Ventilatory Ratio Research Articles

The prognostic value of early measures of the ventilatory ratio in the ARDS ROSE trial

BackgroundThe ventilatory ratio (VR, [minute ventilation × PaCO2]/[predicted body weight × 100 × 37.5]) is associated with mortality in ARDS. The aims of this study were to test whether baseline disease severity or neuromuscular blockade (NMB) modified the relationship between VR and mortality.MethodsThis was a post hoc analysis of the PETAL-ROSE trial, which randomized moderate-to-severe ARDS patients to NMB or control. Survival among patients with different VR trajectories or VR cutoff above and below the median was assessed by Kaplan–Meier analysis. The relationships between single-day or 48-h VR trajectories with 28- or 90-day mortality were tested by logistic regression. Randomization allocation to NMB and markers of disease severity were tested as confounders by multivariable regression and interaction term analyses.ResultsPatients with worsening VR trajectories had significantly lower survival compared to those with improving VR (n = 602, p < 0.05). Patients with VR > 2 (median) at day 1 had a significantly lower 90-day survival compared to patients with VR ≤ 2 (HR 1.36, 95% CI 1.10–1.69). VR at day 1 was significantly associated with 28-day mortality (OR = 1.40, 95% CI 1.15–1.72). There was no interaction between NMB and VR for 28-day mortality. APACHE-III had a significant interaction with VR at baseline for the outcome of 28-day mortality, such that the relationship between VR and mortality was stronger among patients with lower APACHE-III. There was a significant association between rising VR trajectory and mortality that was independent of NMB, baseline PaO2/FiO2 ratio and generalized markers of disease severity (Adjusted OR 1.81, 95% CI 1.28–2.84 for 28-day and OR 2.07 95% CI 1.41–3.10 for 90-day mortality). APACHE-III and NMB were not effect modifiers in the relationship between VR trajectory and mortality.ConclusionsElevated baseline and day 1 VR were associated with higher 28-day mortality. The relationship between baseline VR and mortality was stronger among patients with lower APACHE-III. APACHE-III was not an effect modifier for the relationship between VR trajectory and mortality, so that the VR trajectory may be optimally suited for prognostication and predictive enrichment. VR was not different between patients randomized to NMB or control, indicating that VR can be utilized without correcting for NMB.

The CHARTER-Ireland trial: can nebulised heparin reduce acute lung injury in patients with SARS-CoV-2 requiring advanced respiratory support in Ireland: a study protocol and statistical analysis plan for a randomised control trial

BackgroundCOVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia.MethodsThis is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1β, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1β/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP.DiscussionThis trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection.Trial registrationClinicalTrials.govNCT04511923. Registered on 13 August 2020.Protocol version 8, 22/12/2021Protocol identifier: NUIG-2020-003EudraCT registration number: 2020-003349-12 9 October 2020

P14.06: Lung Procurement: Inclusion of Modern Variables to Assess Its Quality. Descriptive Study in a Public Hospital of the Argentine Republic

Introduction: Over time, the selection criteria for lungs suitable for procurement have been modified. Marginal criteria have even been determined in order to increase the number of potential lung donors. Despite flexibility in the selection criteria, there have been no significant differences in the long-term mortality of patients implanted. In spite of modifications, the PaO2/FiO2 Iindex together with a chest X-ray continue to be the only tools for assessing the state of the lung. The objective of this study is to describe modern variables that might allow identifying the state of the lung in a group of potential lung donor patients in a Public Hospital of the Argentine Republic. Materials and Methods: Descriptive design study. Data was obtained from the electronic medical record. Patients with a diagnosis of brain death who met the criteria for potential lung donors according to the criteria of the Spanish Transplant Society were included. They had been admitted in our institution between January 1 and December 31, 2021. The following variables were analysed: PaO2/FiO2 Index, Respiratory System Compliance (Csr), Ventilatory Ratio (Rv) and Index y/y. A descriptive statistical analysis was carried out. Results: 15 patients were included, of which 9 (60%) met ideal criteria and 6 (40%) marginal criteria as lung donors. Table 1 shows the clinical-demographic characteristics.Of the six who met marginal criteria, four were due to time greater than 72 hours of MV, one for PaO2/FiO2 <300 and another one for being a smoker <20 p/year. Table 2 describes the outcome variables and the ventilator setting of the included patients.Conclusions: Results show that despite having a good PaO2/FiO2 relationship, there is great variability in the other variables. This leads to the following questions: Can the PaO2/FiO2 variable independently define the quality of a lung? Should new variables be incorporated when choosing a potential lung donor? Agradecimiento al Dr. Adrian Tarditti por su labor en el desarrollo de nuestra institución y haciendo posible la realización de dichos trabajos de investigación.

