Hypoxemic Respiratory Failure Research Articles

Time to split: biomarker trajectories in pediatric acute respiratory distress syndrome hint at underlying disease.

Pediatric acute respiratory distress syndrome (ARDS) is severe, noncardiac hypoxemic respiratory failure that carries a substantial risk of death. Given the complexity of this clinically defined syndrome and the repeated failure of therapeutic trials, there has been an effort to identify subphenotypes of ARDS that may share targetable mechanisms of disease. In this issue of the JCI, Yehya and colleagues measured 19 plasma biomarkers in 279 children over the first seven days of ARDS. Increases in select tissue injury makers and inflammatory cytokines in peripheral blood were associated with multiple organ dysfunction syndrome and death, but not persistent ARDS. These findings argue that splitting patients by clinical and molecular phenotype may be more informative than lumping them under the umbrella diagnosis of ARDS. However, future studies are needed to determine whether these plasma factors represent targetable pathways in lung injury or are a consequence of systemic organ dysfunction.

Dysregulated Coagulation and Fibrinolysis Are Present in Patients Admitted to the Emergency Department with Acute Hypoxemic Respiratory Failure: A Prospective Study

Acute hypoxemic respiratory failure (AHRF) is defined as acute and progressive, and patients are at a greater risk of developing acute respiratory distress syndrome (ARDS). Until now, most studies have focused on prognostic and diagnostic biomarkers in ARDS. Since there is evidence supporting a connection between dysregulated coagulant and fibrinolytic pathways in ARDS progression, it is plausible that this dysregulation also exists in AHRF. The aim of this study was to explore whether levels of soluble endothelial protein C receptor (sEPCR) and plasminogen differentiate patients admitted to the emergency department (ED) with AHRF. sEPCR and plasminogen levels were measured in 130 AHRF patients upon ED presentation by ELISA. Our results demonstrated that patients presenting to the ED with AHRF had elevated levels of sEPCR and plasminogen. It seems that dysregulation of coagulation and fibrinolysis occur in the early stages of respiratory failure requiring hospitalisation. Further research is needed to fully comprehend the contribution of sEPCR and plasminogen in AHRF.

HACOR score to predict NIV failure in patients with COVID-related hypoxemic respiratory failure managed in the ordinary ward and in the critical care setting.

We evaluated the prevalence of non-invasive ventilation (NIV) failure among patients with COVID-19-related pneumonia, managed in the ordinary ward and in the HDU/ICU and we tested the prognostic role of the HACOR score in those different settings. This is a retrospective study, conducted in the University-Hospital Careggi. We included all subjects with COVID-19 and ARF requiring NIV between March 2020 and May 2021, respectively managed in the ordinary ward (G1) and in the critical care setting (G2). Clinical parameters, HACOR and SOFA score were evaluated at Day 0 and after 1, 2 and 5days of treatment. The primary outcome was NIV failure. 13% G1 patients and 40% G2 patients underwent endotracheal intubation (ETI). NIV was successful in 60% G1 AND 43% G2 patients (p < 0.001). In G1, compared to those with successful NIV, patients who underwent ETI, had a higher HACOR since the baseline evaluation (T0: 6 [5-6] vs 5 [3-6]; T1: 6 [5-6] vs 5 [3-6], all p < 0.05). An HACOR score > 5 was associated with an increased prevalence of ETI independent to an advanced age and a SOFA score > 5 both in G1 (T1: RR 4.87, 95% CI 1.462-16.275; T5: 3.630, 95% CI 0.979-13.462) and G2 (T0: 1.76, 95% CI 0.906-3.422; T1: 3.38, 95% CI 1.386-8.265). Among patients with COVID-related-ARF, NIV could be managed in the ordinary ward in a consistent proportion of patients and, among them, an HACOR score > 5 was independently associated with increased NIV failure from the earliest evaluations.

