Too Much Oxygen: Hyperoxia and Oxygen Management in Mechanically Ventilated Patients.

Hyperoxia, or excess oxygen supplementation, prevails in the intensive care unit (ICU) without a beneficial effect and, in some instances, may cause harm. Recent interest and surge in clinical studies in mechanically ventilated critically ill patients has brought this to the attention of clinicians and researchers. Hyperoxia can cause alveolar injury, pulmonary edema, and subsequent systemic inflammatory response and is known to augment ventilator-associated lung injury. Liberal oxygenation practices are also associated with increased mortality in subsets of critically ill patients with post-cardiac arrest, stroke, and traumatic brain injury. Most clinicians agree that oxygen titration should be done and, with appropriate safeguards, lower oxygenation targets may be acceptable and possibly beneficial in many critically ill patients. However, this problem is often overlooked. The use of periodic reminders and decision support may facilitate implementation of more precise oxygen titration at the bedside of critically ill patients. For implementing practice change, studies involving education and guidance of all health care staff involved in oxygen management are critical.

Development and validation of severe hypoxemia associated risk prediction model in 1,000 mechanically ventilated patients*.

OBJECTIVES: Patients with severe, persistent hypoxemic respiratory failure have a higher mortality. Early identification is critical for informing clinical decisions, using rescue strategies, and enrollment in clinical trials. The objective of this investigation was to develop and validate a prediction model to accurately and timely identify patients with severe hypoxemic respiratory failure at high risk of death, in whom novel rescue strategies can be efficiently evaluated. DESIGN: Electronic medical record analysis. SETTING: Medical, surgical, and mixed ICU setting at a tertiary care institution. PATIENTS: Mechanically-ventilated ICU patients. MEASUREMENTS AND MAIN RESULTS: Mechanically ventilated ICU patients were screened for severe hypoxemic respiratory failure (Murray lung injury score of ≥ 3). Survival to hospital discharge was the dependent variable. Clinical predictors within 24 hours of onset of severe hypoxemia were considered as the independent variables. An area under the curve and a Hosmer-Lemeshow goodness-of-fit test were used to assess discrimination and calibration. A logistic regression model was developed in the derivation cohort (2005-2007). The model was validated in an independent cohort (2008-2010). Among 79,341 screened patients, 1,032 met inclusion criteria. Mortality was 41% in the derivation cohort (n = 464) and 35% in the validation cohort (n = 568). The final model included hematologic malignancy, cirrhosis, aspiration, estimated dead space, oxygenation index, pH, and vasopressor use. The area under the curve of the model was 0.85 (0.82-0.89) and 0.79 (0.75-0.82) in the derivation and validation cohorts, respectively, and showed good calibration. A modified model, including only physiologic variables, performed similarly. It had comparable performance in patients with acute respiratory distress syndrome and outperformed previous prognostic models. CONCLUSIONS: A model using comorbid conditions and physiologic variables on the day of developing severe hypoxemic respiratory failure can predict hospital mortality.

The role of potentially preventable hospital exposures in the development of acute respiratory distress syndrome: a population-based study.

OBJECTIVE: Acute respiratory distress syndrome is a common complication of critical illness, with high mortality and limited treatment options. Preliminary studies suggest that potentially preventable hospital exposures contribute to acute respiratory distress syndrome development. We aimed to determine the association between specific hospital exposures and the rate of acute respiratory distress syndrome development among at-risk patients. DESIGN: Population-based, nested, Matched case-control study. PATIENTS: Consecutive adults who developed acute respiratory distress syndrome from January 2001 through December 2010 during their hospital stay (cases) were matched to similar-risk patients without acute respiratory distress syndrome (controls). They were matched for 6 baseline characteristics. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Trained investigators blinded to outcome of interest reviewed medical records for evidence of specific exposures, including medical and surgical adverse events, inadequate empirical antimicrobial treatment, hospital-acquired aspiration, injurious mechanical ventilation, transfusion, and fluid and medication administration. Conditional logistic regression was used to calculate the risk associated with individual exposures. During the 10-year period, 414 patients with hospital-acquired acute respiratory distress syndrome were identified and matched to 414 at-risk, acute respiratory distress syndrome-free controls. Adverse events were highly associated with acute respiratory distress syndrome development (odds ratio, 6.2; 95% CI, 4.0-9.7), as were inadequate antimicrobial therapy, mechanical ventilation with injurious tidal volumes, hospital-acquired aspiration, and volume of blood products transfused and fluids administered. Exposure to antiplatelet agents during the at-risk period was associated with a decreased risk of acute respiratory distress syndrome. Rate of adverse hospital exposures and prevalence of acute respiratory distress syndrome decreased during the study period. CONCLUSIONS: Prevention of adverse hospital exposures in at-risk patients may limit the development of acute respiratory distress syndrome.