Correlación entre el aumento del dímero D en sangre con el espacio muerto en pacientes con COVID-19 y síndrome de dificultad respiratoria aguda

IntroductionSince December 2019, a number of cases of CoV2/COVID-19 severe acute respiratory syndrome (SARS) pneumonia in Wuhan China have been identified as a cause of acute respiratory failure and have spread around the world at high speed. Due to the large number of cases and the need to better understand this condition, tools are required to grade the intensity and vital prognosis of patients. The objective of this study is to determine the relationship between the dead space measured by volumetric capnography or ventilatory ratio and the increase in D-dimer levels in patients diagnosed with COVID-19 pneumonia and who meet the Berlin criteria for Acute Respiratory Distress Syndrome (ARDS). Materials and methodsA single-centre observational study of a prospective cohort on the use of D-dimer and the correlation with dead space. Adults older than 18 years with a diagnosis of pneumonia due to COVID-19 and ARDS hospitalized in the intensive care units of Hospital Santa Clara in Bogotá, Colombia, from August 2020 to July 2021 were included. ResultsThe study included 67 patients, all with a confirmed SARS-CoV-2 diagnosis, no association was found between D-dimer and dead space on day 1 and 3 of hospitalization in the ICU. ConclusionsD-dimer was not correlated with increased dead space in our study and was not associated with relevant outcomes in patients with ARDS.

Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients: a preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial

PurposeThe optimal ventilatory settings in patients after cardiac arrest and their association with outcome remain unclear. The aim of this study was to describe the ventilatory settings applied in the first 72 h of mechanical ventilation in patients after out-of-hospital cardiac arrest and their association with 6-month outcomes.MethodsPreplanned sub-analysis of the Target Temperature Management-2 trial. Clinical outcomes were mortality and functional status (assessed by the Modified Rankin Scale) 6 months after randomization.ResultsA total of 1848 patients were included (mean age 64 [Standard Deviation, SD = 14] years). At 6 months, 950 (51%) patients were alive and 898 (49%) were dead. Median tidal volume (VT) was 7 (Interquartile range, IQR = 6.2–8.5) mL per Predicted Body Weight (PBW), positive end expiratory pressure (PEEP) was 7 (IQR = 5–9) cmH20, plateau pressure was 20 cmH20 (IQR = 17–23), driving pressure was 12 cmH20 (IQR = 10–15), mechanical power 16.2 J/min (IQR = 12.1–21.8), ventilatory ratio was 1.27 (IQR = 1.04–1.6), and respiratory rate was 17 breaths/minute (IQR = 14–20). Median partial pressure of oxygen was 87 mmHg (IQR = 75–105), and partial pressure of carbon dioxide was 40.5 mmHg (IQR = 36–45.7). Respiratory rate, driving pressure, and mechanical power were independently associated with 6-month mortality (omnibus p-values for their non-linear trajectories: p < 0.0001, p = 0.026, and p = 0.029, respectively). Respiratory rate and driving pressure were also independently associated with poor neurological outcome (odds ratio, OR = 1.035, 95% confidence interval, CI = 1.003–1.068, p = 0.030, and OR = 1.005, 95% CI = 1.001–1.036, p = 0.048). A composite formula calculated as [(4*driving pressure) + respiratory rate] was independently associated with mortality and poor neurological outcome.ConclusionsProtective ventilation strategies are commonly applied in patients after cardiac arrest. Ventilator settings in the first 72 h after hospital admission, in particular driving pressure and respiratory rate, may influence 6-month outcomes.

