saline flushes should be reviewed.

Pre-admission interventions to improve outcome after elective surgery-protocol for a systematic review.

BACKGROUND: Poor physical health and fitness increases the risk of death and complications after major elective surgery. Pre-admission interventions to improve patients' health and fitness (referred to as prehabilitation) may reduce postoperative complications, decrease the length of hospital stay and facilitate the patient's recovery. We will conduct a systematic review of RCTs to examine the effectiveness of different types of prehabilitation interventions in improving the surgical outcomes of patients undergoing elective surgery. METHODS: This review will be conducted and reported according to the Cochrane and PRISMA reporting guidelines. MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, ISI Web of Science and clinical trial registers will be searched for any intervention administered before any elective surgery (including physical activity, nutritional, educational, psychological, clinical or multicomponent), which aims to improve postoperative outcomes. Reference lists of included studies will be searched, and grey literature including conference proceedings, theses, dissertations and preoperative assessment protocols will be examined. Study quality will be assessed using Cochrane's risk of bias tool, and meta-analyses for trials that use similar interventions and report similar outcomes will be undertaken where possible. DISCUSSION: This systematic review will determine whether different types of interventions administered before elective surgery are effective in improving postoperative outcomes. It will also determine which components or combinations of components would form the most effective prehabilitation intervention. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015019191.

High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669].

INTRODUCTION: To compare the safety and efficacy of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CV) for early intervention in adult respiratory distress syndrome (ARDS), a multi-centre randomized trial in four intensive care units was conducted. METHODS: Patients with ARDS were randomized to receive either HFOV or CV. In both treatment arms a priority was given to maintain lung volume while minimizing peak pressures. CV ventilation strategy was aimed at reducing tidal volumes. In the HFOV group, an open lung strategy was used. Respiratory and circulatory parameters were recorded and clinical outcome was determined at 30 days of follow up. RESULTS: The study was prematurely stopped. Thirty-seven patients received HFOV and 24 patients CV (average APACHE II score 21 and 20, oxygenation index 25 and 18 and duration of mechanical ventilation prior to randomization 2.1 and 1.5 days, respectively). There were no statistically significant differences in survival without supplemental oxygen or on ventilator, mortality, therapy failure, or crossover. Adjustment by a priori defined baseline characteristics showed an odds ratio of 0.80 (95% CI 0.22-2.97) for survival without oxygen or on ventilator, and an odds ratio for mortality of 1.15 (95% CI 0.43-3.10) for HFOV compared with CV. The response of the oxygenation index (OI) to treatment did not differentiate between survival and death. In the HFOV group the OI response was significantly higher than in the CV group between the first and the second day. A post hoc analysis suggested that there was a relatively better treatment effect of HFOV compared with CV in patients with a higher baseline OI. CONCLUSION: No significant differences were observed, but this trial only had power to detect major differences in survival without oxygen or on ventilator. In patients with ARDS and higher baseline OI, however, there might be a treatment benefit of HFOV over CV. More research is needed to establish the efficacy of HFOV in the treatment of ARDS. We suggest that future studies are designed to allow for informative analysis in patients with higher OI.

A randomised controlled trial and cost-effectiveness analysis of high-frequency oscillatory ventilation against conventional artificial ventilation for adults with acute respiratory distress syndrome. The OSCAR (OSCillation in ARDS) study.

BACKGROUND: Patients with the acute respiratory distress syndrome (ARDS) require artificial ventilation but this treatment may produce secondary lung damage. High-frequency oscillatory ventilation (HFOV) may reduce this damage. OBJECTIVES: To determine the clinical benefit and cost-effectiveness of HFOV in patients with ARDS compared with standard mechanical ventilation. DESIGN: A parallel, randomised, unblinded clinical trial. SETTING: UK intensive care units. PARTICIPANTS: Mechanically ventilated patients with a partial pressure of oxygen in arterial blood/fractional concentration of inspired oxygen (P : F) ratio of 26.7 kPa (200 mmHg) or less and an expected duration of ventilation of at least 2 days at recruitment. INTERVENTIONS: Treatment arm HFOV using a Novalung R100(®) ventilator (Metran Co. Ltd, Saitama, Japan) ventilator until the start of weaning. Control arm Conventional mechanical ventilation using the devices available in the participating centres. MAIN OUTCOME MEASURES: The primary clinical outcome was all-cause mortality at 30 days after randomisation. The primary health economic outcome was the cost per quality-adjusted life-year (QALY) gained. RESULTS: One hundred and sixty-six of 398 patients (41.7%) randomised to the HFOV group and 163 of 397 patients (41.1%) randomised to the conventional mechanical ventilation group died within 30 days of randomisation (p = 0.85), for an absolute difference of 0.6% [95% confidence interval (CI) -6.1% to 7.5%]. After adjustment for study centre, sex, Acute Physiology and Chronic Health Evaluation II score, and the initial P : F ratio, the odds ratio for survival in the conventional ventilation group was 1.03 (95% CI 0.75 to 1.40; p = 0.87 logistic regression). Survival analysis showed no difference in the probability of survival up to 12 months after randomisation. The average QALY at 1 year in the HFOV group was 0.302 compared to 0.246. This gives an incremental cost-effectiveness ratio (ICER) for the cost to society per QALY of £88,790 and an ICER for the cost to the NHS per QALY of £ 78,260. CONCLUSIONS: The use of HFOV had no effect on 30-day mortality in adult patients undergoing mechanical ventilation for ARDS and no economic advantage. We suggest that further research into avoiding ventilator-induced lung injury should concentrate on ventilatory strategies other than HFOV. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10416500.

