Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: As of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia. TRIAL DESIGN: Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial. PARTICIPANTS: Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients' participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days. INTERVENTION AND COMPARATOR: Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., 'negative' or 'positive' event). Participants who are officially discharged from hospital care will no longer receive study medication. MAIN OUTCOMES: Primary study endpoint: The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected. RANDOMIZATION: Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacydata, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients). Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1). TRIAL STATUS: The current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021. TRIAL REGISTRATION: The trial was registered before trial start in trial registries: EudraCT , No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Development of an Accurate Bedside Swallowing Evaluation Decision Tree Algorithm for Detecting Aspiration in Acute Respiratory Failure Survivors.

BACKGROUND: The bedside swallowing evaluation (BSE) is an assessment of swallowing function and airway safety during swallowing. After extubation, the BSE often is used to identify the risk of aspiration in acute respiratory failure (ARF) survivors. RESEARCH QUESTION: We conducted a multicenter prospective study of ARF survivors to determine the accuracy of the BSE and to develop a decision tree algorithm to identify aspiration risk. STUDY DESIGN AND METHODS: Patients extubated after ≥ 48 hours of mechanical ventilation were eligible. Study procedures included the BSE followed by a gold standard evaluation, the flexible endoscopic evaluation of swallowing (FEES). RESULTS: Overall, 213 patients were included in the final analysis. Median time from extubation to BSE was 25 hours (interquartile range, 21-45 hours). The FEES was completed 1 hour after the BSE (interquartile range, 0.5-2 hours). A total of 33% (70/213; 95% CI, 26.6%-39.2%) of patients aspirated on at least one FEES bolus consistency test. Thin liquids were the most commonly aspirated consistency: 27% (54/197; 95% CI, 21%-34%). The BSE detected any aspiration with an accuracy of 52% (95% CI, 45%-58%), a sensitivity of 83% (95% CI, 74%-92%), and negative predictive value (NPV) of 81% (95% CI, 72%-91%). Using recursive partitioning analyses, a five-variable BSE-based decision tree algorithm was developed that improved the detection of aspiration with an accuracy of 81% (95% CI, 75%-87%), sensitivity of 95% (95% CI, 90%-98%), and NPV of 97% (95% CI, 95%-99%). INTERPRETATION: The BSE demonstrates variable accuracy to identify patients at high risk for aspiration. Our decision tree algorithm may enhance the BSE and may be used to identify patients at high risk for aspiration, yet requires further validation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02363686; URL: www.clinicaltrials.gov.

A Randomized Trial of Initiation of Chronic Noninvasive Mechanical Ventilation at Home vs In-Hospital in Patients With Neuromuscular Disease and Thoracic Cage Disorder: The Dutch Homerun Trial.

BACKGROUND: There is an increasing demand for home mechanical ventilation (HMV) in patients with chronic respiratory insufficiency. At present, noninvasive ventilation is exclusively initiated in a clinical setting at all four centers for HMV in the Netherlands. In addition to its high societal costs and patient discomfort, commencing HMV is often delayed because of a lack of hospital bed capacity. RESEARCH QUESTION: Is HMV initiation at home, using a telemonitoring approach, noninferior to in-hospital initiation in a nationwide study? STUDY DESIGN AND METHODS: We conducted a nationwide, randomized controlled noninferiority trial, in which every HMV center recruited 24 patients (home [n = 12] vs hospital [n = 12]) with a neuromuscular disease or thoracic cage disorder, all with an indication to start HMV. Change in arterial CO2 (Paco2) over a 6-month period was considered the primary outcome, and quality of life and costs were assessed as secondary outcomes. RESULTS: A total of 96 patients were randomized, most of them diagnosed with neuromuscular disease. We found a significant improvement in Paco2 within both groups (home: from 6.1 to 5.6 kPa [P < .01]; hospital: from 6.3 to 5.6 kPa [P < .01]), with no significant differences between groups. Health-related quality of life showed significant improvement on various subscales; however, no significant differences were observed between the home and hospital groups. From a societal perspective, a cost reduction of more than €3,200 ($3,793) per patient was evident in the home group. INTERPRETATION: This nationwide, multicenter study shows that HMV initiation at home is noninferior to hospital initiation, as it shows the same improvement in gas exchange and health-related quality of life. In fact, from a patient's perspective, it might even be a more attractive approach. In addition, starting at home saves over €3,200 ($3,793) per patient over a 6-month period. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03203577; URL: www.clinicaltrials.gov.

