The PANDORA Study: Prevalence and Outcome of Acute Hypoxemic Respiratory Failure in the Pre-COVID-19 Era.

OBJECTIVES: To establish the epidemiological characteristics, ventilator management, and outcomes in patients with acute hypoxemic respiratory failure (AHRF), with or without acute respiratory distress syndrome (ARDS), in the era of lung-protective mechanical ventilation (MV). DESIGN: A 6-month prospective, epidemiological, observational study. SETTING: A network of 22 multidisciplinary ICUs in Spain. PATIENTS: Consecutive mechanically ventilated patients with AHRF (defined as Pao2/Fio2 ≤ 300 mm Hg on positive end-expiratory pressure [PEEP] ≥ 5 cm H2O and Fio2 ≥ 0.3) and followed-up until hospital discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were prevalence of AHRF and ICU mortality. Secondary outcomes included prevalence of ARDS, ventilatory management, and use of adjunctive therapies. During the study period, 9,803 patients were admitted: 4,456 (45.5%) received MV, 1,271 (13%) met AHRF criteria (1,241 were included into the study: 333 [26.8%] met Berlin ARDS criteria and 908 [73.2%] did not). At baseline, tidal volume was 6.9 ± 1.1 mL/kg predicted body weight, PEEP 8.4 ± 3.1 cm H2O, Fio2 0.63 ± 0.22, and plateau pressure 21.5 ± 5.4 cm H2O. ARDS patients received higher Fio2 and PEEP than non-ARDS (0.75 ± 0.22 vs 0.59 ± 0.20 cm H2O and 10.3 ± 3.4 vs 7.7 ± 2.6 cm H2O, respectively [p < 0.0001]). Adjunctive therapies were rarely used in non-ARDS patients. Patients without ARDS had higher ventilator-free days than ARDS (12.2 ± 11.6 vs 9.3 ± 9.7 d; p < 0.001). All-cause ICU mortality was similar in AHRF with or without ARDS (34.8% [95% CI, 29.7-40.2] vs 35.5% [95% CI, 32.3-38.7]; p = 0.837). CONCLUSIONS: AHRF without ARDS is a very common syndrome in the ICU with a high mortality that requires specific studies into its epidemiology and ventilatory management. We found that the prevalence of ARDS was much lower than reported in recent observational studies.

Stratification for Identification of Prognostic Categories In the Acute RESpiratory Distress Syndrome (SPIRES) Score.

OBJECTIVES: To develop a scoring model for stratifying patients with acute respiratory distress syndrome into risk categories (Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score) for early prediction of death in the ICU, independent of the underlying disease and cause of death. DESIGN: A development and validation study using clinical data from four prospective, multicenter, observational cohorts. SETTING: A network of multidisciplinary ICUs. PATIENTS: One-thousand three-hundred one patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study followed Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines for prediction models. We performed logistic regression analysis, bootstrapping, and internal-external validation of prediction models with variables collected within 24 hours of acute respiratory distress syndrome diagnosis in 1,000 patients for model development. Primary outcome was ICU death. The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score was based on patient's age, number of extrapulmonary organ failures, values of end-inspiratory plateau pressure, and ratio of Pao2 to Fio2 assessed at 24 hours of acute respiratory distress syndrome diagnosis. The pooled area under the receiver operating characteristic curve across internal-external validations was 0.860 (95% CI, 0.831-0.890). External validation in a new cohort of 301 acute respiratory distress syndrome patients confirmed the accuracy and robustness of the scoring model (area under the receiver operating characteristic curve = 0.870; 95% CI, 0.829-0.911). The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score stratified patients in three distinct prognostic classes and achieved better prediction of ICU death than ratio of Pao2 to Fio2 at acute respiratory distress syndrome onset or at 24 hours, Acute Physiology and Chronic Health Evaluation II score, or Sequential Organ Failure Assessment scale. CONCLUSIONS: The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score represents a novel strategy for early stratification of acute respiratory distress syndrome patients into prognostic categories and for selecting patients for therapeutic trials.