PaCO2 is nonlinearly associated with NIV failure in patients with hypoxemic respiratory failure

ObjectiveTo explore the association between PaCO2 and noninvasive ventilation (NIV) failure in patients with hypoxemic respiratory failure.MethodsA retrospective study was performed in a respiratory ICU of a teaching hospital. Patients admitted to ICU between 2011 and 2019 were screened. We enrolled the patients with hypoxemic respiratory failure. However, patients who used NIV due to acute-on-chronic respiratory failure or heart failure were excluded. Data before the use of NIV were collected. Requirement of intubation was defined as NIV failure.ResultsA total of 1029 patients were enrolled in final analysis. The rate of NIV failure was 45% (461/1029). A nonlinear relationship between PaCO2 and NIV failure was found by restricted cubic splines (p = 0.03). The inflection point was 32 mmHg. The rate of NIV failure was 42% (224/535) in patients with PaCO2 >32 mmHg. However, it increased to 48% (237/494) in those with PaCO2 ≤ 32 mmHg. The crude and adjusted hazard ratio (HR) for NIV failure was 1.36 (95%CI:1.13–1.64) and 1.23(1.01–1.49), respectively, if the patients with PaCO2 >32 mmHg were set as reference. In patients with PaCO2 ≤ 32 mmHg, one unit increment of PaCO2 was associated with 5% reduction of NIV failure. However, it did not associate with NIV failure in patients with PaCO2 >32 mmHg.ConclusionsPaCO2 and NIV failure was nonlinear relationship. The inflection point was 32 mmHg. Below the inflection point, lower PaCO2 was associated with higher NIV failure. However, it did not associate with NIV failure above this point.

Effect of immediate initiation of invasive ventilation on mortality in acute hypoxemic respiratory failure: a target trial emulation

PurposeInvasive ventilation is a fundamental treatment in intensive care but its precise timing is difficult to determine. This study aims at assessing the effect of initiating invasive ventilation versus waiting, in patients with hypoxemic respiratory failure without immediate reason for intubation on one-year mortality.MethodsEmulation of a target trial to estimate the benefit of immediately initiating invasive ventilation in hypoxemic respiratory failure, versus waiting, among patients within the first 48-h of hypoxemia. The eligible population included non-intubated patients with SpO2/FiO2 ≤ 200 and SpO2 ≤ 97%. The target trial was emulated using a single-center database (MIMIC-IV) which contains granular information about clinical status. The hourly probability to receive mechanical ventilation was continuously estimated. The hazard ratios for the primary outcome, one-year mortality, and the secondary outcome, 30-day mortality, were estimated using weighted Cox models with stabilized inverse probability weights used to adjust for measured confounding.Results2996 Patients fulfilled the inclusion criteria of whom 792 were intubated within 48 h. Among the non-invasive support devices, the use of oxygen through facemask was the most common (75%). Compared to patients with the same probability of intubation but who were not intubated, intubation decreased the hazard of dying for the first year after ICU admission HR 0.81 (95% CI 0.68–0.96, p = 0.018). Intubation was associated with a 30-day mortality HR of 0.80 (95% CI 0.64–0.99, p = 0.046).ConclusionThe initiation of mechanical ventilation in patients with acute hypoxemic respiratory failure reduced the hazard of dying in this emulation of a target trial.

First-year outcomes of very low birth weight preterm singleton infants with hypoxemic respiratory failure treated with milrinone and inhaled nitric oxide (iNO) compared to iNO alone: A nationwide retrospective study.

Inhaled nitric oxide (iNO) has a beneficial effect on hypoxemic respiratory failure. The increased use of concurrent iNO and milrinone was observed. We aimed to report the trends of iNO use in the past 15 years in Taiwan and compare the first-year outcomes of combining iNO and milrinone to the iNO alone in very low birth weight preterm (VLBWP) infants under mechanical ventilation. This nationwide cohort study enrolled preterm singleton infants with birth weight <1500g treated with iNO from 2004 to 2019. Infants were divided into two groups, with a combination of intravenous milrinone (Group 2, n = 166) and without milrinone (Group 1, n = 591). After propensity score matching (PSM), each group's sample size is 124. The primary outcomes were all-cause mortality and the respiratory condition, including ventilator use and duration. The secondary outcomes were preterm morbidities within one year after birth. After PSM, more infants in Group 2 needed inotropes. The mortality rate was significantly higher in Group 2 than in Group 1 from one month after birth till 1 year of age (55.1% vs. 13.5%) with the adjusted hazard ratio of 4.25 (95%CI = 2.42-7.47, p <0.001). For infants who died before 36 weeks of postmenstrual age (PMA), Group 2 had longer hospital stays compared to Group 1. For infants who survived after 36 weeks PMA, the incidence of moderate and severe bronchopulmonary dysplasia (BPD) was significantly higher in Group 2 than in Group 1. For infants who survived until one year of age, the incidence of pneumonia was significantly higher in Group 2 (28.30%) compared to Group 1 (12.62%) (p = 0.0153). Combined treatment of iNO and milrinone is increasingly applied in VLBWP infants in Taiwan. This retrospective study did not support the benefits of combining iNO and milrinone on one-year survival and BPD prevention. A future prospective study is warranted.