Early Inspiratory Effort Assessment by Esophageal Manometry Predicts Noninvasive Ventilation Outcome in De Novo Respiratory Failure. A Pilot Study.

Rationale: The role of inspiratory effort still has to be determined as a potential predictor of noninvasive mechanical ventilation (NIV) failure in acute hypoxic de novo respiratory failure.Objectives: To explore the hypothesis that inspiratory effort might be a major determinant of NIV failure in these patients.Methods: Thirty consecutive patients with acute hypoxic de novo respiratory failure admitted to a single center and candidates for a 24-hour NIV trial were enrolled. Clinical features, tidal change in esophageal pressure (ΔPes), tidal change in dynamic transpulmonary pressure (ΔPl), expiratory Vt, and respiratory rate were recorded on admission and 2-4 to 12-24 hours after NIV start and were tested for correlation with outcomes.Measurements and Main Results: ΔPes and ΔPes/ΔPl ratio were significantly lower 2 hours after NIV start in patients who successfully completed the NIV trial (n = 18) compared with those who needed endotracheal intubation (n = 12) (median [interquartile range], 11 [8-15] cm H2O vs. 31.5 [30-36] cm H2O; P < 0.0001), whereas other variables differed later. ΔPes was not related to other predictors of NIV failure at baseline. NIV-induced reduction in ΔPes of 10 cm H2O or more after 2 hours of treatment was strongly associated with avoidance of intubation and represented the most accurate predictor of treatment success (odds ratio, 15; 95% confidence interval, 2.8-110; P = 0.001 and area under the curve, 0.97; 95% confidence interval, 0.91-1; P < 0.0001).Conclusions: The magnitude of inspiratory effort relief as assessed by ΔPes variation within the first 2 hours of NIV was an early and accurate predictor of NIV outcome at 24 hours.Clinical trial registered with www.clinicaltrials.gov (NCT03826797).

Home initiation of chronic non-invasive ventilation in COPD patients with chronic hypercapnic respiratory failure: a randomised controlled trial.

INTRODUCTION: Chronic non-invasive ventilation (NIV) has become evidence-based care for stable hypercapnic COPD patients. While the number of patients increases, home initiation of NIV would greatly alleviate the healthcare burden. We hypothesise that home initiation of NIV with the use of telemedicine in stable hypercapnic COPD is non-inferior to in-hospital NIV initiation. METHODS: Sixty-seven stable hypercapnic COPD patients were randomised to initiation of NIV in the hospital or at home using telemedicine. Primary outcome was daytime arterial carbon dioxide pressure (PaCO2) reduction after 6 months NIV, with a non-inferiority margin of 0.4 kPa. Secondary outcomes were health-related quality of life (HRQoL) and costs. RESULTS: Home NIV initiation was non-inferior to in-hospital initiation (adjusted mean difference in PaCO2 change home vs in-hospital: 0.04 kPa (95% CI -0.31 to 0.38 kPa), with both groups showing a PaCO2 reduction at 6 months compared with baseline (home: from 7.3±0.9 to 6.4±0.8 kPa (p<0.001) and in-hospital: from 7.4±1.0 to 6.4±0.6 kPa (p<0.001)). In both groups, HRQoL improved without a difference in change between groups (Clinical COPD Questionnaire total score-adjusted mean difference 0.0 (95% CI -0.4 to 0.5)). Furthermore, home NIV initiation was significantly cheaper (home: median €3768 (IQR €3546-€4163) vs in-hospital: median €8537 (IQR €7540-€9175); p<0.001). DISCUSSION: This is the first study showing that home initiation of chronic NIV in stable hypercapnic COPD patients, with the use of telemedicine, is non-inferior to in-hospital initiation, safe and reduces costs by over 50%. TRIAL REGISTRATION NUMBER: NCT02652559.

Characteristics and outcome of patients set up on high-flow oxygen therapy at home.

