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Abstract Background This study aimed to develop prognostic models for predicting the need for invasive mechanical ventilation (IMV) in intensive care unit (ICU) patients with COVID-19 and compare their performance with the Respiratory rate-OXygenation (ROX) index. Methods A retrospective cohort study was conducted using data collected between March 2020 and August 2021 at three hospitals in Rio de Janeiro, Brazil. ICU patients aged 18 years and older with a diagnosis of COVID-19 were screened. The exclusion criteria were patients who received IMV within the first 24 h of ICU admission, pregnancy, clinical decision for minimal end-of-life care and missing primary outcome data. Clinical and laboratory variables were collected. Multiple logistic regression analysis was performed to select predictor variables. Models were based on the lowest Akaike Information Criteria (AIC) and lowest AIC with significant p values. Assessment of predictive performance was done for discrimination and calibration. Areas under the curves (AUC)s were compared using DeLong’s algorithm. Models were validated externally using an international database. Results Of 656 patients screened, 346 patients were included; 155 required IMV (44.8%), 191 did not (55.2%), and 207 patients were male (59.8%). According to the lowest AIC, arterial hypertension, diabetes mellitus, obesity, Sequential Organ Failure Assessment (SOFA) score, heart rate, respiratory rate, peripheral oxygen saturation (SpO2), temperature, respiratory effort signals, and leukocytes were identified as predictors of IMV at hospital admission. According to AIC with significant p values, SOFA score, SpO2, and respiratory effort signals were the best predictors of IMV; odds ratios (95% confidence interval): 1.46 (1.07–2.05), 0.81 (0.72–0.90), 9.13 (3.29–28.67), respectively. The ROX index at admission was lower in the IMV group than in the non-IMV group (7.3 [5.2–9.8] versus 9.6 [6.8–12.9], p

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

Abstract Background The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure. Methods We profiled 127 hospitalized patients with COVID-19 (n = 79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites. Results Forty-eight species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis, each previously linked to post-acute COVID syndrome or “long COVID,” suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with classifying whether stool was obtained from patients with severe vs. moderate COVID-19, a finding that was externally validated in an independent cohort. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease. Conclusions Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to expand upon these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention.

OBJECTIVES:. Experimental models suggest that prone position and positive end-expiratory pressure (PEEP) homogenize ventral–dorsal ventilation distribution and regional respiratory compliance. However, this response still needs confirmation on humans. Therefore, this study aimed to assess the changes in global and regional respiratory mechanics in supine and prone positions over a range of PEEP levels in acute respiratory distress syndrome (ARDS) patients. DESIGN:. A prospective cohort study. PATIENTS:. Twenty-two intubated patients with ARDS caused by COVID-19 pneumonia. INTERVENTIONS:. Electrical impedance tomography and esophageal manometry were applied during PEEP titrations from 20 cm H2O to 6 cm H2O in supine and prone positions. MEASUREMENTS:. Global respiratory system compliance (Crs), chest wall compliance, regional lung compliance, ventilation distribution in supine and prone positions. MAIN RESULTS:. Compared with supine position, the maximum level of Crs changed after prone position in 59% of ARDS patients (n = 13), of which the Crs decreased in 32% (n = 7) and increased in 27% (n = 6). To reach maximum Crs after pronation, PEEP was changed in 45% of the patients by at least 4 cm H2O. After pronation, the ventilation and compliance of the dorsal region did not consistently change in the entire sample of patients, increasing specifically in a subgroup of patients who showed a positive change in Crs when transitioning from supine to prone position. These combined changes in ventilation and compliance suggest dorsal recruitment postpronation. In addition, the subgroup with increased Crs postpronation demonstrated the most pronounced difference between dorsal and ventral ventilation distribution from supine to prone position (p = 0.01), indicating heterogeneous ventilation distribution in prone position. CONCLUSIONS:. Prone position modifies global respiratory compliance in most patients with ARDS. Only a subgroup of patients with a positive change in Crs postpronation presented a consistent improvement in dorsal ventilation and compliance. These data suggest that the response to pronation on global and regional mechanics can vary among ARDS patients, with some patients presenting more dorsal lung recruitment than others.

Take home message Nitric oxide (NO) is a key molecule involved in the vascular homeostasis and a key player in maintaining multiorgan viability. The therapeutic role of inhaled NO ranges from cardio-cerebrovascular to respiratory diseases to antimicrobial properties.