Longitudinal Changes in Patient-Ventilator Asynchronies and Respiratory System Mechanics Before and After Tracheostomy.

BACKGROUND: This was a pilot study to analyze the effects of tracheostomy on patient-ventilator asynchronies and respiratory system mechanics. Data were extracted from an ongoing prospective, real-world database that stores continuous output from ventilators and bedside monitors. Twenty adult subjects were on mechanical ventilation and were tracheostomized during an ICU stay: 55% were admitted to the ICU for respiratory failure and 35% for neurologic conditions; the median duration of mechanical ventilation before tracheostomy was 12 d; and the median duration of mechanical ventilation was 16 d. METHODS: We compared patient-ventilator asynchronies (the overall asynchrony index and the rates of specific asynchronies) and respiratory system mechanics (respiratory-system compliance and airway resistance) during the 24 h before tracheostomy versus the 24 h after tracheostomy. We analyzed possible differences in these variables among the subjects who underwent surgical versus percutaneous tracheostomy. To compare longitudinal changes in the variables, we used linear mixed-effects models for repeated measures along time in different observation periods. A total of 920 h of mechanical ventilation were analyzed. RESULTS: Respiratory mechanics and asynchronies did not differ significantly between the 24-h periods before and after tracheostomy: compliance of the respiratory system median (IQR) (47.9 [41.3 - 54.6] mL/cm H2O vs 47.6 [40.9 - 54.3] mL/cm H2O; P = .94), airway resistance (9.3 [7.5 - 11.1] cm H2O/L/s vs 7.0 [5.2 - 8.8] cm H2O/L/s; P = .07), asynchrony index (2.0% [1.1 - 3.6%] vs 4.1% [2.3 - 7.6%]; P = .09), ineffective expiratory efforts (0.9% [0.4 - 1.8%] vs 2.2% [1.0 - 4.4%]; P = .08), double cycling (0.5% [0.3 - 1.0%] vs 0.9% [0.5 - 1.9%]; P = .24), and percentage of air trapping (7.6% [4.2 - 13.8%] vs 10.6% [5.9 - 19.2%]; P = .43). No differences in respiratory mechanics or patient-ventilator asynchronies were observed between percutaneous and surgical procedures. CONCLUSIONS: Tracheostomy did not affect patient-ventilator asynchronies or respiratory mechanics within 24 h before and after the procedure.

Pleural Pressure Targeted Positive Airway Pressure Improves Cardiopulmonary Function in Spontaneously Breathing Patients With Obesity.

BACKGROUND: Increased pleural pressure affects the mechanics of breathing of people with class III obesity (BMI > 40 kg/m2). RESEARCH QUESTION: What are the acute effects of CPAP titrated to match pleural pressure on cardiopulmonary function in spontaneously breathing patients with class III obesity? STUDY DESIGN AND METHODS: We enrolled six participants with BMI within normal range (control participants, group I) and 12 patients with class III obesity (group II) divided into subgroups: IIa, BMI of 40 to 50 kg/m2; and IIb, BMI of ≥ 50 kg/m2. The study was performed in two phases: in phase 1, participants were supine and breathing spontaneously at atmospheric pressure, and in phase 2, participants were supine and breathing with CPAP titrated to match their end-expiratory esophageal pressure in the absence of CPAP. Respiratory mechanics, esophageal pressure, and hemodynamic data were collected, and right heart function was evaluated by transthoracic echocardiography. RESULTS: The levels of CPAP titrated to match pleural pressure in group I, subgroup IIa, and subgroup IIb were 6 ± 2 cmH2O, 12 ± 3 cmH2O, and 18 ± 4 cmH2O, respectively. In both subgroups IIa and IIb, CPAP titrated to match pleural pressure decreased minute ventilation (IIa, P = .03; IIb, P = .03), improved peripheral oxygen saturation (IIa, P = .04; IIb, P = .02), improved homogeneity of tidal volume distribution between ventral and dorsal lung regions (IIa, P = .22; IIb, P = .03), and decreased work of breathing (IIa, P < .001; IIb, P = .003) with a reduction in both the work spent to initiate inspiratory flow as well as tidal ventilation. In five hypertensive participants with obesity, BP decreased to normal range, without impairment of right heart function. INTERPRETATION: In ambulatory patients with class III obesity, CPAP titrated to match pleural pressure decreased work of breathing and improved respiratory mechanics while maintaining hemodynamic stability, without impairing right heart function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02523352; URL: www.clinicaltrials.gov.