High-Flow Nasal Cannula Versus Noninvasive Ventilation as Initial Treatment in Acute Hypoxia: A Propensity Score-Matched Study.

Patients presenting to the emergency department (ED) with hypoxemia often have mixed or uncertain causes of respiratory failure. The optimal treatment for such patients is unclear. Both high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) are used. We sought to compare the effectiveness of initial treatment with HFNC versus NIV for acute hypoxemic respiratory failure. We conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with HFNC or NIV within 24 hours of arrival to the University of Michigan adult ED from January 2018 to December 2022. We matched patients 1:1 using a propensity score for odds of receiving NIV. The primary outcome was major adverse pulmonary events (28-d mortality, ventilator-free days, noninvasive respiratory support hours) calculated using a win ratio. A total of 1154 patients were included. Seven hundred twenty-six (62.9%) received HFNC and 428 (37.1%) received NIV. We propensity score matched 668 of 1154 (57.9%) patients. Patients on NIV versus HFNC had lower 28-day mortality (16.5% vs. 23.4%, p = 0.033) and required noninvasive treatment for fewer hours (median 7.5 vs. 13.5, p < 0.001), but had no difference in ventilator-free days (median [interquartile range]: 28 [26, 28] vs. 28 [10.5, 28], p = 0.199). Win ratio for composite major adverse pulmonary events favored NIV (1.38; 95% CI, 1.15-1.65; p < 0.001). In this observational study of patients with acute hypoxemic respiratory failure, initial treatment with NIV compared with HFNC was associated with lower mortality and fewer composite major pulmonary adverse events calculated using a win ratio. These findings underscore the need for randomized controlled trials to further understand the impact of noninvasive respiratory support strategies.

The utility of the respiratory rate-oxygenation index as a predictor of treatment response in dogs receiving high-flow nasal cannula oxygen therapy

ObjectiveThis study aims to evaluate the respiratory rate-oxygenation index (ROX) and the ratio of pulse oximetry saturation (SpO2) to the fraction of inspired oxygen (FiO2) (SpO2/FiO2, [SF]) to determine whether these indices are predictive of outcome in dogs receiving high-flow nasal cannula oxygen therapy (HFNOT).DesignThis is a prospective observational study.SettingThis study was carried out at two university teaching hospitals.AnimalsIn total, 88 dogs treated with HFNOT for hypoxemic respiratory failure due to various pulmonary diseases were selected.Measurements and main resultsThe ROX index was defined as the SF divided by the respiratory rate (RR). ROX and SF were calculated at baseline and for each hour of HFNOT. The overall success rate of HFNOT was 38% (N = 33/88). Variables predicting HFNOT success were determined using logistic regression, and the predictive power of each variable was assessed using the area under the receiver operating curve (AUC). ROX and SF were adequately predictive of HFNOT success when averaged over 0–16 h of treatment, with similar AUCs of 0.72 (95% confidence interval [CI] 0.60–0.83) and 0.77 (95% CI 0.66–0.87), respectively (p &amp;lt; 0.05). SF showed acceptable discriminatory power in predicting HFNOT outcome at 7 h, with an AUC of 0.77 (95% CI 0.61–0.93, p = 0.013), and the optimal cutoff for predicting HFNC failure at 7 h was SF ≤ 191 (sensitivity 83% and specificity 76%).ConclusionThese indices were easily obtained in dogs undergoing HFNOT. The results suggest that ROX and SF may have clinical utility in predicting the outcomes of dogs on HFNOT. Future studies are warranted to confirm these findings in a larger number of dogs in specific disease populations.