Summary: Background: The delirium-sparing effect of nighttime dexmedetomidine has not been studied after surgery. We hypothesised that a nighttime dose of dexmedetomidine would reduce the incidence of postoperative delirium as compared to placebo. Methods: This single-centre, parallel-arm, randomised, placebo-controlled superiority trial evaluated whether a short nighttime dose of intravenous dexmedetomidine (1 μg/kg over 40 min) would reduce the incidence of postoperative delirium in patients 60 years of age or older undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomised to receive dexmedetomidine or placebo in a 1:1 ratio. The primary outcome was delirium on postoperative day one. Secondary outcomes included delirium within three days of surgery, 30-, 90-, and 180-day abbreviated Montreal Cognitive Assessment scores, Patient Reported Outcome Measures Information System quality of life scores, and all-cause mortality. The study was registered as NCT02856594 on ClinicalTrials.gov on August 5, 2016, before the enrolment of any participants. Findings: Of 469 patients that underwent randomisation to placebo (n = 235) or dexmedetomidine (n = 234), 75 met a prespecified drop criterion before the study intervention. Thus, 394 participants (188 dexmedetomidine; 206 placebo) were analysed in the modified intention-to-treat cohort (median age 69 [IQR 64, 74] years; 73.1% male [n = 288]; 26·9% female [n = 106]). Postoperative delirium status on day one was missing for 30 (7.6%) patients. Among those in whom it could be assessed, the primary outcome occurred in 5 of 175 patients (2.9%) in the dexmedetomidine group and 16 of 189 patients (8.5%) in the placebo group (OR 0.32, 95% CI: 0.10–0.83; P = 0.029). A non-significant but higher proportion of participants experienced delirium within three days postoperatively in the placebo group (25/177; 14.1%) compared to the dexmedetomidine group (14/160; 8.8%; OR 0.58; 95% CI, 0.28–1.15). No significant differences between groups were observed in secondary outcomes or safety. Interpretation: Our findings suggested that in elderly cardiac surgery patients with a low baseline risk of postoperative delirium and extubated within 12 h of ICU admission, a short nighttime dose of dexmedetomidine decreased the incidence of delirium on postoperative day one. Although non-statistically significant, our findings also suggested a clinical meaningful difference in the three-day incidence of postoperative delirium. Funding: National Institute on Aging (R01AG053582).

The COVID-19 pandemic has caused tremendous disruptions to non-COVID-19 clinical research. However, there has been little investigation on how patients themselves have responded to clinical trial recruitment during the COVID-19 pandemic. To investigate the effect of the COVID-19 pandemic on rates of patient consent to enrollment into non-COVID-19 clinical trials, we carried out a cross-sectional study using data from the Nitric Oxide/Acute Kidney Injury (NO/AKI) and Minimizing ICU Neurological Dysfunction with Dexmedetomidine-Induced Sleep (MINDDS) trials. All patients eligible for the NO/AKI or MINDDS trials who came to the hospital for cardiac surgery and were approached to gain consent to enrollment were included in the current study. We defined "Before COVID-19" as the time between the start of the relevant clinical trial and the date when efforts toward that clinical trial were deescalated by the hospital due to COVID-19. We defined "During COVID-19" as the time between trial de-escalation and trial completion. 5,015 patients were screened for eligibility. 3,851 were excluded, and 1,434 were approached to gain consent to enrollment. The rate of consent to enrollment was 64% in the "Before COVID-19" group and 45% in the "During COVID-19" group (n = 1,334, P

Background: The optimal ventilatory strategy for the face mask ventilation during anesthesia induction is still unknow.Methods: We evaluated the effect of two positive end-expiratory pressure (PEEP) levels (0 cmH2O and 6 cmH2O) and two oxygen concentration levels (1.0 and .6) on non-hypoxemic apnea time during face mask ventilation of anesthesia induction. Sixty adult patients scheduled for elective surgery were enrolled in this study. The patients were randomized to receive anesthesia induction with four different ventilation strategy under volume-controlled ventilation. Patients assigned to the LOZP group received low fraction of inspiration O2 (FiO2 = .6) and 0 PEEP. Patients assigned to the LOHP group received low fraction of inspiration O2 (FiO2 = .6) and 6 cmH2O PEEP. Patients assigned to the HOZP group received high fraction of inspiration O2 (FiO2 = 1.0) and 0 PEEP. Patients assigned to the HOHP group received high fraction of inspiration O2 (FiO2 = 1.0) and 6cmH2O PEEP. After 3 min of ventilation, the patient was intubated but disconnected from the breathing circuit. Ventilation was not initiated until the pulse oximetry dropped to 90%. The primary outcome was non-hypoxemic apnea time defined as the time from cessation of ventilation to a pulse oximeter reading of 90%. The secondary outcome was the PaO2/FiO2 ratio immediately after ventilation.Results: The non-hypoxemic apnea time was significantly longer in the group of HOHP when compared to the other three groups (192 s ± 70 s, 221 s ± 74 s, 284 s ± 101 s, and 353 s ± 85 s in the LOZP, LOHP, HOZP, and HOHP group, respectively). The PaO2/FiO2 ratio immediately after ventilation was significantly higher in the group of LOHP when compared to the other three groups (LOZP 393 ± 130, LOHP 496 ± 97, HOZP 335 ± 58, HOHP 391 ± 50). When compared the PaO2/FiO2 ratio immediately after ventilation to its value before administration of anesthesia, the PaO2/FiO2 ratio in the group of LOHP was improved, the group LOZP and HOHP remained the same, while the group HOZP significantly decreased.Conclusion: Application of PEEP and 100% of oxygen during face mask ventilation of induction could maximize the non-hypoxemic apnea time. However, the use of PEEP and 60% of oxygen during preoxygenation resulted in improved PaO2/FiO2 ratio.