Driving pressure-guided ventilation decreases the mechanical power compared to predicted body weight-guided ventilation in the Acute Respiratory Distress Syndrome

BackgroundWhether targeting the driving pressure (∆P) when adjusting the tidal volume in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS) may decrease the risk of ventilator-induced lung injury remains a matter of research. In this study, we assessed the effect of a ∆P-guided ventilation on the mechanical power.MethodsWe prospectively included adult patients with moderate-to-severe ARDS. Positive end expiratory pressure was set by the attending physician and kept constant during the study. Tidal volume was first adjusted to target 6 ml/kg of predicted body weight (PBW-guided ventilation) and subsequently modified within a range from 4 to 10 ml/kg PBW to target a ∆P between 12 and 14 cm H2O. The respiratory rate was then re-adjusted within a range from 12 to 40 breaths/min until EtCO2 returned to its baseline value (∆P-guided ventilation). Mechanical power was computed at each step.ResultsFifty-one patients were included between December 2019 and May 2021. ∆P-guided ventilation was feasible in all but one patient. The ∆P during PBW-guided ventilation was already within the target range of ∆P-guided ventilation in five (10%) patients, above in nine (18%) and below in 36 (72%). The change from PBW- to ∆P-guided ventilation was thus accompanied by an overall increase in tidal volume from 6.1 mL/kg PBW [5.9–6.2] to 7.7 ml/kg PBW [6.2–8.7], while respiratory rate was decreased from 29 breaths/min [26–32] to 21 breaths/min [16–28] (p < 0.001 for all comparisons). ∆P-guided ventilation was accompanied by a significant decrease in mechanical power from 31.5 J/min [28–35.7] to 28.8 J/min [24.6–32.6] (p < 0.001), representing a relative decrease of 7% [0–16]. With ∆P-guided ventilation, the PaO2/FiO2 ratio increased and the ventilatory ratio decreased.ConclusionAs compared to a conventional PBW-guided ventilation, a ∆P-guided ventilation strategy targeting a ∆P between 12 and 14 cm H2O required to change the tidal volume in 90% of the patients. Such ∆P-guided ventilation significantly reduced the mechanical power. Whether this physiological observation could be associated with clinical benefit should be assessed in clinical trials.

Decline in Ventilatory Ratio as a Predictor of Mortality in Adults With ARDS Receiving Prone Positioning.

Prone positioning reduces mortality in patients with moderate/severe ARDS. It remains unclear which physiological parameters could guide clinicians to assess which patients are likely to benefit from prone position. This study aimed to determine the association between relative changes in physiological parameters at 24 h of prone positioning and ICU mortality in adult subjects with ARDS. We conducted a cohort study using the VENTILA database, including adults with ARDS receiving prone positioning. We used multivariable logistic regression to assess the association between relative changes in physiological parameters (PaO2 /FIO2 , dynamic driving pressure, PaCO2 , and ventilatory ratio defined as [minute ventilation [mL/min] × PaCO2 [mm Hg]]/[predicted body weight × 100 [mL/min] × 37.5 [mm Hg] with ICU mortality) (primary outcome). We report adjusted odds ratios with 95% CI as measures of association. We included 156 subjects of which 82 (53%) died in the ICU. A relative decline in the ventilatory ratio at 24 h was associated with lower ICU mortality (odds ratio 0.80 [95% CI 0.66-0.97], every 10% decrease). Relative changes in PaO2 /FIO2 (odds ratio 0.89 [95% CI 0.77-1.03], every 25% increase), PaCO2 (odds ratio 0.97 [95% CI 0.82-1.16], every 10% decrease), and dynamic driving pressure (odds ratio 0.98 [95% CI 0.89-1.07], every 10% decrease) were not associated with ICU mortality. In subjects with ARDS receiving prone positioning, a relative decline in the ventilatory ratio at 24 h was associated with lower ICU mortality.

