Prolonged prone position ventilation is associated with reduced mortality in intubated COVID-19 patients.

BACKGROUND: Prone position ventilation (PPV) is resource-intensive, yet the optimal strategy for PPV in intubated patients with COVID-19 is unclear. RESEARCH QUESTION: Does a prolonged (24 or more hours) PPV strategy improve mortality in intubated COVID-19 patients compared to intermittent (∼16 hours with daily supination) PPV? STUDY DESIGN AND METHODS: Multicenter, retrospective cohort study of consecutively admitted intubated COVID-19 patients treated with PPV between March 11 - May 31, 2020. The primary outcome was 30-day all-cause mortality. Secondary outcomes included 90-day all-cause mortality and prone-related complications. Inverse probability treatment weights (IPTW) were used to control for potential treatment selection bias. RESULTS: Of the COVID-19 patients who received PPV, 157 underwent prolonged and 110 underwent intermittent PPV. Patients undergoing prolonged PPV had reduced 30-day (adjusted hazard ratio [aHR] 0.475, 95% CI 0.336-0.670, P value < 0.001) and 90-day (aHR 0.638, 95% CI 0.461-0.883, P value = 0.006) mortality compared to intermittent PPV. In patients with PaO2/FIO2 ≤ 150 at the time of pronation, prolonged PPV was associated with reduced 30-day (aHR 0.357, 95% CI 0.213-0.597, P value < 0.001) and 90-day mortality (aHR 0.562, 95% CI 0.357-0.884, P value = 0.008). Patients treated with prolonged PPV underwent fewer pronation and supination events (median 1, 95% CI 1-2 versus 3, 95% CI 1-4, P value < 0.001). PPV strategy was not associated with overall PPV-related complications though patients receiving prolonged PPV had increased rates of facial edema and lower rates of peri-proning hypotension. INTERPRETATION: Among intubated COVID-19 patients who received PPV, prolonged PPV was associated with reduced mortality. Prolonged PPV was associated with fewer pronation and supination events and a small increase in rates of facial edema. These findings suggest that prolonged PPV is a safe, effective strategy for mortality reduction in intubated COVID-19 patients.

A Prospective Observational Study on Short and Long-Term Outcomes of COVID-19 Patients with Acute Hypoxic Respiratory Failure Treated with High-Flow Nasal Cannula.

(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.

Code status orders in patients admitted to the intensive care unit with COVID-19: A retrospective cohort study.

Purpose: Code status orders impact clinical outcomes as well as patients' and surrogates' experiences. This is the first multicenter cohort examining code status orders of ICU patients with COVID-19 reported to date. Materials and methods: This is a retrospective cohort study including adult patients who tested positive for SARS-CoV-2 and were admitted to the ICU at three hospitals in Massachusetts from March 11, 2020 - May 31, 2020. We examined differences in code status orders at multiple timepoints and performed multivariable regression analysis to identify variables associated with code status at admission. Results: Among 459 ICU patients with COVID-19, 421 (91.7%) were Full Code at hospital admission. Age and admission from a facility were positively associated with DNR status (adjusted OR 1.10, 95% CI 1.05-1.15, p < 0.001 and adjusted OR 2.68, CI 1.23-5.71, p = 0.011, respectively) while non-English preferred language was negatively associated with DNR status (adjusted OR 0.29, 95% CI 0.10-0.74, p = 0.012). Among 147 patients who died during hospitalization, 95.2% (140) died with DNR code status; most (86.4%) died within two days of final code status change. Conclusions: The association of non-English preferred language with Full Code status in critically ill COVID-19 patients highlights the importance of medical interpreters in the ICU. Patients who died were transitioned to DNR more than in previous studies, possibly reflecting changes in practice during a novel pandemic.

Code status orders in patients admitted to the intensive care unit with COVID-19: a retrospective cohort study

Purpose Code status orders impact clinical outcomes as well as patients’ and surrogates’ experiences. This is the first multicenter cohort examining status orders of ICU patients with COVID-19 reported to date. Materials and methods This is a retrospective cohort study including adult patients who tested positive for SARS-CoV-2 and were admitted to the ICU at three hospitals in Massachusetts from March 11, 2020 - May 31, 2020. We examined differences in code status orders at multiple timepoints and performed multivariable regression analysis to identify variables associated with code status at admission. Results Among 459 ICU patients with COVID-19, 421 (91.7%) were Full Code at hospital admission. Age and admission from a facility were positively associated with DNR status (adjusted OR 1.10, 95% CI 1.05-1.15, p < 0.001;adjusted OR 2.68, CI 1.23-5.71, p = 0.011) while non-English preferred language was negatively associated with DNR status (adjusted OR 0.29, 95% CI 0.10-0.74, p = 0.012). Among 147 patients who died during hospitalization, 95.2% (140) died with DNR code status;most (86.4%) died within two days of final code status change. Conclusions The association of non-English preferred language with Full Code status in critically ill COVID-19 patients highlights the importance of medical interpreters in the ICU. Patients who died were transitioned to DNR more than in previous studies, possibly reflecting changes in practice during a novel pandemic.