Abstract The significant mortality rate and prolonged ventilator days associated with invasive mechanical ventilation (IMV) in patients with severe COVID-19 have incited a debate surrounding the use of noninvasive respiratory support (NIRS) (i.e., HFNC, CPAP, NIV) as a potential treatment strategy. Central to this debate is the role of NIRS in preventing intubation in patients with mild respiratory disease and the potential beneficial effects on both patient outcome and resource utilization. However, there remains valid concern that use of NIRS may prolong time to intubation and lung protective ventilation in patients with more advanced disease, thereby worsening respiratory mechanics via self-inflicted lung injury. In addition, the risk of aerosolization with the use of NIRS has the potential to increase healthcare worker (HCW) exposure to the virus. We review the existing literature with a focus on rationale, patient selection and outcomes associated with the use of NIRS in COVID-19 and prior pandemics, as well as in patients with acute respiratory failure due to different etiologies (i.e., COPD, cardiogenic pulmonary edema, etc.) to understand the potential role of NIRS in COVID-19 patients. Based on this analysis we suggest an algorithm for NIRS in COVID-19 patients which includes indications and contraindications for use, monitoring recommendations, systems-based practices to reduce HCW exposure, and predictors of NIRS failure. We also discuss future research priorities for addressing unanswered questions regarding NIRS use in COVID-19 with the goal of improving patient outcomes.

Perioperative organ injury remains a medical, social and economic problem in cardiac surgery. Patients with postoperative organ dysfunction have increases in morbidity, length of stay, long-term mortality, treatment costs and rehabilitation time. Currently, there are no pharmaceutical technologies or non-pharmacological interventions that can mitigate the continuum of multiple organ dysfunction and improve the outcomes of cardiac surgery. It is essential to identify agents that trigger or mediate an organ-protective phenotype during cardiac surgery. The authors highlight nitric oxide (NO) ability to act as an agent for perioperative protection of organs and tissues, especially in the heart–kidney axis. NO has been delivered in clinical practice at an acceptable cost, and the side effects of its use are known, predictable, reversible and relatively rare. This review presents basic data, physiological research and literature on the clinical application of NO in cardiac surgery. Results support the use of NO as a safe and promising approach in perioperative patient management. Further clinical research is required to define the role of NO as an adjunct therapy that can improve outcomes in cardiac surgery. Clinicians also have to identify cohorts of responders for perioperative NO therapy and the optimal modes for this technology.

Abstract Background The surge of critically ill patients due to the coronavirus disease-2019 (COVID-19) overwhelmed critical care capacity in areas of northern Italy. Anesthesia machines have been used as alternatives to traditional ICU mechanical ventilators. However, the outcomes for patients with COVID-19 respiratory failure cared for with Anesthesia Machines is currently unknow. We hypothesized that COVID-19 patients receiving care with Anesthesia Machines would have worse outcomes compared to standard practice. Methods We designed a retrospective study of patients admitted with a confirmed COVID-19 diagnosis at a large tertiary urban hospital in northern Italy. Two care units were included: a 27-bed standard ICU and a 15-bed temporary unit emergently opened in an operating room setting. Intubated patients assigned to Anesthesia Machines (AM group) were compared to a control cohort treated with standard mechanical ventilators (ICU-VENT group). Outcomes were assessed at 60-day follow-up. A multivariable Cox regression analysis of risk factors between survivors and non-survivors was conducted to determine the adjusted risk of death for patients assigned to AM group. Results Complete daily data from 89 mechanically ventilated patients consecutively admitted to the two units were analyzed. Seventeen patients were included in the AM group, whereas 72 were in the ICU-VENT group. Disease severity and intensity of treatment were comparable between the two groups. The 60-day mortality was significantly higher in the AM group compared to the ICU-vent group (12/17 vs. 27/72, 70.6% vs. 37.5%, respectively, p = 0.016). Allocation to AM group was associated with a significantly increased risk of death after adjusting for covariates (HR 4.05, 95% CI: 1.75–9.33, p = 0.001). Several incidents and complications were reported with Anesthesia Machine care, raising safety concerns. Conclusions Our results support the hypothesis that care associated with the use of Anesthesia Machines is inadequate to provide long-term critical care to patients with COVID-19. Added safety risks must be considered if no other option is available to treat severely ill patients during the ongoing pandemic. Clinical trial number Not applicable.

Abstract Children and adolescents account for ~ 13% of total COVID-19 cases in the United States. However, little is known about the nature of the illness in children. The reopening of schools underlines the importance of understanding the epidemiology of pediatric COVID-19 infections. We sought to assess the clinical characteristics and outcomes in pediatric COVID-19 patients. We conducted a retrospective cross-sectional analysis of pediatric patients diagnosed with COVID-19 from healthcare organizations in the United States. The study outcomes (hospitalization, mechanical ventilation, critical care) were assessed using logistic regression. The subgroups of sex and race were compared after propensity score matching. Among 12,306 children with lab-confirmed COVID-19, 16.5% presented with respiratory symptoms (cough, dyspnea), 13.9% had gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), 8.1% had dermatological symptoms (rash), 4.8% had neurological (headache), and 18.8% had other non-specific symptoms (fever, malaise, myalgia, arthralgia and disturbances of smell or taste). In the study cohort, the hospitalization frequency was 5.3%, with 17.6% needing critical care services and 4.1% requiring mechanical ventilation. Following propensity score matching, the risk of all outcomes was similar between males and females. Following propensity score matching, the risk of hospitalization was greater in non-Hispanic Black (RR 1.97 [95% CI 1.49–2.61]) and Hispanic children (RR 1.31 [95% CI 1.03–1.78]) compared with non-Hispanic Whites. In the pediatric population infected with COVID-19, a substantial proportion were hospitalized due to the illness and developed adverse clinical outcomes.