Personalized mechanical ventilation guided by ultrasound in patients with acute respiratory distress syndrome (PEGASUS): study protocol for an international randomized clinical trial

BackgroundAcute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on “focal” or “non-focal” lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish “focal” from “non-focal” lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation.MethodsThe Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as “focal” or “non-focal”. Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for “non-focal” ARDS and lower PEEP and prone positioning for “focal” ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated.DiscussionPEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach.Trial registrationThe PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344).

Retrospective evaluation of the respiratory rate-oxygenation index to predict the outcome of high-flow nasal cannula oxygen therapy in dogs (2018-2021): 81 cases.

To evaluate the respiratory rate-oxygenation index (ROX), modified ROX index (ROX-HR), and the ratio of pulse oximetry saturation (Spo2) to Fio2 (SF) to determine if these indices over time are predictive of outcome in dogs treated with high-flow nasal cannula oxygen therapy (HFNC). Retrospective study. Two university teaching hospitals. Eighty-one client-owned dogs treated with HFNC for hypoxemic respiratory failure. None. The ROX was defined as the SF divided by the respiratory rate (RR), and the ROX-HR was defined as the ROX divided by the heart rate multiplied by 100. The overall success rate of HFNC was 44% (n=36/81). Dogs weaned from HFNC had a significantly higher ROX (P<0.0001) at 1-3, 5-10, 12, and 15hours than dogs that failed HFNC. Both the ROX and SF showed excellent discriminatory power in predicting HFNC failure at 6hours, with an area under receiver operating curve of 0.85 (95% confidence interval: 0.72-0.99; P<0.002) and 0.86 (95% confidence interval: 0.73-0.99; P<0.001), respectively. The optimal cutoff values for predicting HFNC failure at 6hours were a ROX ≤3.68 (sensitivity 72%, specificity 92%) and an SF ≤143 (sensitivity 79%, specificity 93%). These results suggest that similar to people, the ROX and SF are useful predictors of HFNC failure. These indices are easy to measure at the bedside and may have clinical use. Future prospective studies are warranted to confirm the findings and to optimize cutoff values in a larger population of dogs undergoing HFNC.

Abstract PO1-05-04: CDK4/6 inhibitor-induced Interstitial Lung Disease (ILD) - A Case Series

Abstract Introduction: CDK4/6 inhibitors interrupt cell cycle by inhibiting intracellular and hormonal signals responsible for proliferation of malignant cells, making them an effective treatment for patients with HR+ advanced breast cancer. Pre-clinical data demonstrates that CDK4/6 inhibitors allow for inflammatory cell recruitment, inducing pulmonary inflammation and thereby increasing the risk of ILD. The overall risk of ILD was 1.6% in a meta-analysis of over 16,000 patients treated with CDK4/6 inhibitors while individual reported risk was 1%, 1.6% and 3% for palbociclib, ribociclib, and abemaciclib respectively. Objective: The aim of this case series is to add to the body of literature about this rare but possibly serious side effect of CDK4/6 inhibitor associated ILD. Early detection and prompt management are essential for improved patient outcomes. Case 1 A 61 year-old female was diagnosed with metastatic breast cancer to brain and bones after being admitted for evaluation of acute vision loss. She started on palbociclib and letrozole and subsequently had 2 hospitalizations for acute hypoxemic respiratory failure with unremarkable infectious workup. CT scan was significant for bilateral pulmonary infiltrates raising suspicion for CDK4/6 inhibitor-induced pneumonitis; subsequently palbociclib was discontinued and the patient was started on steroid taper resulting in improvement of her respiratory status. Case 2 A 71 year-old female with a remote history of left breast cancer and sarcoidosis presented with respiratory symptoms. She was found to have metastatic breast cancer with CT scan revealing hilar and mediastinal adenopathy. The patient initially received taxol with near resolution of disease on imaging. The patient was subsequently started on palbociclib + letrozole. After 9 months of treatment, the patient was admitted for pneumonia and discharged home with oxygen. PFTs at the time were suggestive of restrictive pathology related to obesity hypoventilation. Six months later, the patient was admitted for worsening respiratory failure; CT scan revealed interstitial changes likely due to multifactorial etiologies including palbociclib-induced pneumonitis. The patient subsequently passed away. Case 3 An 81 year-old female diagnosed with remote history of L. breast cancer presented with shortness of breath and weakness. CT scan revealed a nodule and lymphadenopathy; biopsy of nodule was consistent with breast primary. The patient was initially started on ribociclib which was discontinued after 4 cycles due to transaminitis. She was switched to palbociclib, however 2 months after initiation, the patient presented with flu-like symptoms. CT revealed scattered subpleural ground-glass opacities. Infectious workup was negative; pulmonary consultation believed this was likely due to drug-induced pneumonitis and palbociclib was discontinued and she was treated with a steroid taper. Patient was switched to fulvestrant; and after 9 months she was diagnosed with stage IV tongue cancer and her breast cancer therapy was discontinued. Discussion CDK4/6 inhibitors have improved survival in patients with metastatic breast cancer, however they are associated with rare but serious adverse effects like ILD. ILD is a challenging clinical diagnosis as it refers to a cluster of disorders of varying presentation and pathophysiology, and as a result can be missed. Conclusion This case series demonstrates that CDK4/6 inhibitor-associated ILD may be more prevalent than originally reported. It is important to identify early by performing a thorough workup, including a detailed history and physical exam, medication list review, infectious work-up, chest imaging, PFTs and pulmonology consultation. Publishing a set of standardized guidelines to diagnose and treat CDK4/6 inhibitor-induced ILD is necessary as more cases are identified. Citation Format: Ami Chitalia, Krishna Shah. CDK4/6 inhibitor-induced Interstitial Lung Disease (ILD) - A Case Series [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-04.