BACKGROUND: High-flow oxygen therapy (HFOT) is increasingly used for acute respiratory failure. Few data support its use at home for the treatment of chronic respiratory failure. Our aim was to report the pattern of the use of long-term HFOT in our center and the outcome of patients setup on long-term HFOT. METHODS: A retrospective monocentric study including all patients setup on long-term HFOT between January 2011 and April 2018 in Rouen University Hospital was carried out. Patients were divided into two groups, patients with hypoxemic respiratory failure treated with nasal HFOT (nHFOT) and tracheotomized patients treated with tracheal HFOT (tHFOT). RESULTS: A total of 71 patients were established on long-term HFOT. Out of these 43 (61%) were included in the nHFOT group and 28 (39%) were included in the tHFOT group. In the nHFOT group, underlying respiratory diseases were interstitial lung disease (n = 15, 35%), pulmonary hypertension (n = 12, 28%), lung cancer (n = 9, 21%), and chronic airway disease (n = 7, 16%). In the tHFOT group, the number of admissions for exacerbation decreased by -0.78 per year (-2 to 0) (p = 0.045). In total, 51 (72%) patients were discharged to their homes and 20 (28%) went to a post-acute re-enablement facility. Median survival following HFOT was 7.5 months. Survival was significantly lower in the nHFOT group with a median survival of 3.6 months whereas median survival was not reached in the tHFOT group (p < 0.001). Monthly costs associated with home delivery of HFOT were €476 (296-533) with significant differences in costs between the nHFOT group of €520 (408-628) and costs in the tHFOT group of €296 (261-475) (p < 0.001). CONCLUSIONS: The use of long-term HFOT allows very severe patients to be discharged at a reasonable cost from acute care facilities. The reviews of this paper are available via the supplementary material section.

Forced expiratory volumes in 3 s is a sensitive clinical measure for assessment of bronchodilator reversibility in elderly Chinese with severe lung function impairment.

Purpose: Sensitively assessing bronchial reversibility by spirometry is difficult in patients with serious airflow limitation and the elderly. Some patients cannot exhale for ≥6 s to achieve FVC testing criteria. The aim of this study was to assess if FEV3 could be a more sensitive and an acceptable surrogate for evaluating bronchial reversibility in such patients. Patients and methods: Subjects who had undergone pulmonary function examination in Beijing hospital from July 2003 to April 2015 were included in the study. Patients with FEV1<50% of the predicted value were classified as the severely lung function-impaired group. Correlation between the severity of lung function impairment and changes in FEV1, FEV3 and FVC in response to a bronchodilator was estimated. Results: A total of 7745 tests on elderly subjects with a median age of 71 years were reviewed. The severely lung function-impaired group of 1728 accounted for 22.3% of the total number of subjects. There were significantly more patients in the severely lung function-impaired group who exhibited positive response in FEV3 or FVC and negative response in FEV1 after bronchodilator test (FEV1 negative response but FVC positive response, χ2=626.97, P<0.001; FEV1 negative response but FEV3 positive response, χ2=372.83, P<0.001). With the progressive increase in lung function impairment, ΔFEV1 increased and then declined, while ΔFVC and ΔFEV3 increased progressively. Changes in FEV3 or FVC significantly exceeded the change in FEV1 in the severely lung function-impaired groups (P<0.001). Conclusion: In elderly subjects, especially those with severe lung function impairment, FEV3 combined with FVC is a more effective and sensitive primary clinical outcome measure to detect bronchial reversibility. In subjects who cannot complete ≥6 s forced expiration and whose FVC is unreliable, FEV3 combined with FEV1 might be clinically more valuable in detecting bronchial reversibility.

Serial ultrasound assessment of diaphragmatic function and clinical outcome in patients with amyotrophic lateral sclerosis.

BACKGROUND: Diaphragmatic assessment by ultrasound (US) is a non-invasive and useful method in the clinical management of patients with Amyotrophic Lateral Sclerosis (ALS). The aim of our observational study was to evaluate the impact of serial assessment of the diaphragmatic function by US on long-term outcomes in a series of patients suffering from ALS and to correlate US indices of diaphragmatic function and respiratory function tests with these outcomes. METHODS: A cohort of 39 consecutive patients has been followed up to 24 months. Both lung volume (forced vital capacity, FVC) and diaphragmatic pressure generating capacity (by sniff inspiratory nasal pressure (SNIP) and by both US thickening fraction, ΔTdi, and the ratio of the thickening fraction between tidal volume and maximal lung capacity, ΔTmax) were recorded at baseline and every 3 months. Parameters were then correlated with outcomes (nocturnal hypoventilation, daily hypercapnia, start of ventilatory support (NIV), and death at 1 year) over time. RESULTS: The occurrence of ΔTmax > 0.75 increased the risk to start NIV (HR = 5.6, p = 0.001) and to die (HR = 3.7, p = 0.0001) compared with patients maintaining lower values. Moreover, compared with the occurrence of FVC < 50% of predicted, ΔTmax > 0.75 appeared slightly better correlated with NIV commencement within 6 months. CONCLUSIONS: Serial diaphragmatic assessment by ultrasound is a useful and accurate method to predict the initiation of NIV earlier in patients with ALS.