(1) The use of high-flow nasal cannula (HFNC) combined with frequent respiratory monitoring in patients with acute hypoxic respiratory failure due to COVID-19 has been shown to reduce intubation and mechanical ventilation. (2) This prospective, single-center, observational study included consecutive adult patients with COVID-19 pneumonia treated with a high-flow nasal cannula. Hemodynamic parameters, respiratory rate, inspiratory fraction of oxygen (FiO2), saturation of oxygen (SpO2), and the ratio of oxygen saturation to respiratory rate (ROX) were recorded prior to treatment initiation and every 2 h for 24 h. A 6-month follow-up questionnaire was also conducted. (3) Over the study period, 153 of 187 patients were eligible for HFNC. Of these patients, 80% required intubation and 37% of the intubated patients died in hospital. Male sex (OR = 4.65; 95% CI [1.28; 20.6], p = 0.03) and higher BMI (OR = 2.63; 95% CI [1.14; 6.76], p = 0.03) were associated with an increased risk for new limitations at 6-months after hospital discharge. (4) 20% of patients who received HFNC did not require intubation and were discharged alive from the hospital. Male sex and higher BMI were associated with poor long-term functional outcomes.

Objective: To evaluate the race-stratified state-level prevalence of health determinants and the racial disparities in coronavirus disease 2019 (COVID-19) cumulative incidence and mortality in the United States. Patients and Methods: The age-adjusted race-stratified prevalence of comorbidities (hypertension, diabetes, dyslipidemia, and obesity), preexisting medical conditions (pulmonary disease, heart disease, stroke, kidney disease, and malignant neoplasm), poor health behaviors (smoking, alcohol abuse, and physical inactivity), and adverse socioeconomic factors (education, household income, and health insurance) was computed in 435,139 American adult participants from the 2017 Behavioral Risk Factor Surveillance System survey. Correlation was assessed between health determinants and the race-stratified COVID-19 crude mortality rate and infection-fatality ratio computed from respective state public health departments in 47 states. Results: Blacks had a higher prevalence of comorbidities (63.3%; 95% CI, 62.4% to 64.2% vs 55.1%; 95% CI, 54.7% to 55.5%) and adverse socioeconomic factors (47.0%; 95% CI, 46.0% to 47.9% vs 30.9%; 95% CI, 30.6% to 31.3%) than did whites. The prevalence of preexisting medical conditions was similar in blacks (30.4%; 95% CI, 28.8% to 32.1%) and whites (30.8%; 95% CI, 30.2% to 31.4%). The prevalence of poor health behaviors was higher in whites (57.2%; 95% CI, 56.3% to 58.0%) than in blacks (50.2%; 95% CI,46.2% to 54.2%). Comorbidities and adverse socioeconomic factors were highest in the southern region, and poor health behaviors were highest in the western region. The cumulative incidence rate (per 100,000 persons) was 3-fold higher in blacks (1546.4) than in whites (540.4). The crude mortality rate (per 100,000 persons) was 2-fold higher in blacks (83.2) than in whites (33.2). However, the infection-fatality ratio (per 100 cases) was similar in whites (6.2) and blacks (5.4). Within racial groups, the geographic distribution of health determinants did not correlate with the state-level COVID-19 mortality and infection-fatality ratio (P>.05 for all). Conclusion: Racial disparities in COVID-19 are largely driven by the higher cumulative incidence of infection in blacks. There is a discordance between the geographic dispersion of COVID-19 mortality and the regional distribution of health determinants.

Abstract Background Topical anesthesia is a crucial step in awake endotracheal intubation for providing favorable intubation conditions. The standard of care technique for awake intubation at our institution, which consists of oropharyngeal tetracaine spray, can result in inadequate mucosal anesthesia. Therefore, we sought to compare the effectiveness of dyclonine hydrochloride mucilage to the standard of care tetracaine in achieving anesthesia of the upper airways for awake endotracheal intubation. Methods This is a randomized, assessor-blinded, prospective study. From Jun. 1st, 2019 to Aug. 1st, 2019, patients scheduled for either endoscopic submucosal dissection or peroral endoscopic myotomy were enrolled and randomly allocated into two groups after obtaining written informed consent: patients allocated to novel awake intubation care (Group N-AIC) received a single administration of oral dyclonine hydrochloride mucilage, whereas patients allocated to standard awake intubation care (Group S-AIC) received three oropharyngeal tetracaine sprays before transcricoid tetracaine injection before awake intubation. Mean arterial pressure (MAP), which was the primary outcome of this study, as well as heart rate (HR) were recorded throughout the procedure and compared between the two groups. Feeling of numbness, nausea, and intubation conditions after topical anesthesia were also assessed. Results Sixty patients were enrolled and completed the study. Baseline MAP and HR were similar between the two groups. However, hemodynamic responses to intubation and gastrointestinal endoscopy, especially MAP, were significantly less elevated in Group N-AIC. The degree of numbness of the oropharyngeal mucosa after topical anesthesia did not differ between the two groups, neither did the feeling of nausea during laryngoscopy. The amount of pharyngeal secretions before intubation was less in Group N-AIC. Total intubation time was significantly shorter in Group N-AIC when compared to Group S-AIC (18.4 ± 2.86 vs. 22.3 ± 6.47, P

Abstract Those involved in the airway management of COVID-19 patients are particularly at risk. Here, we describe a practical, stepwise protocol for safe in-hospital airway management in patients with suspected or confirmed COVID-19 infection.