Synergistic Role of NK Cells and Monocytes in Promoting Atherogenesis in Severe COVID-19 Patients.

Clinical data demonstrate an increased predisposition to cardiovascular disease (CVD) following severe COVID-19 infection. This may be driven by a dysregulated immune response associated with severe disease. Monocytes and vascular tissue resident macrophages play a critical role in atherosclerosis, the main pathology leading to ischemic CVD. Natural killer (NK) cells are a heterogenous group of cells that are critical during viral pathogenesis and are known to be dysregulated during severe COVID-19 infection. Their role in atherosclerotic cardiovascular disease has recently been described. However, the contribution of their altered phenotypes to atherogenesis following severe COVID-19 infection is unknown. We demonstrate for the first time that during and after severe COVID-19, circulating proinflammatory monocytes and activated NK cells act synergistically to increase uptake of oxidized low-density lipoprotein (Ox-LDL) into vascular tissue with subsequent foam cell generation leading to atherogenesis despite recovery from acute infection. Our data provide new insights, revealing the roles of monocytes/macrophages, and NK cells in COVID-19-related atherogenesis.

Rationale and design of a randomized controlled clinical trial; Titration of Oxygen Levels (TOOL) during mechanical ventilation.

BACKGROUND: Both hyperoxemia and hypoxemia are deleterious in critically ill patients. Targeted oxygenation is recommended to prevent both of these extremes, however this has not translated to the bedside. Hyperoxemia likely persists more than hypoxemia due to absence of immediate discernible adverse effects, cognitive biases and delay in prioritization of titration. METHODS: We present the methodology for the Titration Of Oxygen Levels (TOOL) trial, an open label, randomized controlled trial of an algorithm-based FiO2 titration with electronic medical record-based automated alerts. We hypothesize that the study intervention will achieve targeted oxygenation by curbing episodes of hyperoxemia while preventing hypoxemia. In the intervention arm, electronic alerts will be used to titrate FiO2 if SpO2 is ≥94% with FiO2 levels ≥0.4 over 45 min. FiO2 will be titrated per standard practice in the control arm. This study is being carried out with deferred consent. The sample size to determine efficacy is 316 subjects, randomized in a 1:1 ratio to the intervention vs. control arm. The primary outcome is proportion of time during mechanical ventilation spent with FiO2 ≥ 0.4 and SpO2 ≥ 94%. We will also assess proportion of time during mechanical ventilation spent with SpO2 < 88%, duration of mechanical ventilation, length of ICU and hospital stay, hospital mortality, and adherence to electronic alerts as secondary outcomes. CONCLUSION: This study is designed to evaluate the efficacy of a high fidelity, bioinformatics-based, electronic medical record derived electronic alert system to improve targeted oxygenation in mechanically ventilated patients by reducing excessive FiO2 exposure.

Early Titration of Oxygen During Mechanical Ventilation Reduces Hyperoxemia in a Pilot, Feasibility, Randomized Control Trial for Automated Titration of Oxygen Levels.

Timely regulation of oxygen (Fio2) is essential to prevent hyperoxemia or episodic hypoxemia. Exposure to excessive Fio2 is often noted early after onset of mechanical ventilation. In this pilot study, we examined the feasibility, safety, and efficacy of a clinical trial to prioritize Fio2 titration with electronic alerts to respiratory therapists. STUDY DESIGN: Open-labeled, randomized control pilot trial. SETTING: Medical ICU. SUBJECTS: Adults requiring mechanical ventilation. INTERVENTIONS: Protocolized oxygen titration was initiated one hour after initiation of mechanical ventilation. When Spo2 exceeded 92% while on Fio2 ≥ 0.5, an electronic alert to respiratory therapists was triggered at 30-minute intervals. In the control arm, respiratory therapists titrated Fio2 by standard physician's orders. MEASUREMENTS AND MAIN RESULTS: The primary end point was to determine if early Fio2 titration based on automated alerts was feasible in terms of reducing hyperoxemia. Secondary analyses included the number and frequency of alerts, mechanical ventilation duration, and ICU length of stay. Among 135 randomized patients, 72 were assigned to the intervention arm and 63 to the control arm. A total 877 alerts were sent. Exposure to hyperoxemia was significantly reduced in the intervention group by a median of 7.5 hours (13.7 [interquartile range (IQR), 2.9-31.1] vs 21.2 [IQR, 10.9-64.4]; p < 0.0004). Maximal Fio2 titration during the first quartile resulted in significant reduction in mechanical ventilation duration and ICU stay. Minor hypoxemic events (Spo2 < 88%) represented 12% of alerts, 9% were transient and responded to a single Fio2 increase, whereas 3% of alerts were associated with recurrent transient hypoxemia. CONCLUSIONS: Our pilot study indicates that early Fio2 titration driven by automated alerts is feasible in the ICU, as reflected by a statistically significant reduction of hyperoxemia exposure, limited consequential hypoxemia, and reduced ICU resource utilization. The encouraging results of this pilot study need to be validated in a larger ICU cohort.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