Inhaled Nitric Oxide Delivery Systems for Mechanically Ventilated and Nonintubated Patients: A Review.

Nitric oxide (NO) is a biologically active molecule approved for the treatment of pulmonary hypertension in newborn patients. Commercially available NO delivery systems use pressurized cylinders as the source of NO and a sensor to control the concentrations of NO and nitrogen dioxide (NO2) delivered. Cylinder-based delivery systems are safe and widely used around the world, but they are bulky, expensive, and reliant on a robust supply chain. In the past few years, novel NO generators and delivery systems have been developed to overcome these limitations. Electric NO generators produce NO from ambient air using high-voltage electrical discharge to ionize air, which leads to the formation of NO, NO2, and ozone (O3). A scavenging system is incorporated to reduce the concentration of the toxic byproducts generated in this type of system. NO can also be generated by the reduction of NO2 by ascorbic acid or released from liquid solutions or solid nanoparticles. The development of easy-to-use, safe, and portable NO delivery systems may enable the delivery of NO in the out-patient setting or at home. Furthermore, non-cylinder-based NO generators reduce the cost of NO production and storage and may therefore make NO delivery feasible in low-resource settings. Here we review commercially available systems that can generate and administer inhalable NO.

Weaning patients with obesity from ventilatory support.

PURPOSE OF REVIEW: Obesity prevalence is increasing in most countries in the world. In the United States, 42% of the population is obese (body mass index (BMI) > 30) and 9.2% is obese class III (BMI > 40). One of the greatest challenges in critically ill patients with obesity is the optimization of mechanical ventilation. The goal of this review is to describe respiratory physiologic changes in patients with obesity and discuss possible mechanical ventilation strategies to improve respiratory function. RECENT FINDINGS: Individualized mechanical ventilation based on respiratory physiology after a decremental positive end-expiratory pressure (PEEP) trial improves oxygenation and respiratory mechanics. In a recent study, mortality of patients with respiratory failure and obesity was reduced by about 50% when mechanical ventilation was associated with the use of esophageal manometry and electrical impedance tomography (EIT). SUMMARY: Obesity greatly alters the respiratory system mechanics causing atelectasis and prolonged duration of mechanical ventilation. At present, novel strategies to ventilate patients with obesity based on individual respiratory physiology showed to be superior to those based on standard universal tables of mechanical ventilation. Esophageal manometry and EIT are essential tools to systematically assess respiratory system mechanics, safely adjust relatively high levels of PEEP, and improve chances for successful weaning.

Clusters of Double Triggering Impact Clinical Outcomes: Insights From the EPIdemiology of Patient-Ventilator aSYNChrony (EPISYNC) Cohort Study.

OBJECTIVES: To measure the impact of clusters of double triggering on clinical outcomes. DESIGN: Prospective cohort study. SETTING: Respiratory ICU in Brazil. PATIENTS: Adult patients under recent mechanical ventilation and with expectation of mechanical ventilation for more than 24 hours after enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used a dedicated software to analyze ventilator waveforms throughout the entire period of mechanical ventilation and detect double triggering. We defined a cluster of double triggering as a period of time containing at least six double triggering events in a 3-minute period. Patients were followed until hospital discharge. We addressed the association between the presence and the duration of clusters with clinical outcomes. A total of 103 patients were enrolled in the study and 90 (87%) had at least one cluster of double triggering. The median number of clusters per patient was 19 (interquartile range, 6-41), with a median duration of 8 minutes (6-12 min). Compared with patients who had no clusters, patients with at least one cluster had longer duration of mechanical ventilation (7 d [4-11 d] vs 2 d [2-3 d]) and ICU length of stay (9 d [7-16 d] vs 13 d [2-8 d]). Thirty-three patients had high cumulative duration of clusters of double triggering (≥ 12 hr), and it was associated with longer duration of mechanical ventilation, fewer ventilator-free days, and longer ICU length of stay. Adjusted by duration of mechanical ventilation and severity of illness, high cumulative duration of clusters was associated with shorter survival at 28 days (hazard ratio, 2.09 d; 95% CI, 1.04-4.19 d). CONCLUSIONS: Clusters of double triggering are common and were associated with worse clinical outcomes. Patients who had a high cumulative duration of clusters had fewer ventilator-free days, longer duration of mechanical ventilation, longer ICU length of stay, and shorter survival than patients with low cumulative duration of cluster.