Association of Opioid and Benzodiazepine Use with Adverse Respiratory Events in Older Adults with Chronic Obstructive Pulmonary Disease.

Rationale: Older adults with chronic obstructive pulmonary disease (COPD) are at substantially increased risk for medication-related adverse events. Two frequently prescribed classes of drugs that pose a particular risk to this patient group are opioids and benzodiazepines. Research on this topic has yielded conflicting findings.Objectives: The purpose of this study was to examine, among older adults with COPD, whether: 1) independent or concurrent use of opioid and benzodiazepine medications was associated with hospitalizations for respiratory events, and 2) this association was exacerbated by the presence of obstructive sleep apnea (OSA).Methods: We conducted a case-control study of Medicare beneficiaries aged ≥66 years, who were diagnosed with COPD in 2013, using the 5% national Medicare database. Cases (n = 3,232) were defined as patients hospitalized for a primary COPD-related respiratory diagnosis in 2014 and were matched with up to two control subjects (n = 6,247) on index date, age, sex, socioeconomic status, comorbidity, presence of OSA, COPD medication, and COPD complexity.Results: In comparison to the referent (no opioid or benzodiazepine use), opioid use alone (adjusted odds ratio [aOR], 1.73; 95% confidence interval [CI], 1.52-1.97), benzodiazepine use alone (aOR, 1.42; 95% CI, 1.21-1.66), and concurrent opioid/ benzodiazepine use (aOR, 2.32; 95% CI, 1.94-2.77) in the 30 days before the event/index date were all associated with an increased risk of hospitalization for a respiratory condition. Risk of hospitalization was higher with concurrent opioid and benzodiazepine use when compared with use of either medication alone. There was no statistically significant interaction between OSA and either of the drugs, alone or in combination. However, the adverse respiratory effects of concurrent opioid and benzodiazepine use were increased in patients with a high degree of COPD complexity. All of the above findings persisted using exposure windows that extended to 60 and 90 days before the event/index date.Conclusions: Among older adults with COPD, use of opioid and benzodiazepine medications alone or in combination were associated with increased adverse respiratory events. The adverse effects of these medications were not exacerbated in patients with COPD-OSA overlap syndrome. However, the adverse impact of dual opioid and benzodiazepine was greater in patients with high-complexity COPD.

Evaluating the efficacy of Seattle-PAP for the respiratory support of premature neonates: study protocol for a randomized controlled trial.

BACKGROUND: At birth, the majority of neonates born at <30 weeks of gestation require respiratory support to facilitate transition and ensure adequate gas exchange. Although the optimal approach to the initial respiratory management is uncertain, the American Academy of Pediatrics endorses noninvasive respiratory support with nasal continuous positive airway pressure (nCPAP) for premature neonates with respiratory insufficiency. Despite evidence for its use, nCPAP failure, requiring intubation and mechanical ventilation, is common. Recently, investigators have described a novel method to deliver bubble nCPAP, termed Seattle-PAP. While preclinical and pilot studies are encouraging regarding the potential value of Seattle-PAP, a large trial is needed to compare Seattle-PAP directly with the current standard of care for bubble nCPAP (Fisher & Paykel CPAP or FP-CPAP). METHODS/DESIGN: We designed a multicenter, non-blinded, randomized controlled trial that will enroll 230 premature infants (220/7 to 296/7 weeks of gestation). Infants will be randomized to receive Seattle-PAP or FP-CPAP. The primary outcome is respiratory failure requiring intubation and mechanical ventilation. Secondary outcomes include measures of short- and long-term respiratory morbidity and cost-effectiveness. DISCUSSION: This trial will assess whether Seattle-PAP is more efficacious and cost-effective than FP-CPAP in real-world practice among premature neonates. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03085329 . Registered on 21 March 2017.

Interhospital ECMO Transport: Regional Focus.