Exercise performance in patients with post-acute sequelae of SARS-CoV-2 infection compared to patients with unexplained dyspnea.

BACKGROUND: Dyspnea and exercise intolerance are commonly reported post-acute sequelae of SARS-CoV-2 infection (PASC), but routine diagnostic testing is often normal. Cardiopulmonary exercise testing (CPET) offers comprehensive assessment of dyspnea to characterize pulmonary PASC. METHODS: We performed a retrospective cohort study of CPET performed on patients reporting dyspnea and/or exercise intolerance following confirmed Covid-19 between August 1, 2020 and March 1, 2021, and compared them to age- and sex-matched patients with unexplained dyspnea referred for CPET at the same center in the pre-Covid-19 era. FINDINGS: Compared to matched unexplained dyspnea comparators, PASC patients shared similar medical comorbidities and subjective dyspnea at referral (mMRC score 1.6 ± 0.9 vs. 1.4 ± 0.9, P = 0.5). Fifteen (83.3%) PASC patients underwent high resolution computed tomography of the chest, of which half (46.7%) were normal, and 17 (94.4%) patients had pulmonary function testing, of which the majority (76.5%) were normal. All patients underwent CPET, and 12 (67%) had normal findings. Compared to matched comparators, PASC patients had similar peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and ventilatory efficiency measured by the minute ventilation to carbon dioxide production (VE/VCO2) slope. INTERPRETATION: Despite prominent dyspnea, physiological abnormalities on CPET were mild across a range of initial Covid-19 severity and similar to matched comparators referred for dyspnea without antecedent SARS-CoV-2. FUNDING: The project was supported by the NHLBI (R01HL131029, R01HL151841, U10HL110337, T32HL116275) and a KL2 award (5KL2TR002542-02) from Harvard Catalyst.

Soluble Suppression of Tumorigenicity-2 Associates With Ventilator Dependence in Coronavirus Disease 2019 Respiratory Failure.

OBJECTIVES: We hypothesize that elevated soluble suppression of tumorigenicity-2 concentrations, a marker of pulmonary epithelial injury, reflect ongoing lung injury in acute hypoxemic respiratory failure due to coronavirus disease 2019 and associate with continued ventilator dependence. DESIGN: We associated serial plasma soluble suppression of tumorigenicity-2 levels and markers of systemic inflammation including d-dimer, C-reactive protein, and erythrocyte sedimentation rate with 30-day mortality and ventilator dependence. SETTING: Adult medical ICUs and general medicine wards at an academic teaching hospital in Boston, MA. PATIENTS: Adult patients with severe acute respiratory syndrome coronavirus 2 infection and acute hypoxemic respiratory failure admitted to the ICU (n = 72) and non-ICU patients managed with supplemental oxygen (n = 77). INTERVENTIONS: Observational study from April 25 to June 25, 2020. MEASUREMENTS AND MAIN RESULTS: ICU patients had a higher baseline body mass index and median soluble suppression of tumorigenicity-2, d-dimer, and C-reactive protein concentrations compared with non-ICU patients. Among ICU patients, elevated baseline modified Sequential Organ Failure Assessment score and log (soluble suppression of tumorigenicity-2) were associated with 30-day mortality, whereas initial Pao2/Fio2 and markers of systemic inflammation were similar between groups. Only log (soluble suppression of tumorigenicity-2) associated with ventilator dependence over time, with the last measured log (soluble suppression of tumorigenicity-2) concentration obtained on ICU day 11.5 (interquartile range [7-17]) higher in patients who required reintubation or tracheostomy placement compared with patients who were successfully extubated (2.10 [1.89-2.26] vs 1.87 ng/mL [1.72-2.13 ng/mL]; p = 0.03). Last measured systemic inflammatory markers, modified Sequential Organ Failure Assessment score, and Pao2/Fio2 were not different between patients who were successfully extubated compared with those with continued ventilator dependence. CONCLUSIONS: Plasma soluble suppression of tumorigenicity-2 is a biomarker readily measured in blood that can provide dynamic information about the degree of a patient's lung injury and real-time assessment of the likelihood of extubation success. Measures of systemic inflammation, illness severity, and oxygenation did not associate with ventilator outcomes.