Electronic Medical Record-Based Pager Notification Reduces Excess Oxygen Exposure in Mechanically Ventilated Subjects.

BACKGROUND: Liberal oxygenation during mechanical ventilation is harmful in critically ill patients and in certain subsets of patients, including those with stroke, acute myocardial infarction, and cardiac arrest. Surveillance through electronic medical records improves safety of mechanical ventilation in the ICU. To date, this practice has not been used for oxygen titration ([Formula: see text]) in adults. We hypothesize that a surveillance system based on the electronic medical record to alert respiratory therapists to titrate [Formula: see text] is feasible, safe, and efficacious. METHODS: In this pilot study, mechanically ventilated subjects were randomized to respiratory therapist-driven [Formula: see text] titration after an electronic alert versus standard of care (ie, titration based on physician order). An automated surveillance system utilizing a hyperoxemia-detection algorithm generated an electronic alert to a respiratory therapist's pager. Hyperoxemia was defined as [Formula: see text] > 0.5 and [Formula: see text] > 95% for > 30 min. No other aspects of treatment were changed. We assessed feasibility, safety, and preliminary efficacy. Primary outcome was duration of hyperoxemia during mechanical ventilation. An unsafe outcome was identified as hypoxemia ([Formula: see text] < 88%) within 1 h after titration per alert. Feasibility was assessed by a survey of respiratory therapists. RESULTS: Of 226 randomized subjects, 31 were excluded (eg, programming errors of the electronic alerts, no consent, physician discretion). We included 195 subjects, of whom 86 were in the intervention arm. Alert accuracy was 78%, and respiratory therapists responded to 64% of the alerts. During mechanical ventilation, exposure to hyperoxemia significantly decreased in the intervention group (median 13.5 h [interquartile range 6.2-29.4] vs 18.8 h [interquartile range 9.6-37.4]). No episodes of significant hypoxemia were registered. Most respiratory therapists agreed that the alert was helpful in reducing excessive oxygen exposure. CONCLUSIONS: Use of an electronic surveillance system to titrate [Formula: see text] was safe and feasible and showed preliminary efficacy in reducing hyperoxemia. Our study serves to justify larger randomized controlled trials for [Formula: see text] titration.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

BACKGROUND: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. METHODS: The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. DISCUSSION: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Passive Immunity Trial for Our Nation (PassITON): study protocol for a randomized placebo-control clinical trial evaluating COVID-19 convalescent plasma in hospitalized adults.

Background: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods: The Pass ive I mmunity T rial for O ur N ation (PassITON), is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the United States to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial Registration: ClinicalTrials.gov: NCT04362176. Date of trial registration: April 24, 2020, https://clinicaltrials.gov/ct2/show/NCT04362176.

A Comparative Effectiveness Study of Rescue Strategies in 1,000 Subjects With Severe Hypoxemic Respiratory Failure.