Utilization of extracorporeal membrane oxygenation (ECMO) has increased dramatically over the last decade. Despite this trend, many medical centers have limited, if any, access to this technology or the resources necessary to manage these complex patients. In an effort to improve the current infrastructure of regional ECMO care, ECMO centers of excellence have an obligation to partner with facilities within their communities and regions to increase access to this potentially life-saving technology. While the need for this infrastructure is widely acknowledged in the ECMO community, few reports describe the actual mechanisms by which a successful interfacility transport program can operate. As such, the purpose of this document is to describe the elements of and methods for providing safe and efficient mobile ECMO services from the perspective of an experienced, high-volume tertiary ECMO center of excellence in the Southeastern United States.

Minute ventilation assessment in the PACU is useful to predict postoperative respiratory depression following discharge to the floor: A prospective cohort study.

STUDY OBJECTIVE: Reliably identifying patients at risk for postoperative respiratory depression (RD) remains an unmet need. We hypothesized that defined low minute ventilation events (LMVe) near the end of the post-anesthesia care unit (PACU) stay identifies patients at RD risk on the general hospital floor (GHF). DESIGN: Prospective observational study. SETTING: Tertiary care, urban academic medical center. PACU and GHF during the first postoperative night. PATIENTS: One hundred-and-nineteen adult, ASA I - III patients undergoing elective surgery under general anesthesia completed the study. INTERVENTIONS: Data collection from a non-invasive respiratory volume monitor and the patients' medical record perioperatively through the first postoperative night. MEASUREMENTS: Minute ventilation (MV), tidal volume (TV) and respiratory rate (RR) were measured continuously in the PACU and on the GHF. MV was counted as the percent of individual predicted MV (MVPRED), and RD was defined as ≥1 LMVe/h on the GHF. Based on the number of LMVes within 30 min before PACU discharge, patients were grouped into A, 'Not-At-Risk': 0 LMVe and B, 'At-Risk': ≥1 LMVes. Unpaired t-test, Mann-Whitney U test, ANOVA, Kruskal-Wallis test, Fisher's exact test, sensitivity and specificity and ROC curve analyses were applied as appropriate. MAIN RESULTS: One hundred-and-six (89%) and 13 (11%) patients met Group A and B criteria respectively. The latter had more LMVe/h on the GHF (median 0.81 vs 0, p ≤ 0.001), and their MVPRED was significantly less. Following opioid administration, the LMVe likelihood was 43% in Group B and 5.6% in Group A. As a predictor for RD on the GHF, the number of LMVe in the last 30 min of PACU, had positive and negative predictive values of 61.5% and 90.6%, respectively. CONCLUSION: Minute ventilation assessment in the PACU as described in this study can be useful to identify patients at risk for postoperative respiratory depression.

Prospective Assessment of the Feasibility of a Trial of Low-Tidal Volume Ventilation for Patients with Acute Respiratory Failure.

RATIONALE: Low-tidal volume ventilation (LTVV; 6 ml/kg) benefits patients with acute respiratory distress syndrome and may aid those with other causes of respiratory failure. Current early ventilation practices are poorly defined. OBJECTIVES: We observed patients with acute respiratory failure to assess the feasibility of a pragmatic trial of LTVV and to guide experimental design. METHODS: We prospectively enrolled consecutive patients with acute respiratory failure admitted to intensive care units expected to participate in the proposed trial. We collected clinical data as well as information on initial and daily ventilator settings and inpatient mortality. We estimated the benefit of LTVV using predictive linear and nonlinear models. We simulated models to estimate power and feasibility of a cluster-randomized trial of LTVV versus usual care in acute respiratory failure. RESULTS: We included 2,484 newly mechanically ventilated patients (31% with acute respiratory distress syndrome) from 49 hospitals. Hospital mortality was 28%. Mean initial tidal volume was 7.1 ml/kg predicted body weight (95% confidence interval, 7.1-7.2), with 78% of patients receiving tidal volumes less than or equal to 8 ml/kg. Our models estimated a mortality benefit of 0-2% from LTVV compared with usual care. Simulation of a stepped-wedged cluster-randomized trial suggested that enrollment of 106,361 patients would be necessary to achieve greater than 90% power. CONCLUSIONS: Use of initial tidal volumes less than 8 ml/kg predicted body weight was common at hospitals participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. After considering the size and budgetary requirement for a cluster-randomized trial of LTVV versus usual care in acute respiratory failure, the PETAL Network deemed the proposed trial infeasible. A rapid observational study and simulations to model anticipated power may help better design trials.

Respiratory Failure, Noninvasive Ventilation, and Symptom Burden: An Observational Study.