Individualized Multimodal Physiologic Approach to Mechanical Ventilation in Patients With Obesity and Severe Acute Respiratory Distress Syndrome Reduced Venovenous Extracorporeal Membrane Oxygenation Utilization.

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.

Respiratory Physiology of Prone Positioning With and Without Inhaled Nitric Oxide Across the Coronavirus Disease 2019 Acute Respiratory Distress Syndrome Severity Spectrum.

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.

Yield of Severe Acute Respiratory Syndrome Coronavirus 2 Lower Respiratory Tract Testing After a Negative Nasopharyngeal Test Among Hospitalized Persons Under Investigation for Coronavirus Disease 2019.

Among hospitalized persons under investigation for coronavirus disease 2019 (COVID-19), more repeated severe acute respiratory syndrome coronavirus 2 nucleic acid amplification tests (NAATs) after a negative NAAT were positive from lower than from upper respiratory tract specimens (1.9% vs 1.0%, P = .033). Lower respiratory testing should be prioritized among patients displaying respiratory symptoms with moderate-to-high suspicion for COVID-19 after 1 negative upper respiratory NAAT.

Obesity and Critical Illness in COVID-19: Respiratory Pathophysiology.

OBJECTIVE: Recent cohort studies have identified obesity as a risk factor for poor outcomes in coronavirus disease 2019 (COVID-19). To further explore the relationship between obesity and critical illness in COVID-19, the association of BMI with baseline demographic and intensive care unit (ICU) parameters, laboratory values, and outcomes in a critically ill patient cohort was examined. METHODS: In this retrospective study, the first 277 consecutive patients admitted to Massachusetts General Hospital ICUs with laboratory-confirmed COVID-19 were examined. BMI class, initial ICU laboratory values, physiologic characteristics including gas exchange and ventilatory mechanics, and ICU interventions as clinically available were measured. Mortality, length of ICU admission, and duration of mechanical ventilation were also measured. RESULTS: There was no difference found in respiratory system compliance or oxygenation between patients with and without obesity. Patients without obesity had higher initial ferritin and D-dimer levels than patients with obesity. Standard acute respiratory distress syndrome management, including prone ventilation, was equally distributed between BMI groups. There was no difference found in outcomes between BMI groups, including 30- and 60-day mortality and duration of mechanical ventilation. CONCLUSIONS: In this cohort of critically ill patients with COVID-19, obesity was not associated with meaningful differences in respiratory physiology, inflammatory profile, or clinical outcomes.

Lung Histopathology in Coronavirus Disease 2019 as Compared With Severe Acute Respiratory Sydrome and H1N1 Influenza: A Systematic Review.

BACKGROUND: Patients with severe coronavirus disease 2019 (COVID-19) have respiratory failure with hypoxemia and acute bilateral pulmonary infiltrates, consistent with ARDS. Respiratory failure in COVID-19 might represent a novel pathologic entity. RESEARCH QUESTION: How does the lung histopathology described in COVID-19 compare with the lung histopathology described in SARS and H1N1 influenza? STUDY DESIGN AND METHODS: We conducted a systematic review to characterize the lung histopathologic features of COVID-19 and compare them against findings of other recent viral pandemics, H1N1 influenza and SARS. We systematically searched MEDLINE and PubMed for studies published up to June 24, 2020, using search terms for COVID-19, H1N1 influenza, and SARS with keywords for pathology, biopsy, and autopsy. Using PRISMA-Individual Participant Data guidelines, our systematic review analysis included 26 articles representing 171 COVID-19 patients; 20 articles representing 287 H1N1 patients; and eight articles representing 64 SARS patients. RESULTS: In COVID-19, acute-phase diffuse alveolar damage (DAD) was reported in 88% of patients, which was similar to the proportion of cases with DAD in both H1N1 (90%) and SARS (98%). Pulmonary microthrombi were reported in 57% of COVID-19 and 58% of SARS patients, as compared with 24% of H1N1 influenza patients. INTERPRETATION: DAD, the histologic correlate of ARDS, is the predominant histopathologic pattern identified in lung pathology from patients with COVID-19, H1N1 influenza, and SARS. Microthrombi were reported more frequently in both patients with COVID-19 and SARS as compared with H1N1 influenza. Future work is needed to validate this histopathologic finding and, if confirmed, elucidate the mechanistic underpinnings and characterize any associations with clinically important outcomes.

Development and Prospective Validation of a Deep Learning Algorithm for Predicting Need for Mechanical Ventilation.