The relationship between ventilatory ratio (VR) and 28-day hospital mortality by restricted cubic splines (RCS) in 14,328 mechanically ventilated ICU patients

BackgroundPrevious studies found that high levels of ventilatory ratio (VR) were associated with a poor prognosis due to worse ventilatory efficiency in acute respiratory distress syndrome patients. However, relatively few large studies have assessed the association between VR and intensive care unit (ICU) mortality in the general adult ventilated population.MethodsThe present study is a retrospective cohort study. Patients mechanically ventilated for more than 12 h were included. VR was calculated based on a previously reported formula. Restricted cubic spline models were used to fit the relationship between VR and mortality risks.ResultsA total of 14,328 mechanically ventilated ICU patients were included in the study, of which 1311 died within 28 days. The results of the study are as follows: (1) In the general adult ventilated population, VR was positively associated with 28-day mortality when VR ≥ 1.3 (increase of 0.1 per VR; HR 1.05, p < 0.001). The same tendency was also observed in the populations of severe hypoxemia with a PaO2/FiO2 (P/F) ratio < 200 mmHg. (2) However, in the population with a P/F ratio ≥ 200, a J-shaped dose–response association between VR and the risk of mortality was observed, with the risk of death positively associated with VR when VR ≥ 0.9 (10% increase in HR for every 0.1 increase in VR, p = 0.000) but negatively associated with VR when VR < 0.9 (10% decrease in HR for every 0.1 increase in VR, p = 0.034). In the population of P/F ratio ≥ 200 with VR less than 0.9, compared to the survival group, the nonsurvival group had a lower level PCO2 (33 mmHg [29.1, 37.9] vs. 34.4 mmHg [30.6, 38.5]), rather than a significant level of measured minute ventilation or P/F ratio.ConclusionsVR was positively associated with the risk of death in the general ICU population; however, VR was inversely associated with 28-day mortality in the population with a P/F ratio ≥ 200 and low VR . Further research should investigate this relationship, and VR should be interpreted with caution in clinical practice.

Vasculopathy and Increased Vascular Congestion in Fatal COVID-19 and Acute Respiratory Distress Syndrome.

Rationale: The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective: To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods: This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non-COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results: In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions: Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.

High flow nasal cannula improves breathing efficiency and ventilatory ratio in COPD patients recovering from an exacerbation.

High flow nasal cannula (HFNC) may improve CO2 elimination by washing out CO2 from the upper airways. This study aimed at assessing the effect of HFNC on minute ventilation and ventilatory ratio (VR), a surrogate of dead space, in patients hospitalized for acute hypercapnic COPD exacerbation. Physiological study comparing HFNC at 40 L/min to low flow oxygen. Variations of tidal volume (VT) and minute ventilation between the two treatments were estimated from chest plethysmography. Respiratory rate (RR) and arterial blood gases were measured. Variations in VR were calculated. Data were compared using Wilcoxon tests. Recordings performed in 10 patients. Minute ventilation was reduced with HFNC by -16.2 [-30.9-0.4] % (p = 0.049). VT was not different but RR was lower during HFNC. PaCO2 was lower with HFNC compared to standard oxygen: 48.7 [46.4-58.1] vs 50.7 [48.4-57.5] mmHg (p = 0.020). VR decreased by -18.0 [-34.7 - -4.0] % (p = 0.020) with HFNC. In patients recovering from acute COPD exacerbation, the use of HFNC reduced RR, minute ventilation, PaCO2 and VR compared to standard oxygen. These changes are consistent with a decrease in physiologic dead space with HFNC.

Ventilatory Ratio Is a Valuable Prognostic Indicator in an Observational Cohort of Patients With ARDS.