BACKGROUND: Noninvasive ventilation (NIV) is commonly used to manage acute respiratory failure due to decompensated cardiorespiratory disease. We describe symptom burden in this population. MEASURES: Fifty consecutive, consenting, English-speaking, cognitively intact patients, admitted to wards other than the intensive care unit in a tertiary teaching hospital and treated with NIV for hypercapnic respiratory failure, were recruited. The 14-item Condensed Memorial Symptom Assessment Scale was used to assess physical and psychological symptoms within 36 hours of commencing NIV. Breathlessness (using Borg score), pain location and intensity using a numerical rating scale, and four symptoms potentially prevalent in patients undergoing NIV (cough, sputum, gastric bloating, and dry eyes) were also assessed. OUTCOMES: Patients reported a median of 10 symptoms (IQR 9-13). A median of five symptoms (IQR 3-7) were rated as severe. Breathlessness was the most prevalent and most distressing symptom, with participants reporting a mean maximum Borg score of 7.55 over the 24 hours before admission. Dry mouth, lack of energy, cough, sputum, difficulty sleeping, and psychological symptoms were prevalent. Pain, when reported, was of moderate intensity and contributed to distress. CONCLUSIONS/LESSONS LEARNED: This study describes the patient-reported symptoms occurring during an episode of acute respiratory failure. Understanding the symptom profile of patients in this setting may allow clinicians to target symptom relief while simultaneously managing respiratory failure, enhancing care.

National survey: current prevalence and characteristics of home mechanical ventilation in Hungary.

BACKGROUND: Home mechanical ventilation is an established treatment for chronic respiratory failure resulting in improved survival and quality of life. Technological advancement, evolving health care reimbursement systems and newly implemented national guidelines result in increased utilization worldwide. Prevalence shows great geographical variations and data on East-Central European practice has been scarce to date. The aim of the current study was to evaluate prevalence and characteristics of home mechanical ventilation in Hungary. METHODS: We conducted a nationwide study using an online survey focusing on patients receiving ventilatory support at home. The survey focused on characterization of the site (affiliation, type), experience with home mechanical ventilation, number of patients treated, indication for home mechanical ventilation (disease type), description of home mechanical ventilation (invasive/noninvasive, ventilation hours, duration of ventilation) and description of the care provided (type of follow up visits, hospitalization need, reimbursement). RESULTS: Our survey uncovered a total of 384 patients amounting to a prevalence of 3.9/100,000 in Hungary. 10.4% of patients received invasive, while 89.6% received noninvasive ventilation. The most frequent diagnosis was central hypopnea syndromes (60%), while pulmonary (20%), neuromuscular (11%) and chest wall disorders (7%) were less frequent indications. Daily ventilation need was less than 8 h in 74.2%, between 8 and 16 h in 15.4% and more than 16 h in 10.4% of patients reported. When comparing sites with a limited (< 50 patients) versus substantial (> 50 patients) case number, we found the former had significantly higher ratio of neuromuscular conditions, were more likely to ventilate invasively, with more than 16 h/day ventilation need and were more likely to provide home visits and readmit patients (p < 0,001). CONCLUSIONS: Our results show a reasonable current estimate and characterization of home mechanical ventilation practice in Hungary. Although a growing practice can be assumed, current prevalence is still markedly reduced compared to international data reported, the duality of current data hinting to a possible gap in diagnosis and care for more dependent patients. This points to the importance of establishing home mechanical ventilation centers, where increased experience will enable state of the art care to more dependent patients as well, increasing overall prevalence.

Prediction of prognosis in chronic obstructive pulmonary disease patients with respiratory failure: A comparison of three nutritional assessment methods.

OBJECTIVES: Due to their increased energy expenditure, chronic obstructive pulmonary disease (COPD) patients with respiratory failure are susceptible to malnutrition. This study aimed to compare the predictive values of the following three widely used nutritional assessment methods for the clinical prognosis of COPD patients with respiratory failure: body mass index (BMI), Nutritional Risk Screening 2002 (NRS 2002), and serum albumin (ALB) level. METHODS: COPD patients with respiratory failure treated in our center from June 2013 to June 2016 were retrospectively included. Patient BMI, NRS 2002 and ALB values were measured to assess their nutritional status. A multivariable analysis was conducted, and receiver operating characteristic (ROC) curves were generated to explore the predictive factors for clinical prognoses. RESULTS: A total of 438 qualified patients were enrolled in our study. Multivariable analysis revealed that the BMI and ALB values independently predicted in-hospital mortality, the BMI and NRS 2002 predicted 1-year mortality, and all three methods (BMI, NRS 2002, and ALB) predicted 30-day readmission after discharge (P < 0.05). Regarding the results of the AUROC analysis, the optimal cutoff values that maximized the ability to predict the prognosis were an ALB level of 30.5 g/L for in-hospital mortality, an NRS 2002 score of 3 points for 1-year mortality, and an ALB level of 30.1 g/L for readmission within 30 days following discharge. CONCLUSIONS: For COPD patients with respiratory failure, ALB level was superior for predicting in-hospital mortality and 30-day readmission after discharge, and NRS 2002 was superior for long-term prognosis of 1-year mortality.