BACKGROUND: Objective and early identification of hospitalized patients, and particularly those with novel coronavirus disease 2019 (COVID-19), who may require mechanical ventilation (MV) may aid in delivering timely treatment. RESEARCH QUESTION: Can a transparent deep learning (DL) model predict the need for MV in hospitalized patients and those with COVID-19 up to 24 h in advance? STUDY DESIGN AND METHODS: We trained and externally validated a transparent DL algorithm to predict the future need for MV in hospitalized patients, including those with COVID-19, using commonly available data in electronic health records. Additionally, commonly used clinical criteria (heart rate, oxygen saturation, respiratory rate, Fio2, and pH) were used to assess future need for MV. Performance of the algorithm was evaluated using the area under receiver operating characteristic curve (AUC), sensitivity, specificity, and positive predictive value. RESULTS: We obtained data from more than 30,000 ICU patients (including more than 700 patients with COVID-19) from two academic medical centers. The performance of the model with a 24-h prediction horizon at the development and validation sites was comparable (AUC, 0.895 vs 0.882, respectively), providing significant improvement over traditional clinical criteria (P < .001). Prospective validation of the algorithm among patients with COVID-19 yielded AUCs in the range of 0.918 to 0.943. INTERPRETATION: A transparent deep learning algorithm improves on traditional clinical criteria to predict the need for MV in hospitalized patients, including in those with COVID-19. Such an algorithm may help clinicians to optimize timing of tracheal intubation, to allocate resources and staff better, and to improve patient care.

Filter clotting with continuous renal replacement therapy in COVID-19.

Coronavirus disease 2019 (COVID-19) appears to be associated with increased arterial and venous thromboembolic disease. These presumed abnormalities in hemostasis have been associated with filter clotting during continuous renal replacement therapy (CRRT). We aimed to characterize the burden of CRRT filter clotting in COVID-19 infection and to describe a CRRT anticoagulation protocol that used anti-factor Xa levels for systemic heparin dosing. Multi-center study of consecutive patients with COVID-19 receiving CRRT. Primary outcome was CRRT filter loss. Sixty-five patients were analyzed, including 17 using an anti-factor Xa protocol to guide systemic heparin dosing. Fifty-four out of 65 patients (83%) lost at least one filter. Median first filter survival time was 6.5 [2.5, 33.5] h. There was no difference in first or second filter loss between the anti-Xa protocol and standard of care anticoagulation groups, however fewer patients lost their third filter in the protocolized group (55% vs. 93%) resulting in a longer median third filter survival time (24 [15.1, 54.2] vs. 17.3 [9.5, 35.1] h, p = 0.04). The rate of CRRT filter loss is high in COVID-19 infection. An anticoagulation protocol using systemic unfractionated heparin, dosed by anti-factor Xa levels is reasonable approach to anticoagulation in this population.

Veno-venous Extracorporeal Membrane Oxygenation for Respiratory Failure in COVID-19 Patients: Early Experience From a Major Academic Medical Center in North America.

AND BACKGROUND DATA: VV ECMO can be utilized as an advanced therapy in select patients with COVID-19 respiratory failure refractory to traditional critical care management and optimal mechanical ventilation. Anticipating a need for such therapies during the pandemic, our center created a targeted protocol for ECMO therapy in COVID-19 patients that allows us to provide this life-saving therapy to our sickest patients without overburdening already stretched resources or excessively exposing healthcare staff to infection risk. METHODS: As a major regional referral program, we used the framework of our well-established ECMO service-line to outline specific team structures, modified patient eligibility criteria, cannulation strategies, and management protocols for the COVID-19 ECMO program. RESULTS: During the first month of the COVID-19 outbreak in Massachusetts, 6 patients were placed on VV ECMO for refractory hypoxemic respiratory failure. The median (interquartile range) age was 47 years (43-53) with most patients being male (83%) and obese (67%). All cannulations were performed at the bedside in the intensive care unit in patients who had undergone a trial of rescue therapies for acute respiratory distress syndrome including lung protective ventilation, paralysis, prone positioning, and inhaled nitric oxide. At the time of this report, 83% (5/6) of the patients are still alive with 1 death on ECMO, attributed to hemorrhagic stroke. 67% of patients (4/6) have been successfully decannulated, including 2 that have been successfully extubated and one who was discharged from the hospital. The median duration of VV ECMO therapy for patients who have been decannulated is 12 days (4-18 days). CONCLUSIONS: This is 1 the first case series describing VV ECMO outcomes in COVID-19 patients. Our initial data suggest that VV ECMO can be successfully utilized in appropriately selected COVID-19 patients with advanced respiratory failure.