Designing a Bayesian adaptive clinical trial to evaluate novel mechanical ventilation strategies in acute respiratory failure using integrated nested Laplace approximations

BackgroundAdaptive trials usually require simulations to determine values for design parameters, demonstrate error rates, and establish the sample size. We designed a Bayesian adaptive trial comparing ventilation strategies for patients with acute hypoxemic respiratory failure using simulations. The complexity of the analysis would usually require computationally expensive Markov Chain Monte Carlo methods but this barrier to simulation was overcome using the Integrated Nested Laplace Approximations (INLA) algorithm to provide fast, approximate Bayesian inference. MethodsWe simulated two-arm Bayesian adaptive trials with equal randomization that stratified participants into two disease severity states. The analysis used a proportional odds model, fit using INLA. Trials were stopped based on pre-specified posterior probability thresholds for superiority or futility, separately for each state. We calculated the type I error and power across 64 scenarios that varied the probability thresholds and the initial minimum sample size before commencing adaptive analyses. Two designs that maintained a type I error below 5%, a power above 80%, and a feasible mean sample size were evaluated further to determine the optimal design. ResultsPower generally increased as the initial sample size and the futility threshold increased. The chosen design had an initial recruitment of 500 and a superiority threshold of 0.9925, and futility threshold of 0.95. It maintained high power and was likely to reach a conclusion before exceeding a feasible sample size. ConclusionsWe designed a Bayesian adaptive trial to evaluate novel strategies for ventilation using the INLA algorithm to efficiently evaluate a wide range of designs through simulation.

The Synthetic Surfactant CHF5633 Restores Lung Function and Lung Architecture in Severe Acute Respiratory Distress SyndromeinAdult Rabbits.

Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants. This study aimed to investigate the activity in vitro and the bolus effect (200mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP-B and SP-C, or natural surfactant Poractant alfa (Curosurf®, both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressurearterial oxygen and fractionof inspired oxygen, P/F ratio ≤ 13.3kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated. Both surfactant preparationsyielded comparable improvements in lung function parameters,reductions inlung injuryscore, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls. This study indicates that surfactant replacement therapy with CHF5633 improves lung function andlung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects.