An algorithm for the sedation of patients with obstructive sleep apnea by non-anesthesiologists.

OBJECTIVE: Patients with obstructive sleep apnea (OSA) are at risk for adverse events when moderate sedation is administered by nurse protocols (NAMS) under the guidance of non-anesthesiologists. An algorithm was applied for the appropriate section of patients to receive NAMS and the application of continuous positive airway pressure (CPAP). METHODS: An algorithm was developed for patients with OSA who were scheduled for gastroenterology, radiology, and cardiology procedures using NAMS. Those with normal airways and without contraindications for NAMS were classified as CPAP-independent (CPAP-I; not routinely used) or CPAP-dependent (CPAP-D; always used). CPAP machines were brought in by CPAP-D patients or supplied by the hospital and set at a patient's routine setting or 10 cm H2O if not known. CPAP-D patients for procedures for which CPAP could not be applied were done under anesthesia care. We retrospectively examined this program for the 2008-2018 period. RESULTS: Since the inception of this protocol in 2008, 803 patients with OSA safely underwent procedures using either personal CPAP or CPAP provided by the hospital. CONCLUSIONS: Patients with OSA can safely have NAMS for procedures when CPAP is applied based on a protocol that considers airway evaluation, the procedure, and whether there is dependence upon CPAP.

High Pleural Pressure Prevents Alveolar Overdistension and Hemodynamic Collapse in Acute Respiratory Distress Syndrome with Class III Obesity. A Clinical Trial.

Rationale: Obesity is characterized by elevated pleural pressure (Ppl) and worsening atelectasis during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS).Objectives: To determine the effects of a lung recruitment maneuver (LRM) in the presence of elevated Ppl on hemodynamics, left and right ventricular pressure, and pulmonary vascular resistance. We hypothesized that elevated Ppl protects the cardiovascular system against high airway pressure and prevents lung overdistension.Methods: First, an interventional crossover trial in adult subjects with ARDS and a body mass index ≥ 35 kg/m2 (n = 21) was performed to explore the hemodynamic consequences of the LRM. Second, cardiovascular function was studied during low and high positive end-expiratory pressure (PEEP) in a model of swine with ARDS and high Ppl (n = 9) versus healthy swine with normal Ppl (n = 6).Measurements and Main Results: Subjects with ARDS and obesity (body mass index = 57 ± 12 kg/m2) after LRM required an increase in PEEP of 8 (95% confidence interval [95% CI], 7-10) cm H2O above traditional ARDS Network settings to improve lung function, oxygenation and [Formula: see text]/[Formula: see text] matching, without impairment of hemodynamics or right heart function. ARDS swine with high Ppl demonstrated unchanged transmural left ventricular pressure and systemic blood pressure after the LRM protocol. Pulmonary arterial hypertension decreased (8 [95% CI, 13-4] mm Hg), as did vascular resistance (1.5 [95% CI, 2.2-0.9] Wood units) and transmural right ventricular pressure (10 [95% CI, 15-6] mm Hg) during exhalation. LRM and PEEP decreased pulmonary vascular resistance and normalized the [Formula: see text]/[Formula: see text] ratio.Conclusions: High airway pressure is required to recruit lung atelectasis in patients with ARDS and class III obesity but causes minimal overdistension. In addition, patients with ARDS and class III obesity hemodynamically tolerate LRM with high airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT02503241).