The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study.

BACKGROUND: Pulmonary vascular leakage occurs early in acute respiratory distress syndrome (ARDS). Mortality is high (35-45%), but no effective pharmacotherapy exists. Production of anti-inflammatory adenosine by ecto-5'-nucleotidase (CD73) helps maintain endothelial barrier function. We tested whether interferon-beta-1a (IFN-beta-1a), which increases CD73 synthesis, can reduce vascular leakage and mortality in patients with ARDS. METHODS: In ex-vivo studies, we first established that IFN-beta-1a induced CD73 up-regulation in cultured human lung tissue samples. We then tested the safety, tolerability, and efficacy of intravenous human recombinant IFN-beta-1a (FP-1201) in patients with ARDS in an open-label study (comprising dose-escalation and expansion phases). We recruited patients from eight intensive care units in the UK. Eligible patients were aged 18 years or older, had ARDS, and were being treated with assisted ventilation. We established an optimal tolerated dose (OTD) in the first, dose-escalation phase. Once established, we gave all subsequently enrolled patients the OTD of intravenous FP-1201 for 6 days. We assessed 28-day mortality (our primary endpoint) in all patients receiving the OTD versus 28-day mortality in a group of patients who did not receive treatment (this control group comprised patients in the study but who did not receive treatment because they were screened during the safety windows after dose escalation). This trial is registered with ClinicalTrials.gov, number NCT00789685, and the EU Clinical Trials Register EudraCT, number 2008-000140-13. FINDINGS: IFN-beta-1a increased the number of CD73-positive vessels in lung culture by four times on day 1 (p=0·04) and by 14·3 times by day 4 (p=0·004). For the clinical trial, between Feb 23, 2009, and April 7, 2011, we identified 150 patients, of whom 37 were enrolled into the trial and given treatment. The control group consisted of 59 patients who were recruited to take part in the study, but who did not receive treatment. Demographic characteristics and severity of illness did not differ between treatment and control groups. The optimal tolerated FP-1201 dose was 10 µg per day for 6 days. By day 28, 3 (8%) of 37 patients in the treatment cohort and 19 (32%) of 59 patients in the control cohort had died-thus, treatment with FP-1201 was associated with an 81% reduction in odds of 28-day mortality (odds ratio 0·19 [95% CI 0·03-0·72]; p=0·01). INTERPRETATION: FP-1201 up-regulates human lung CD73 expression, and is associated with a reduction in 28-day mortality in patients with ARDS. Our findings need to be substantiated in large, prospective randomised trials, but suggest that FP-1201 could be the first effective, mechanistically targeted, disease-specific pharmacotherapy for patients with ARDS.

Percutaneous dilation tracheostomy during high-frequency oscillatory ventilation.

OBJECTIVE: To ascertain the feasibility and the safety of percutaneous dilational tracheostomy in patients with acute respiratory distress syndrome receiving high-frequency oscillatory ventilation. DESIGN: Case series. SETTING: Tertiary adult intensive care unit in a university teaching hospital. PATIENTS: Five patients with acute respiratory distress syndrome. INTERVENTIONS: Percutaneous dilational tracheostomy during high-frequency oscillatory ventilation. MEASUREMENTS AND MAIN RESULTS: Percutaneous dilational tracheostomy was safely performed on all five patients. Hemodynamic and respiratory variables remained stable during the procedure. No complications were attributable to either the percutaneous dilational tracheostomy or high-frequency oscillatory ventilation. CONCLUSIONS: Percutaneous dilational tracheostomy can be safely performed on patients with acute respiratory distress syndrome during high-frequency oscillatory ventilation.

Clinically practical blood volume assessment with fluorescein-labeled HES.

BACKGROUND: Standard techniques for measuring blood volume (BV) entail administering radioactivity and human albumin. This is laborious, expensive, and impractical in acute settings. An alternative method suitable for widespread routine application was assessed. STUDY DESIGN AND METHODS: Seventy-nine ambulant outpatients and 18 intensive care unit (ICU) patients were prospectively recruited. Measurements of RBC volume (RCV) and plasma volume (PV) were performed with radiochromium-labeled RBCs (51Cr), radioiodinated albumin (125I), and fluorescein-labeled HES (FITC-HES). Small molecules overestimate PV because of vascular endothelial dysfunction (ED) and increased capillary permeability; a reference value for PV was therefore derived with the RCV and Hct. RESULTS: Mean PV with 125I dilution was 230 mL (SD, 185 mL) greater than that with FITC-HES in outpatients. This difference was more exaggerated, 345 mL (SD, 371 mL), in ICU patients likely to have ED. Both the PV measured with FITC-HES and the 125I dilution correlated closely with the PV derived with RCV and Hct (r = 0.950 and 0.925, respectively) in the ICU patients. CONCLUSION: FITC-HES estimates PV more accurately than 125I. FITC-HES should replace radioactive tracers for assessing BV. Comparing the estimates of PV with molecules of differing molecular weights may have clinical utility as an indicator of ED.