The role of electrical impedance tomography in predicting the failure of non-invasive ventilation in patients with COVID-19-associated hypoxemic acute respiratory failure: a prospective observational study

INTRODUCTION: Data on prediction of the failure of non-invasive lung ventilation (NIV) in patients with respiratory failure associated with COVID-19, based on electrical impedance tomography (EIT) patterns are limited. OBJECTIVE: To identify predictors of non-invasive lung ventilation failure in patients with respiratory insufficiency associated with COVID-19, using electrical impedance tomography data. MATERIALS AND METHODS: A monocenter prospective cohort observational study was conducted in patients with moderate-to-severe COVID-19-associated acute respiratory failure, who underwent NIV in the ICU (n = 43). EIT was used to measure the actual ventilation area (SVENT), hyperinflation area (SHYPER), ventilation delay zone (SRVD), and calculate the proportion of ventilated lungs (AVENT), proportion of hyperinflation area (ZHYPER), proportion of RVD area (ZRVD), as well as the duration of hyperinflation during one respiratory cycle (THYPER), and the ratio of hyperinflation time to inhalation time. RESULTS: The study included 43 patients admitted 15 (10–22) days after the onset of COVID-19. Patients with NIV failure (n = 34) had higher ZHYPER values on the first day (19.5 (16.3–30.5) in the NIV success group and 35.2 (25.0–45.0) in the failure group, AUROC 0.80, p = 0.004, Cut-off 39.7, Se 85 %, Sp 89 %) and the last day (20.6 (10.4–28.5) in the success group and 32.7 (26.4–43.3) in the failure group, AUROC 0.92, p = 0.003, Cut-off 32.7, Se 50 %, Sp 100 %), as well as a higher THYPER/TINSP ratio on the last day of NIV (37.5 (31.0–47.9) in the success group and 65.3 (43.7–88.4) in the failure group, AUROC 0.87, p = 0.001, Cut-off 52.7, Se 71 %, Sp 100 %). AVENT, ZRVD, and inhalation time did not show prognostic significance. CONCLUSIONS: EIT can predict the NIV failure in moderate-to-severe ARDS associated with COVID-19, based on the assessment of alveolar overdistention zones. Further research are needed to investigate this theory.

Using the ROX Index to Predict Treatment Outcome for High-Flow Nasal Cannula and/or Noninvasive Ventilation in Patients With COPD Exacerbations.

The ratio of oxygen saturation index (ROX index; or SpO2 /FIO2 /breathing frequency) has been shown to predict risk of intubation after high-flow nasal cannula (HFNC) support among adults with acute hypoxemic respiratory failure primarily due to pneumonia. However, its predictive value for other subtypes of respiratory failure is unknown. This study investigated whether the ROX index predicts liberation from HFNC or noninvasive ventilation (NIV), intubation with mechanical ventilation, or death in adults admitted for respiratory failure due to an exacerbation of COPD. We performed a retrospective study of 260 adults hospitalized with a COPD exacerbation and treated with HFNC and/or NIV (continuous or bi-level). ROX index scores were collected at treatment initiation and predefined time intervals throughout HFNC and/or NIV treatment or until the subject was intubated or died. A ROX index score of ≥ 4.88 was applied to the cohort to determine if the same score would perform similarly in this different cohort. Accuracy of the ROX index was determined by calculating the area under the receiver operator curve. A total of 47 subjects (18%) required invasive mechanical ventilation or died while on HFNC/NIV. The ROX index at treatment initiation, 1 h, and 6 h demonstrated the best prediction accuracy for avoidance of invasive mechanical ventilation or death (area under the receiver operator curve 0.73 [95% CI 0.66-0.80], 0.72 [95% CI 0.65-0.79], and 0.72 [95% CI 0.63-0.82], respectively). The optimal cutoff value for sensitivity (Sn) and specificity (Sp) was a ROX index score > 6.88 (sensitivity 62%, specificity 57%). The ROX index applied to adults with COPD exacerbations treated with HFNC and/or NIV required higher scores to achieve similar prediction of low risk of treatment failure when compared to subjects with hypoxemic respiratory failure/pneumonia. ROX scores < 4.88 did not accurately predict intubation or death.