Measured CPAP in a Noninvasive Pediatric Airway and Lung Model.

BACKGROUND: Bronchiolitis is the most common cause of admission in children < 2 y of age in the United States. The standard of care involves supportive measures, including noninvasive interventions such as CPAP. CPAP is traditionally delivered through a full face mask; however, pediatric ICUs have been exploring the use of the RAM cannula by Neotech as a mode of CPAP delivery. The level of CPAP delivered via the RAM cannula is uncertain. We performed an in vitro study to determine the level of CPAP delivered via the RAM cannula utilizing a pediatric lung model. METHODS: Models of 7 sizes of pediatric upper airways, produced with a 3-dimensional printer, were connected to a breathing simulator. We applied each size of RAM cannula to weight-appropriate airway and lung compliance parameters, delivering pressures of 5, 7, and 10 cm H2O using a ventilator in the CPAP mode. Leaks of 0%, 20%, 40%, and 60% were generated to emulate a complete seal, a poor fit, and open-mouth breathing. The outcome measure was the difference in CPAP, referred to as "%leak effect," measured by the lung simulator relative to the CPAP set on the ventilator. RESULTS: We found that set CPAP of 5-10 cm H2O generated measured CPAP ranging from 2.6 to 9.7 cm H2O. For the set CPAP levels of 5, 7, and 10 cm H2O, the mean %leak effect values of measured CPAP from the set CPAP were -25%, -26%, and -25.7%, respectively. For each specific cannula-airway combination, increasing the set pressure and decreasing the air leak resulted in higher levels of CPAP delivered. CONCLUSIONS: The RAM cannula delivered varying amounts of CPAP, with a percent loss of approximately -25% depending on the level of leak in the system. With minimal leak, it is conceivable that the RAM cannula can be used to deliver clinically meaningful CPAP.

Rescue Treatment With High-Dose Gaseous Nitric Oxide in Spontaneously Breathing Patients With Severe Coronavirus Disease 2019.

Treatment options are limited for patients with respiratory failure due to coronavirus disease 2019. Conventional oxygen therapy and awake proning are options, but the use of high-flow nasal cannula and continuous positive airway pressure are controversial. There is an urgent need for effective rescue therapies. Our aim is to evaluate the role of inhaled nitric oxide 160 ppm as a possible rescue therapy in nonintubated coronavirus disease 2019 patients. DESIGN: Retrospective evaluation of coronavirus disease 2019 patients in respiratory distress receiving nitric oxide gas as rescue therapy. SETTING: Massachusetts General Hospital, between March 18, 2020, and May 20, 2020, during the local coronavirus disease 2019 surge. PATIENTS: Coronavirus disease 2019 patients at high risk for acute hypoxemic respiratory failure with worsening symptoms despite use of supplemental oxygen and/or awake proning. INTERVENTIONS: Patients received nitric oxide at concentrations of 160 ppm for 30 minutes twice per day via a face mask until resolution of symptoms, discharge, intubation, or the transition to comfort measures only. MEASUREMENTS AND MAIN RESULTS: Between March 18, 2020, and May 20, 2020, five patients received nitric oxide inhalation as a rescue therapy for coronavirus disease 2019 at Massachusetts General Hospital. All received at least one dosage. The three patients that received multiple treatments (ranging from five to nine) survived and were discharged home. Maximum methemoglobin concentration after 30 minutes of breathing nitric oxide was 2.0% (1.7-2.3%). Nitrogen dioxide was below 2 ppm. No changes in mean arterial pressure or heart rate were observed during or after nitric oxide treatment. Oxygenation and the respiratory rate remained stable during and after nitric oxide treatments. For two patients, inflammatory marker data were available and demonstrate a reduction or a cessation of escalation after nitric oxide treatment. CONCLUSIONS: Nitric oxide at 160 ppm may be an effective adjuvant rescue therapy for patients with coronavirus disease 2019.

