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Oxygen delivery in critical care: can you have too much of a good thing?
Several trials assessing optimal oxygenation targets in critically ill patients have reported worse outcomes from hyperoxaemia, but the evidence is inconsistent. In a multicentre, randomised controlled trial which enrolled 400 critically ill patients with systemic inflammatory response syndrome, Gelissen et al (JAMA 2021;326:940) investigated whether a low-normal oxygenation target (PaO2 8–12 kPa, n=205) reduces organ dysfunction compared with a high-normal target (PaO2 14–18 kPa, n=195). In contrast to earlier work FiO2 was limited to 0.6 to prevent direct oxygen toxicity. The primary endpoint was the Sequential Organ Failure Assessment (SOFARANK), a measure of non-respiratory organ failure trajectory; for each patient, the non-respiratory components of the SOFA score, minus baseline SOFA score, were summed over the first 14 study days. Patients were ranked from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). There was a trend towards improved resolution of organ failure in the high-normal oxygenation group compared with the low-normal group (median SOFARANK −40 vs −35), but the difference was non-significant (median difference 10, 95% CI 0 to 21, p=0.06). There was also no significant difference in 90-day mortality, median duration of mechanical ventilation or other clinical outcome measures. Serious adverse events were similar between groups. The data do not demonstrate clear benefit of either a conservative or liberal approach to oxygen therapy in this clinical group and optimal oxygenation targets remain altogether unclear. This study does, however, open up an interesting discussion on use of novel surrogate endpoints in critical care trials.
Adjuvant icotinib in resected EGFR-mutant non-small-cell lung cancer: improved disease-free survival
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown efficacy in the adjuvant setting for patients with EGFR-mutant, non-small cell lung cancer (NSCLC); further data comparing effectiveness to standard chemotherapy is warranted. He et al (Lancet Respir Med 2021;9:1021) report the survival analysis from EVIDENCE, a randomised, open-label, phase III trial. A total of 322 treatment-naïve patients with EGFR-mutant, resected, stage II-IIIA NSCLC were randomly assigned (1:1) to receive either 2 years of icotinib (first generation EGFR-TKI) or four 21-day cycles of standard chemotherapy. Median disease-free survival was significantly longer in the icotinib group at 47 months (95% CI 36.4 to not reached) vs 22.1 months (95% CI 16.8 to 30.4) in the chemotherapy group (HR 0.36, 95% CI 0.24 to 0.55; p<0.0001). At 3 years, disease-free survival was 63.9% in the icotinib group compared with 32.5% of those who received chemotherapy. There was no significant difference noted in overall survival. Importantly, icotinib also had a better tolerability profile with fewer treatment-related serious adverse events (1%) compared with the chemotherapy group (14%). Despite these clinically meaningful results, longer follow-up is required to determine if the prolonged disease-free survival translates into significant overall survival.
Preventing Staphylococcus aureus ventilator-associated pneumonia: encouraging results from a pilot trial of suvratoxumab
Ventilator-associated pneumonia (VAP) remains a common cause of morbidity and mortality within critical care. Preventative antibiotics are not recommended due to potential resistance but monoclonal antibodies (mAb) targeting pathogen-specific virulence factors are a novel prophylactic strategy. François et al (Lancet Infectious Diseases 2021;21:1313) investigated the safety and efficacy of suvratoxumab, a mAb targeting the alpha toxin of S.aureus, in reducing the 30-day incidence of Staphylococcus aureus VAP. SAATELLITE was a phase 2, multicentre, double-blind, clinical trial which randomised 213 patients on mechanical ventilation who had quantitative PCR-confirmed S. aureus colonisation of the lower respiratory tract and no diagnosis of pneumonia or S. aureus infection, to receive a single intravenous infusion of either suvratoxumab 2000 mg (enrolment discontinued after 1 year due to low serum exposure), suvratoxumab 5000 mg (n=96) or placebo (n=100). At 30 days post-treatment, the incidence of S.aureus VAP was not significantly different between the suvratoxumab 5000 mg (18%) and placebo groups (26%) (p=0.17). Compared with the placebo group, suvratoxumab 5000 mg was associated with a reduced incidence of S. aureus pneumonia in patients ≤65 years according to prespecified subgroup analysis Relative risk reduction(RRR) 47.4% (90% CI 3.5% to 71.4%); p=0.075), and in patients with a low S. aureus colonisation load according to post hoc analysis (RRR 66.7% (90% CI 21.3% to 86.2%); p=0.069). Treatment-emergent adverse events were similar between groups. Serious adverse events were more common in the suvratoxumab 5000 mg group but no specific event appeared to contribute to the difference. This study highlights the feasibility of a preventive VAP strategy based on rapid detection of S. aureus colonisation. However, larger efficacy studies are warranted, particularly to identify optimal treatment targets.
Physician-assigned diagnosis and severity of asthma, COPD and overlap: limited value in differentiating clinically important phenotypes
Diagnostic criteria for Chronic obstructive pulmonary disease (COPD), asthma and overlap syndrome used in clinical practice and clinical trials varies considerably leading to difficulty in moving towards personalised medicine. Reddel et al (Eur Respir J 2021;58:2003927) report the initial results of NOVELTY, a global, 3-year prospective observational study which enrolled 11 243 patients based on a physician-assigned diagnosis of asthma (52.8%), COPD (34.8%) or both (12.4%), with no diagnostic criteria specified. Patients were further stratified based on physician-assessed severity (mild, moderate, severe) again without using objective parameters. Marked heterogeneity within and overlapping distributions between groups was observed for symptoms, spirometry and health status. Only 63.9% of those with COPD but almost one-quarter (23.2%) of those with asthma had persistent airflow limitation (postbronchodilator FEV1/FVC<lower limit of normal). Bronchodilator reversibility (FEV1 increase ≥200 mL and ≥12%) was comparable across all diagnoses (asthma 15.9%, overlap 19.1%, COPD 13.1%). Furthermore, many of those with mild COPD had a postbronchodilator FEV1 <80% predicted, highlighting a discrepancy between physician assessment and GOLD classifications. In addition to poor lung function in some with physician-assigned mild disease, 24.3%, 37.4% and 20.4% with mild asthma, overlap and COPD, respectively, reported ≥1 exacerbation in the previous 12 months. The study highlights that there remains significant disparity between patient reported and physician assessed severity which may impact on management decisions and highlights the limited insights of current diagnostic and severity classifications in differentiating clinical phenotypes in these heterogeneous conditions. To advance personalised medicine and improve outcomes, new classifications based on identification of distinct clinical phenotypes and molecular endotypes are required.
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Footnotes
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.