Case study observational research: inflammatory cytokines in the bronchial epithelial lining fluid of COVID-19 patients with acute hypoxemic respiratory failure

BackgroundIn this study, the concentrations of inflammatory cytokines were measured in the bronchial epithelial lining fluid (ELF) and plasma in patients with acute hypoxemic respiratory failure (AHRF) secondary to severe coronavirus disease 2019 (COVID-19).MethodsWe comprehensively analyzed the concentrations of 25 cytokines in the ELF and plasma of 27 COVID-19 AHRF patients. ELF was collected using the bronchial microsampling method through an endotracheal tube just after patients were intubated for mechanical ventilation.ResultsCompared with those in healthy volunteers, the concentrations of interleukin (IL)-6 (median 27.6 pmol/L), IL-8 (1045.1 pmol/L), IL-17A (0.8 pmol/L), IL-25 (1.5 pmol/L), and IL-31 (42.3 pmol/L) were significantly greater in the ELF of COVID-19 patients than in that of volunteers. The concentrations of MCP-1 and MIP-1β were significantly greater in the plasma of COVID-19 patients than in that of volunteers. The ELF/plasma ratio of IL-8 was the highest among the 25 cytokines, with a median of 737, and the ELF/plasma ratio of IL-6 (median: 218), IL-1β (202), IL-31 (169), MCP-1 (81), MIP-1β (55), and TNF-α (47) were lower.ConclusionsThe ELF concentrations of IL-6, IL-8, IL-17A, IL-25, and IL-31 were significantly increased in COVID-19 patients. Although high levels of MIP-1 and MIP-1β were also detected in the blood samples collected simultaneously with the ELF samples, the results indicated that lung inflammation was highly compartmentalized. Our study demonstrated that a comprehensive analysis of cytokines in the ELF is a feasible approach for understanding lung inflammation and systemic interactions in patients with severe pneumonia.

Transbronchial Lung Cryobiopsies, Transbronchial Forceps Lung Biopsies, and Surgical Lung Biopsies in Mechanically Ventilated Patients with Acute Hypoxemic Respiratory Failure: A Retrospective Cohort Study.

Lung biopsies are sometimes performed in mechanically ventilated patients with acute hypoxemic respiratory failure (AHRF) of unknown etiology to guide patient management. While surgical lung biopsies (SLB) offer high diagnostic rates, they may also cause significant complications. Transbronchial forceps lung biopsies (TBLB) are less invasive but often produce non-contributive specimens. Transbronchial lung cryobiopsies (TBLC) yield specimens of potentially better quality than TBLB, but due to their novel implementation in the intensive care unit (ICU), their accuracy and safety are still unclear. Our main objective was to evaluate the risk of adverse events in patients with AHRF following the three biopsy techniques. Our secondary objectives were to assess the diagnostic yield and associated modifications of patient management of each technique. We conducted a retrospective cohort study comparing TBLC, TBLB, and SLB in mechanically ventilated patients with AHRF. The primary outcome was the proportion of patients with at least one complication, and secondary outcomes included complication rates, diagnostic yields, treatment modifications, and mortality. Of the 26 patients who underwent lung biopsies from 2018 to 2022, all TBLC and SLB patients and 60% of TBLB patients had at least one complication. TBLC patients had higher unadjusted numbers of total and severe complications, but also worse Sequential Organ Failure Assessment scores and P/F ratios. A total of 25 biopsies (25/26, 96%) provided histopathological diagnoses, 88% (22/25) of which contributed to patient management. ICU mortality was high for all modalities (63% for TBLC, 60% for TBLB and 50% for SLB). All biopsy methods had high diagnostic yields and the great majority contributed to patient management; however, complication rates were elevated. Further research is needed to determine which patients may benefit from lung biopsies and to determine the best biopsy modality.

The effect of immunosuppressive therapies on the endothelial host response in critically ill COVID-19 patients