Chinese version of the severe respiratory insufficiency questionnaire for patients with COPD receiving long-term oxygen therapy.

Purpose: Patients with advanced-stage COPD often experience severe hypoxemia. Treatment with long-term oxygen therapy (LTOT) may relieve patients' symptoms and increase survival. As COPD is incurable, improving patients' health-related quality of life is important. The Chinese version of the Severe Respiratory Insufficiency Questionnaire (SRI) is valid for patients with hypercapnic COPD undergoing noninvasive positive airway pressure ventilation at home. However, the reliability and validity of the Chinese SRI for patients with COPD undergoing LTOT have not been investigated. Patients and methods: We analyzed reliability using Cronbach's α coefficient. Construct validity was assessed with principal, exploratory, and confirmatory factor analysis. Concurrent validity was evaluated through the correlation between SRI domains and Chronic Respiratory Disease Questionnaire (CRQ) domains. Content validity was assessed by calculating the correlation between each SRI item score and the total score for the relevant domain. Results: In total, 161 patients participated in this study. The Cronbach's α coefficient for all SRI domains was >0.7, except for the attendant symptoms and sleep domain. Exploratory and confirmatory factor analysis showed a good model fit for each domain, but the factors extracted from each domain were correlated. SRI and CRQ domains correlated well with respect to similar aspects of health-related quality of life, indicating good concurrent validity. Content validity was indirectly shown by a good correlation between each item score and the total score of the relevant domain. Conclusion: The Chinese version of the SRI has a good reliability and validity for patients with COPD undergoing LTOT in China.

High-Flow Nasal Cannula Oxygen in Adults: An Evidence-based Assessment.

High-flow nasal cannula oxygenation has distinct advantages over other oxygen devices because of its unique effects on respiratory physiology. In particular, adjustable oxygen delivery and flow-dependent carbon dioxide clearance reduce work of breathing and better match inspiratory demand during respiratory distress. Historically, few studies had evaluated whether the physiologic effects of these devices translated into clinical benefit. However, recent publications have begun to address this knowledge gap. High-flow nasal cannula oxygenation has been shown to have similar, and in some cases superior clinical efficacy compared with conventional low-flow oxygen supplementation and noninvasive positive pressure ventilation in acute hypoxemic respiratory failure. High-flow nasal cannula oxygenation also prevents reintubations in medical and postoperative surgical populations, provides preoxygenation for laryngoscopy, and supports oxygenation during bronchoscopy. This review examines the evidence for high-flow nasal cannula oxygenation use in adults, including a focus on the unique effects of high flow on respiratory physiology and keys for tailoring flow for specific clinical scenarios.

Nasal high flow therapy: a novel treatment rather than a more expensive oxygen device.

Nasal high flow is a promising novel oxygen delivery device, whose mechanisms of action offer some beneficial effects over conventional oxygen systems. The administration of a high flow of heated and humidified gas mixture promotes higher and more stable inspiratory oxygen fraction values, decreases anatomical dead space and generates a positive airway pressure that can reduce the work of breathing and enhance patient comfort and tolerance. Nasal high flow has been used as a prophylactic tool or as a treatment device mostly in patients with acute hypoxaemic respiratory failure, with the majority of studies showing positive results. Recently, its clinical indications have been expanded to post-extubated patients in intensive care or following surgery, for pre- and peri-oxygenation during intubation, during bronchoscopy, in immunocompromised patients and in patients with "do not intubate" status. In the present review, we differentiate studies that suggest an advantage (benefit) from other studies that do not suggest an advantage (no benefit) compared to conventional oxygen devices or noninvasive ventilation, and propose an algorithm in cases of nasal high flow application in patients with acute hypoxaemic respiratory failure of almost any cause.