BACKGROUND: Subjects with severe hypoxemic respiratory failure have shown a high mortality in previous studies. METHODS: All adult ICU patients requiring mechanical ventilation from 2005 to 2010 at Mayo Clinic were screened for severe hypoxemia (Murray lung injury score of ≥ 3). Extracorporeal membrane oxygenation, prone positioning, high-frequency oscillatory ventilation (HFOV), and inhaled vasodilators were considered as rescue strategies. A propensity-based scoring was created for the indication or predilection to use each strategy. A model was created to evaluate the association of each rescue strategy with hospital mortality. RESULTS: Among 1,032 subjects with severe hypoxemia, 239 subjects received some form of rescue strategy (59 received a combination of therapies, and 180 received individual therapies). Inhaled vasodilators were the most common, followed by HFOV. Rescue strategies were used in younger subjects with severe oxygenation deficits. Subjects receiving rescue strategies had higher mortality and longer ICU stays. None of the strategies individually or in combination showed a significant association with hospital mortality after adjusting covariates by propensity scoring. Adjusted Odds ratios and respective 95% CI were as follows: HFOV 0.67 (0.35-1.27), extracorporeal membrane oxygenation 0.63 (0.18-1.92), prone position 1.07 (0.49-2.28), and inhaled vasodilators 1.17 (0.78-1.77). CONCLUSIONS: In this retrospective comparative effectiveness study, there was no association of rescue strategies with hospital mortality in subjects with severe hypoxemia.

Refractory Hypoxemia and Use of Rescue Strategies. A U.S. National Survey of Adult Intensivists.

RATIONALE: The management of severe and refractory hypoxemia in critically ill adult patients is practice based. Variability across individual practitioners and institutions is not well documented. OBJECTIVES: To conduct a nationwide survey of critical care physicians in the United States regarding accepted definitions and management strategies for severe and refractory hypoxemia. METHODS: A web-based survey was distributed to a stratified random sample of adult intensivists listed in the American Medical Association Physician Masterfile. The survey was generated by using a mixed-methods approach. MEASUREMENTS AND MAIN RESULTS: In the survey, 4,865 e-mails were sent and 791 (16.3%) were opened. Among those who opened the e-mail message, 50% (n = 396) responded, representing 8.1% of total surveys sent. Seventy-two percent stated that their institutions lacked a protocol for identification and management of severe or refractory hypoxemia in the setting of acute respiratory failure. While the majority of respondents used low-Vt ventilation (81%), high positive end-expiratory pressure (86%), recruitment maneuvers (89%), and either bolus or infusion neuromuscular blockade (94%), there was marked variability in the use of specific rescue strategies as tier 1 or 2 interventions: prone position (27.8% vs. 47.8%, respectively), extracorporeal membrane oxygenation (2.3% vs. 51.2%, respectively), airway pressure release ventilation (49% vs. 34.5%, respectively), inhaled vasodilators (30.1% vs. 40%, respectively), and high-frequency oscillatory ventilation (7.8% vs. 40%, respectively). The variability was partly explained by providers' expertise with particular rescue strategies (77.7%), advance directives (70.1%), the training of allied health staff (62.3%), and institutional availability (53.8%). CONCLUSIONS: U.S. adult critical care physicians predominantly employ lung-protective ventilation for severe hypoxemia. A wide variation in other rescue strategies is noted, which is partly explained by user expertise and availability. Less than 30% institutions have formal protocols for management of refractory hypoxemia.

Early prediction of extracorporeal membrane oxygenation eligibility for severe acute respiratory distress syndrome in adults.

PURPOSE: Appropriately identifying and triaging patients with newly diagnosed acute respiratory distress syndrome (ARDS) who may progress to severe ARDS is a common clinical challenge without any existing tools for assistance. MATERIALS AND METHODS: Using a retrospective cohort, a simple prediction score was developed to improve early identification of ARDS patients who were likely to progress to severe ARDS within 7 days. A broad array of comorbidities and physiologic variables were collected for the 12-hour period starting from intubation for ARDS. Extracorporeal membrane oxygenation (ECMO) eligibility was determined based on published criteria from recent ECMO guidelines and clinical trials. Separate data-driven and expert opinion approaches to prediction score creation were completed. RESULTS: The study included 767 patients with moderate or severe ARDS who were admitted to the intensive care unit between January 1, 2005, and December 31, 2010. In the data-driven approach, incorporating the ARDS index (a novel variable incorporating oxygenation index and estimated dead space), aspiration, and change of Pao2/fraction of inspired oxygen ratio into a simple prediction model yielded a c-statistic (area under the receiver operating characteristic curve) of 0.71 in the validation cohort. The expert opinion-based prediction score (including oxygenation index, change of Pao2/fraction of inspired oxygen ratio, obesity, aspiration, and immunocompromised state) yielded a c-statistic of 0.61 in the validation cohort. CONCLUSIONS: The data-driven early prediction ECMO eligibility for severe ARDS score uses commonly measured variables of ARDS patients within 12 hours of intubation and could be used to identify those patients who may merit early transfer to an ECMO-capable medical center.