While several effective therapies for critically ill patients with COVID-19 have been identified in large, well-conducted trials, the mechanisms underlying these therapies have not been investigated in depth. Our aim is to investigate the association between various immunosuppressive therapies (corticosteroids, tocilizumab and anakinra) and the change in endothelial host response over time in critically ill COVID-19 patients. We conducted a pre-specified multicenter post-hoc analysis in a Dutch cohort of COVID-19 patients admitted to the ICU between March 2020 and September 2021 due to hypoxemic respiratory failure. A panel of 18 immune response biomarkers in the complement, coagulation and endothelial function domains were measured using ELISA or Luminex. Biomarkers were measured on day 0–1, day 2–4 and day 6–8 after start of COVID-19 treatment. Patients were categorized into four treatment groups: no immunomodulatory treatment, corticosteroids, anakinra plus corticosteroids, or tocilizumab plus corticosteroids. The association between treatment group and the change in concentrations of biomarkers was estimated with linear mixed-effects models, using no immunomodulatory treatment as reference group. 109 patients with a median age of 62 years [IQR 54–70] of whom 72% (n = 78) was male, were included in this analysis. Both anakinra plus corticosteroids (n = 22) and tocilizumab plus corticosteroids (n = 38) were associated with an increase in angiopoietin-1 compared to no immune modulator (n = 23) (beta of 0.033 [0.002–0.064] and 0.041 [0.013–0.070] per day, respectively). These treatments, as well as corticosteroids alone (n = 26), were further associated with a decrease in the ratio of angiopoietin-2/angiopoietin-1 (beta of 0.071 [0.034–0.107], 0.060 [0.030–0.091] and 0.043 [0.001–0.085] per day, respectively). Anakinra plus corticosteroids and tocilizumab plus corticosteroids were associated with a decrease in concentrations of complement complex 5b-9 compared to no immunomodulatory treatment (0.038 [0.006–0.071] and 0.023 [0.000–0.047], respectively). Currently established treatments for critically ill COVID-19 patients are associated with a change in biomarkers of the angiopoietin and complement pathways, possibly indicating a role for stability of the endothelium. These results increase the understanding of the mechanisms of interventions and are possibly useful for stratification of patients with other inflammatory conditions which may potentially benefit from these treatments.

Severe pulmonary hypertension and circulatory failure associated with Congenital syphilis. Case report.

Congenital syphilis is a vertical infection caused by Treponema pallidum. Despite the implementation of preventive strategies during pregnancy, its incidence is increasing, and it constitutes an important public health problem. Most patients with congenital syphilis are asymptomatic; however, a small group may develop severe disease at birth with the need of advanced resuscitation in the delivery room, acute hypoxemic respiratory failure, and hemodynamic instability. Therefore, awareness is needed. This series describes the clinical course of two late preterm infants with congenital syphilis who developed acute hypoxemic respiratory failure, pulmonary hypertension, and circulatory collapse early after birth. Integrated hemodynamic evaluation with neonatologist-performed echocardiography (NPE) and therapeutic management is provided. A comprehensive hemodynamic evaluation including early and serial functional echocardiography in these patients is needed to address the underlying complex pathophysiology and to help to establish accurate treatment.

A randomised clinical trial of awake prone positioning in COVID-19 suspects with acute hypoxemic respiratory failure

BackgroundAwake prone position (APP) has been reported to improve oxygenation in patients with COVID-19 disease and to reduce the requirement for invasive mechanical ventilation for patients requiring support with high flow nasal cannula. There is conflicting data for patients requiring lower-level oxygen support. Research questionDoes APP reduce escalation of oxygen support in COVID-19 patients requiring supplementary oxygen?The primary outcome was defined as an escalation of oxygen support from simple supplementary oxygen (NP, HM, NRB) to NIV (CPAP or BiPAP), HFNC or IMV; OR from NIV (CPAP or BiPAP) or HFNC to IMV by day30. Study designTwo center, prospective, non-blind, randomised controlled trial. Patients with confirmed or suspected COVID-19 pneumonia requiring ≥ 5 liters/min oxygen to maintain saturations ≥ 94 % were randomised to either APP or control group. The APP group received a 3-h APP session three times per day for three days. ResultsBetween 9 May and July 13, 2021, 89 adults were screened and 61 enrolled, 31 to awake prone position and 30 controls. There was no difference in the primary outcome, 7 (22.6 %) patients randomised to APP and 9 (30.0 %) controls required escalation of oxygen support (OR 0.68 (0.22–2.14), P = 0.51). There were no differences in any secondary outcomes, in APP did not improve oxygenation. InterpretationIn COVID-19 patients, the use of APP did not prevent escalation of oxygen support from supplementary to invasive or non-invasive ventilation or improve patient respiratory physiology. Trial registrationNCT04853979 (clinicaltrials.gov).