Prevalence and Outcomes of Acute Hypoxaemic Respiratory Failure in Wales: The PANDORA-WALES Study.

BACKGROUND: We aimed to identify the prevalence of acute hypoxaemic respiratory failure (AHRF) in the intensive care unit (ICU) and its associated mortality. The secondary aim was to describe ventilatory management as well as the use of rescue therapies. METHODS: Multi-centre prospective study in nine hospitals in Wales, UK, over 2-month periods. All patients admitted to an ICU were screened for AHRF and followed-up until discharge from the ICU. Data were collected from patient charts on patient demographics, clinical characteristics, management and outcomes. RESULTS: Out of 2215 critical care admissions, 886 patients received mechanical ventilation. A total of 197 patients met inclusion criteria and were recruited. Seventy (35.5%) were non-survivors. Non-survivors were significantly older, had higher SOFA scores and received more vasopressor support than survivors. Twenty-five (12.7%) patients who fulfilled the Berlin definition of acute respiratory distress syndrome (ARDS) during the ICU stay without impact on overall survival. Rescue therapies were rarely used. Analysis of ventilation showed that median Vt was 7.1 mL/kg PBW (IQR 5.9-9.1) and 21.3% of patients had optimal ventilation during their ICU stay. CONCLUSIONS: One in four mechanically ventilated patients have AHRF. Despite advances of care and better, but not optimal, utilisation of low tidal volume ventilation, mortality remains high.

Awake prone positioning does not reduce the risk of intubation in COVID-19 treated with high-flow nasal oxygen therapy: a multicenter, adjusted cohort study.

BACKGROUND: Awake prone positioning (awake-PP) in non-intubated coronavirus disease 2019 (COVID-19) patients could avoid endotracheal intubation, reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNO) with awake-PP prevents the need for intubation when compared to HFNO alone. METHODS: Prospective, multicenter, adjusted observational cohort study in consecutive COVID-19 patients with acute respiratory failure (ARF) receiving respiratory support with HFNO from 12 March to 9 June 2020. Patients were classified as HFNO with or without awake-PP. Logistic models were fitted to predict treatment at baseline using the following variables: age, sex, obesity, non-respiratory Sequential Organ Failure Assessment score, APACHE-II, C-reactive protein, days from symptoms onset to HFNO initiation, respiratory rate, and peripheral oxyhemoglobin saturation. We compared data on demographics, vital signs, laboratory markers, need for invasive mechanical ventilation, days to intubation, ICU length of stay, and ICU mortality between HFNO patients with and without awake-PP. RESULTS: A total of 1076 patients with COVID-19 ARF were admitted, of which 199 patients received HFNO and were analyzed. Fifty-five (27.6%) were pronated during HFNO; 60 (41%) and 22 (40%) patients from the HFNO and HFNO + awake-PP groups were intubated. The use of awake-PP as an adjunctive therapy to HFNO did not reduce the risk of intubation [RR 0.87 (95% CI 0.53-1.43), p = 0.60]. Patients treated with HFNO + awake-PP showed a trend for delay in intubation compared to HFNO alone [median 1 (interquartile range, IQR 1.0-2.5) vs 2 IQR 1.0-3.0] days (p = 0.055), but awake-PP did not affect 28-day mortality [RR 1.04 (95% CI 0.40-2.72), p = 0.92]. CONCLUSION: In patients with COVID-19 ARF treated with HFNO, the use of awake-PP did not reduce the need for intubation or affect mortality.

Systemic Effects Induced by Hyperoxia in a Preclinical Model of Intra-abdominal Sepsis.