Abstract Background Limited data exist regarding ventilation in patients with class III obesity [body mass index (BMI) > 40 kg/m2] and acute respiratory distress syndrome (ARDS). The aim of the present study was to determine whether an individualized titration of mechanical ventilation according to cardiopulmonary physiology reduces the mortality in patients with class III obesity and ARDS. Methods In this retrospective study, we enrolled adults admitted to the ICU from 2012 to 2017 who had class III obesity and ARDS and received mechanical ventilation for > 48 h. Enrolled patients were divided in two cohorts: one cohort (2012–2014) had ventilator settings determined by the ARDSnet table for lower positive end-expiratory pressure/higher inspiratory fraction of oxygen (standard protocol-based cohort); the other cohort (2015–2017) had ventilator settings determined by an individualized protocol established by a lung rescue team (lung rescue team cohort). The lung rescue team used lung recruitment maneuvers, esophageal manometry, and hemodynamic monitoring. Results The standard protocol-based cohort included 70 patients (BMI = 49 ± 9 kg/m2), and the lung rescue team cohort included 50 patients (BMI = 54 ± 13 kg/m2). Patients in the standard protocol-based cohort compared to lung rescue team cohort had almost double the risk of dying at 28 days [31% versus 16%, P = 0.012; hazard ratio (HR) 0.32; 95% confidence interval (CI95%) 0.13–0.78] and 3 months (41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16–0.74), and this effect persisted at 6 months and 1 year (incidence of death unchanged 41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16–0.74). Conclusion Individualized titration of mechanical ventilation by a lung rescue team was associated with decreased mortality compared to use of an ARDSnet table.

Abstract Background The effect of nitric oxide (NO) on renal function is controversial in critical illness. We performed a systematic meta-analysis and trial sequential analysis to determine the effect of NO gas on renal function and other clinical outcomes in patients requiring cardiopulmonary bypass (CPB). The primary outcome was the relative risk (RR) of acute kidney injury (AKI), irrespective of the AKI stage. The secondary outcome was the mean difference (MD) in the length of ICU and hospital stay, the RR of postoperative hemorrhage, and the MD in levels of methemoglobin. Trial sequential analysis (TSA) was performed for the primary outcome. Results 54 trials were assessed for eligibility and 5 studies (579 patients) were eligible for meta-analysis. NO was associated with reduced risk of AKI (RR 0.76, 95% confidential interval [CI], 0.62 to 0.93, I 2 = 0%). In the subgroup analysis by NO initiation timing, NO did not decrease the risk of AKI when started at the end of CPB (RR 1.20, 95% CI 0.52–2.78, I 2 = 0%). However, NO did significantly reduce the risk of AKI when started from the beginning of CPB (RR 0.71, 95% CI 0.54–0.94, I 2 = 10%). We conducted TSA based on three trials (400 patients) using KDIGO criteria and with low risk of bias. TSA indicated a CI of 0.50–1.02 and an optimal information size of 589 patients, suggesting a lack of definitive conclusion. Furthermore, NO does not affect the length of ICU and hospital stay or the risk of postoperative hemorrhage. NO slightly increased the level of methemoglobin at the end of CPB (MD 0.52%, 95% CI 0.27–0.78%, I 2 = 90%), but it was clinically negligible. Conclusions NO appeared to reduce the risk of postoperative AKI in patients undergoing CPB. Additional studies are required to ascertain the finding and further determine the dosage, timing and duration of NO administration.