Supplemental oxygen is a supportive treatment in patients with sepsis to balance tissue oxygen delivery and demand in the tissues. However, hyperoxia may induce some pathological effects. We sought to assess organ damage associated with hyperoxia and its correlation with the production of reactive oxygen species (ROS) in a preclinical model of intra-abdominal sepsis. For this purpose, sepsis was induced in male, Sprague-Dawley rats by cecal ligation and puncture (CLP). We randomly assigned experimental animals to three groups: control (healthy animals), septic (CLP), and sham-septic (surgical intervention without CLP). At 18 h after CLP, septic (n = 39), sham-septic (n = 16), and healthy (n = 24) animals were placed within a sealed Plexiglas cage and randomly distributed into four groups for continuous treatment with 21%, 40%, 60%, or 100% oxygen for 24 h. At the end of the experimental period, we evaluated serum levels of cytokines, organ damage biomarkers, histological examination of brain and lung tissue, and ROS production in each surviving animal. We found that high oxygen concentrations increased IL-6 and biomarkers of organ damage levels in septic animals, although no relevant histopathological lung or brain damage was observed. Healthy rats had an increase in IL-6 and aspartate aminotransferase at high oxygen concentration. IL-6 levels, but not ROS levels, are correlated with markers of organ damage. In our study, the use of high oxygen concentrations in a clinically relevant model of intra-abdominal sepsis was associated with enhanced inflammation and organ damage. These findings were unrelated to ROS release into circulation. Hyperoxia could exacerbate sepsis-induced inflammation, and it could be by itself detrimental. Our study highlights the need of developing safer thresholds for oxygen therapy.

Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial.

PURPOSE: We hypothesized that neurally adjusted ventilatory assist (NAVA) compared to conventional lung-protective mechanical ventilation (MV) decreases duration of MV and mortality in patients with acute respiratory failure (ARF). METHODS: We carried out a multicenter, randomized, controlled trial in patients with ARF from several etiologies. Intubated patients ventilated for ≤ 5 days expected to require MV for ≥ 72 h and able to breathe spontaneously were eligible for enrollment. Eligible patients were randomly assigned based on balanced treatment assignments with a computerized randomization allocation sequence to two ventilatory strategies: (1) lung-protective MV (control group), and (2) lung-protective MV with NAVA (NAVA group). Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days (VFDs) at 28 days. Secondary outcome was all-cause hospital mortality. All analyses were done according to the intention-to-treat principle. RESULTS: Between March 2014 and October 2019, we enrolled 306 patients and randomly assigned 153 patients to the NAVA group and 153 to the control group. Median VFDs were higher in the NAVA than in the control group (22 vs. 18 days; between-group difference 4 days; 95% confidence interval [CI] 0 to 8 days; p = 0.016). At hospital discharge, 39 (25.5%) patients in the NAVA group and 47 (30.7%) patients in the control group had died (between-group difference - 5.2%, 95% CI - 15.2 to 4.8, p = 0.31). Other clinical, physiological or safety outcomes did not differ significantly between the trial groups. CONCLUSION: NAVA decreased duration of MV although it did not improve survival in ventilated patients with ARF.

High Concentrations of Nitric Oxide Inhalation Therapy in Pregnant Patients With Severe Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Rescue therapies to treat or prevent progression of coronavirus disease 2019 (COVID-19) hypoxic respiratory failure in pregnant patients are lacking. METHOD: To treat pregnant patients meeting criteria for severe or critical COVID-19 with high-dose (160-200 ppm) nitric oxide by mask twice daily and report on their clinical response. EXPERIENCE: Six pregnant patients were admitted with severe or critical COVID-19 at Massachusetts General Hospital from April to June 2020 and received inhalational nitric oxide therapy. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A total of 39 treatments was administered. An improvement in cardiopulmonary function was observed after commencing nitric oxide gas, as evidenced by an increase in systemic oxygenation in each administration session among those with evidence of baseline hypoxemia and reduction of tachypnea in all patients in each session. Three patients delivered a total of four neonates during hospitalization. At 28-day follow-up, all three patients were home and their newborns were in good condition. Three of the six patients remain pregnant after hospital discharge. Five patients had two negative test results on nasopharyngeal swab for SARS-CoV-2 within 28 days from admission. CONCLUSION: Nitric oxide at 160-200 ppm is easy to use, appears to be well tolerated, and might be of benefit in pregnant patients with COVID-19 with hypoxic respiratory failure.