IMPORTANCE:. Factors associated with mortality in coronavirus disease 2019 patients on invasive mechanical ventilation are still not fully elucidated. OBJECTIVES:. To identify patient-level parameters, readily available at the bedside, associated with the risk of in-hospital mortality within 28 days from commencement of invasive mechanical ventilation or coronavirus disease 2019. DESIGN, SETTING, AND PARTICIPANTS:. Prospective observational cohort study by the global Coronavirus Disease 2019 Critical Care Consortium. Patients with laboratory-confirmed coronavirus disease 2019 requiring invasive mechanical ventilation from February 2, 2020, to May 15, 2021. MAIN OUTCOMES AND MEASURES:. Patient characteristics and clinical data were assessed upon ICU admission, the commencement of invasive mechanical ventilation and for 28 days thereafter. We primarily aimed to identify time-independent and time-dependent risk factors for 28-day invasive mechanical ventilation mortality. RESULTS:. One-thousand five-hundred eighty-seven patients were included in the survival analysis; 588 patients died in hospital within 28 days of commencing invasive mechanical ventilation (37%). Cox-regression analysis identified associations between the hazard of 28-day invasive mechanical ventilation mortality with age (hazard ratio, 1.26 per 10-yr increase in age; 95% CI, 1.16–1.37; p < 0.001), positive end-expiratory pressure upon commencement of invasive mechanical ventilation (hazard ratio, 0.81 per 5 cm H2O increase; 95% CI, 0.67–0.97; p = 0.02). Time-dependent parameters associated with 28-day invasive mechanical ventilation mortality were serum creatinine (hazard ratio, 1.28 per doubling; 95% CI, 1.15–1.41; p < 0.001), lactate (hazard ratio, 1.22 per doubling; 95% CI, 1.11–1.34; p < 0.001), Paco2 (hazard ratio, 1.63 per doubling; 95% CI, 1.19–2.25; p < 0.001), pH (hazard ratio, 0.89 per 0.1 increase; 95% CI, 0.8–14; p = 0.041), Pao2/Fio2 (hazard ratio, 0.58 per doubling; 95% CI, 0.52–0.66; p < 0.001), and mean arterial pressure (hazard ratio, 0.92 per 10 mm Hg increase; 95% CI, 0.88–0.97; p = 0.003). CONCLUSIONS AND RELEVANCE:. This international study suggests that in patients with coronavirus disease 2019 on invasive mechanical ventilation, older age and clinically relevant variables monitored at baseline or sequentially during the course of invasive mechanical ventilation are associated with 28-day invasive mechanical ventilation mortality hazard. Further investigation is warranted to validate any causative roles these parameters might play in influencing clinical outcomes.

The acute respiratory distress syndrome (ARDS) is a severe form of acute hypoxemic respiratory failure caused by an insult to the alveolar-capillary membrane, resulting in a marked reduction of aerated alveoli, increased vascular permeability and subsequent interstitial and alveolar pulmonary edema, reduced lung compliance, increase of physiological dead space, and hypoxemia. Most ARDS patients improve their systemic oxygenation, as assessed by the ratio between arterial partial pressure of oxygen and inspired oxygen fraction, with conventional intensive care and the application of moderate-to-high levels of positive end-expiratory pressure. However, in some patients hypoxemia persisted because the lungs are markedly injured, remaining unresponsive to increasing the inspiratory fraction of oxygen and positive end-expiratory pressure. For decades, mechanical ventilation was the only standard support technique to provide acceptable oxygenation and carbon dioxide removal. Mechanical ventilation provides time for the specific therapy to reverse the disease-causing lung injury and for the recovery of the respiratory function. The adverse effects of mechanical ventilation are direct consequences of the changes in pulmonary airway pressures and intrathoracic volume changes induced by the repetitive mechanical cycles in a diseased lung. In this article, we review 14 major successful and unsuccessful randomized controlled trials conducted in patients with ARDS on a series of techniques to improve oxygenation and ventilation published since 2010. Those trials tested the effects of adjunctive therapies (neuromuscular blocking agents, prone positioning), methods for selecting the optimum positive end-expiratory pressure (after recruitment maneuvers, or guided by esophageal pressure), high-frequency oscillatory ventilation, extracorporeal oxygenation, and pharmacologic immune modulators of the pulmonary and systemic inflammatory responses in patients affected by ARDS. We will briefly comment physiology-based gaps of negative trials and highlight the possible needs to address in future clinical trials in ARDS.

OBJECTIVE:. To investigate whether individualized optimization of mechanical ventilation through the implementation of a lung rescue team could reduce the need for venovenous extracorporeal membrane oxygenation in patients with obesity and acute respiratory distress syndrome and decrease ICU and hospital length of stay and mortality. DESIGN:. Single-center, retrospective study at the Massachusetts General Hospital from June 2015 to June 2019. PATIENTS:. All patients with obesity and acute respiratory distress syndrome who were referred for venovenous extracorporeal membrane oxygenation evaluation due to hypoxemic respiratory failure. INTERVENTION:. Evaluation and individualized optimization of mechanical ventilation by the lung rescue team before the decision to proceed with venovenous extracorporeal membrane oxygenation. The control group was those patients managed according to hospital standard of care without lung rescue team evaluation. MEASUREMENT AND MAIN RESULTS:. All 20 patients (100%) allocated in the control group received venovenous extracorporeal membrane oxygenation, whereas 10 of 13 patients (77%) evaluated by the lung rescue team did not receive venovenous extracorporeal membrane oxygenation. Patients who underwent lung rescue team evaluation had a shorter duration of mechanical ventilation (p = 0.03) and shorter ICU length of stay (p = 0.03). There were no differences between groups in in-hospital, 30-day, or 1–year mortality. CONCLUSIONS:. In this hypothesis-generating study, individualized optimization of mechanical ventilation of patients with acute respiratory distress syndrome and obesity by a lung rescue team was associated with a decrease in the utilization of venovenous extracorporeal membrane oxygenation, duration of mechanical ventilation, and ICU length of stay. Mortality was not modified by the lung rescue team intervention.

Introduction: In patients with acute respiratory distress syndrome (ARDS), the PaO2/FiO2 ratio at the time of ARDS diagnosis is weakly associated with mortality. We hypothesized that setting a PaO2/FiO2 threshold in 150 mm Hg at 24 h from moderate/severe ARDS diagnosis would improve predictions of death in the intensive care unit (ICU). Methods: We conducted an ancillary study in 1303 patients with moderate to severe ARDS managed with lung-protective ventilation enrolled consecutively in four prospective multicenter cohorts in a network of ICUs. The first three cohorts were pooled (n = 1000) as a testing cohort; the fourth cohort (n = 303) served as a confirmatory cohort. Based on the thresholds for PaO2/FiO2 (150 mm Hg) and positive end-expiratory pressure (PEEP) (10 cm H2O), the patients were classified into four possible subsets at baseline and at 24 h using a standardized PEEP-FiO2 approach: (I) PaO2/FiO2 ≥ 150 at PEEP < 10, (II) PaO2/FiO2 ≥ 150 at PEEP ≥ 10, (III) PaO2/FiO2 < 150 at PEEP < 10, and (IV) PaO2/FiO2 < 150 at PEEP ≥ 10. Primary outcome was death in the ICU. Results: ICU mortalities were similar in the testing and confirmatory cohorts (375/1000, 37.5% vs. 112/303, 37.0%, respectively). At baseline, most patients from the testing cohort (n = 792/1000, 79.2%) had a PaO2/FiO2 < 150, with similar mortality among the four subsets (p = 0.23). When assessed at 24 h, ICU mortality increased with an advance in the subset: 17.9%, 22.8%, 40.0%, and 49.3% (p < 0.0001). The findings were replicated in the confirmatory cohort (p < 0.0001). However, independent of the PEEP levels, patients with PaO2/FiO2 < 150 at 24 h followed a distinct 30-day ICU survival compared with patients with PaO2/FiO2 ≥ 150 (hazard ratio 2.8, 95% CI 2.2–3.5, p < 0.0001). Conclusions: Subsets based on PaO2/FiO2 thresholds of 150 mm Hg assessed after 24 h of moderate/severe ARDS diagnosis are clinically relevant for establishing prognosis, and are helpful for selecting adjunctive therapies for hypoxemia and for enrolling patients into therapeutic trials.

Mitochondrial dysfunction has been implicated in the pathogenesis of inflammation and multi-organ dysfunction in major trauma, including burn injury. Coenzyme Q10 (CoQ10) is a metabolite of the mevalonate pathway and an essential cofactor for the electron transport in the mitochondria. In addition, its reduced form (ubiquinol) functions as an antioxidant. Little is known as to whether oral CoQ10 supplementation effectively increases intracellular CoQ10 levels in humans. To study the bioavailability of CoQ10 supplementation, we conducted a randomized, double-blind, placebo-controlled study of reduced CoQ10 (ubiquinol-10) (1800 mg/day, t.i.d.) in burn patients at a single, tertiary-care hospital. Baseline plasma CoQ10 levels were significantly lower in burn patients than in healthy volunteers, although plasma CoQ10/cholesterol ratio did not differ between the groups. CoQ10 supplementation increased plasma concentrations of total and reduced CoQ10 and total CoQ10 content in peripheral blood mononuclear cells (PBMCs) in burn patients compared with the placebo group. CoQ10 supplementation did not significantly change circulating levels of mitochondrial DNA, inflammatory markers (e.g., interleukins, TNF-α, IFN-γ), or Sequential Organ Failure Assessment (SOFA) scores compared with the placebo group. This study showed that a relatively high dose of reduced CoQ10 supplementation increased the intracellular CoQ10 content in PBMCs as well as plasma concentrations in burn patients.

IMPORTANCE:. Prone positioning improves clinical outcomes in moderate-to-severe acute respiratory distress syndrome and has been widely adopted for the treatment of patients with acute respiratory distress syndrome due to coronavirus disease 2019. Little is known about the effects of prone positioning among patients with less severe acute respiratory distress syndrome, obesity, or those treated with pulmonary vasodilators. OBJECTIVES:. We characterize the change in oxygenation, respiratory system compliance, and dead-space-to-tidal-volume ratio in response to prone positioning in patients with coronavirus disease 2019 acute respiratory distress syndrome with a range of severities. A subset analysis of patients treated with inhaled nitric oxide and subsequent prone positioning explored the influence of pulmonary vasodilation on the physiology of prone positioning. DESIGN, SETTING, AND PARTICIPANTS:. Retrospective cohort study of all consecutively admitted adult patients with acute respiratory distress syndrome due to coronavirus disease 2019 treated with mechanical ventilation and prone positioning in the ICUs of an academic hospital between March 11, 2020, and May 1, 2020. MAIN OUTCOMES AND MEASURES:. Respiratory system mechanics and gas exchange during the first episode of prone positioning. RESULTS:. Among 122 patients, median (interquartile range) age was 60 years (51–71 yr), median body mass index was 31.5 kg/m2 (27–35 kg/m2), and 50 patients (41%) were female. The ratio of Pao2 to Fio2 improved with prone positioning in 90% of patients. Prone positioning was associated with a significant increase in the ratio of Pao2 to Fio2 (from median 149 [123–170] to 226 [169–268], p < 0.001) but no change in dead-space-to-tidal-volume ratio or respiratory system compliance. Supine ratio of Pao2 to Fio2, respiratory system compliance, positive end-expiratory pressure, and body mass index did not correlate with absolute change in the ratio of Pao2 to Fio2 with prone positioning. However, patients with ratio of Pao2 to Fio2 less than 150 experienced a greater relative improvement in oxygenation with prone positioning than patients with ratio of Pao2 to Fio2 greater than or equal to 150 (median percent change in ratio of Pao2 to Fio2 62 [29–107] vs 30 [10–70], p = 0.002). Among 12 patients, inhaled nitric oxide prior to prone positioning was associated with a significant increase in the ratio of Pao2 to Fio2 (from median 136 [77–168] to 170 [138–213], p = 0.003) and decrease in dead-space-to-tidal-volume ratio (0.54 [0.49–0.58] to 0.46 [0.44–0.53], p = 0.001). Subsequent prone positioning in this subgroup further improved the ratio of Pao2 to Fio2 (from 145 [122–183] to 205 [150–232], p = 0.017) but did not change dead-space-to-tidal-volume ratio. CONCLUSIONS AND RELEVANCE:. Prone positioning improves oxygenation across the acute respiratory distress syndrome severity spectrum, irrespective of supine respiratory system compliance, positive end-expiratory pressure, or body mass index. There was a greater relative benefit among patients with more severe disease. Prone positioning confers an additive benefit in oxygenation among patients treated with inhaled nitric oxide.

Background: Acute respiratory distress syndrome (ARDS) secondary to coronavirus disease-2019 (COVID-19) is characterized by substantial heterogeneity in clinical, biochemical, and physiological characteristics. However, the pathophysiology of severe COVID-19 infection is poorly understood. Previous studies established clinical and biological phenotypes among classical ARDS cohorts, with important therapeutic implications. The phenotypic profile of COVID-19 associated ARDS remains unknown. Methods: We used latent class modeling via a multivariate mixture model to identify phenotypes from clinical and biochemical data collected from 263 patients admitted to Massachusetts General Hospital intensive care unit with COVID-19-associated ARDS between March 13 and August 2, 2020. Findings: We identified two distinct phenotypes of COVID-19-associated ARDS, with substantial differences in biochemical profiles despite minimal differences in respiratory dynamics. The minority phenotype (class 2, n = 70, 26·6%) demonstrated increased markers of coagulopathy, with mild relative hyper-inflammation and dramatically increased markers of end-organ dysfunction (e.g., creatinine, troponin). The odds of 28-day mortality among the class 2 phenotype was more than double that of the class 1 phenotype (40·0% vs.· 23·3%, OR = 2·2, 95% CI [1·2, 3·9]). Interpretation: We identified distinct phenotypic profiles in COVID-19 associated ARDS, with little variation according to respiratory physiology but with important variation according to systemic and extra-pulmonary markers. Phenotypic identity was highly associated with short-term mortality. The class 2 phenotype exhibited prominent signatures of coagulopathy, suggesting that vascular dysfunction may play an important role in the clinical progression of severe COVID-19-related disease.

The global COVID-19 pandemic has become the largest public health challenge of recent years. The incidence of COVID-19-related acute hypoxemic respiratory failure (AHRF) occurs in up to 15% of hospitalized patients. Antiviral drugs currently available to clinicians have little to no effect on mortality, length of in-hospital stay, the need for mechanical ventilation, or long-term effects. Inhaled nitric oxide (iNO) administration is a promising new non-standard approach to directly treat viral burden while enhancing oxygenation. Along with its putative antiviral affect in COVID-19 patients, iNO can reduce inflammatory cell-mediated lung injury by inhibiting neutrophil activation, lowering pulmonary vascular resistance and decreasing edema in the alveolar spaces, collectively enhancing ventilation/perfusion matching. This narrative review article presents recent literature on the iNO therapy use for COVID-19 patients. The authors suggest that early administration of the iNO therapy may be a safe and promising approach for the treatment of COVID-19 patients. The authors also discuss unconventional approaches to treatment, continuous versus intermittent high-dose iNO therapy, timing of initiation of therapy (early versus late), and novel delivery systems. Future laboratory and clinical research is required to define the role of iNO as an adjunct therapy against bacterial, viral, and fungal infections.

Background. Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. The gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers. Conclusions. High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans.

Hypoxemia of the acute respiratory distress syndrome can be reduced by turning patients prone. Prone positioning (PP) is labor intensive, risks unplanned tracheal extubation, and can result in facial tissue injury. We retrospectively examined prolonged, repeated, and early versus later PP for 20 patients with COVID-19 respiratory failure. Blood gases and ventilator settings were collected before PP, at 1, 7, 12, 24, 32, and 39 h after PP, and 7 h after completion of PP. Analysis of variance was used for comparisons with baseline values at supine positions before turning prone. PP for >39 h maintained PaO2/FiO2 (P/F) ratios when turned supine; the P/F decrease at 7 h was not significant from the initial values when turned supine. Patients turned prone a second time, when again turned supine at 7 h, had significant decreased P/F. When PP started for an initial P/F ≤ 150 versus P/F > 150, the P/F increased throughout the PP and upon return to supine. Our results show that a single turn prone for >39 h is efficacious and saves the burden of multiple prone turns, and there is no significant advantage to initiating PP when P/F > 150 compared to P/F ≤ 150.