How indices specific to respiratory compromise contribute to prognostication in patients with ARDS is not well characterized in general clinical populations. The primary objective of this study was to identify variables specific to respiratory failure that might add prognostic value to indicators of systemic illness severity in an observational cohort of subjects with ARDS. Fifty subjects with ARDS were enrolled in a single-center, prospective, observational cohort. We tested the contribution of respiratory variables (oxygenation index, ventilatory ratio [VR], and the radiographic assessment of lung edema score) to logistic regression models of 28-d mortality adjusted for indicators of systemic illness severity (the Acute Physiology and Chronic Health Evaluation [APACHE] III score or severity of shock as measured by the number of vasopressors required at baseline) using likelihood ratio testing. We also compared a model utilizing APACHE III with one including baseline number of vasopressors by comparing the area under the receiver operating curve (AUROC). VR significantly improved model performance by likelihood ratio testing when added to APACHE III (P = .036) or the number of vasopressors at baseline (P = .01). Number of vasopressors required at baseline had similar prognostic discrimination to the APACHE III. A model including the number of vasopressors and VR (AUROC 0.77 [95% CI 0.64-0.90]) was comparable to a model including APACHE III and VR (AUROC 0.81 [95% CI 0.68-0.93]; P for comparison = .58.). In this observational cohort of subjects with ARDS, the VR significantly improved discrimination for mortality when combined with indicators of severe systemic illness. The number of vasopressors required at baseline and APACHE III had similar discrimination for mortality when combined with VR. VR is easily obtained at the bedside and offers promise for clinical prognostication.

Potential for the lung recruitment and the risk of lung overdistension during 21\xa0days of mechanical ventilation in patients with\xa0 COVID-19 after noninvasive ventilation failure: the COVID-VENT observational trial

BackgroundData on the lung respiratory mechanics and gas exchange in the time course of COVID-19-associated respiratory failure is limited. This study aimed to explore respiratory mechanics and gas exchange, the lung recruitability and risk of overdistension during the time course of mechanical ventilation.MethodsThis was a prospective observational study in critically ill mechanically ventilated patients (n = 116) with COVID-19 admitted into Intensive Care Units of Sechenov University. The primary endpoints were: «optimum» positive end-expiratory pressure (PEEP) level balanced between the lowest driving pressure and the highest SpO2 and number of patients with recruitable lung on Days 1 and 7 of mechanical ventilation. We measured driving pressure at different levels of PEEP (14, 12, 10 and 8 cmH2O) with preset tidal volume, and with the increase of tidal volume by 100 ml and 200 ml at preset PEEP level, and calculated static respiratory system compliance (CRS), PaO2/FiO2, alveolar dead space and ventilatory ratio on Days 1, 3, 5, 7, 10, 14 and 21.ResultsThe «optimum» PEEP levels on Day 1 were 11.0 (10.0–12.8) cmH2O and 10.0 (9.0–12.0) cmH2O on Day 7. Positive response to recruitment was observed on Day 1 in 27.6% and on Day 7 in 9.2% of patients. PEEP increase from 10 to 14 cmH2O and VT increase by 100 and 200 ml led to a significant decrease in CRS from Day 1 to Day 14 (p < 0.05). Ventilatory ratio was 2.2 (1.7–2,7) in non-survivors and in 1.9 (1.6–2.6) survivors on Day 1 and decreased on Day 7 in survivors only (p < 0.01). PaO2/FiO2 was 105.5 (76.2–141.7) mmHg in non-survivors on Day 1 and 136.6 (106.7–160.8) in survivors (p = 0.002). In survivors, PaO2/FiO2 rose on Day 3 (p = 0.008) and then between Days 7 and 10 (p = 0.046).ConclusionLung recruitability was low in COVID-19 and decreased during the course of the disease, but lung overdistension occurred at «intermediate» PEEP and VT levels. In survivors gas exchange improvements after Day 7 mismatched CRS.Trial registrationClinicalTrials.gov, NCT04445961. Registered 24 June 2020—Retrospectively registered.

Mortality and Pulmonary Embolism in Acute Respiratory Distress Syndrome From COVID-19 vs. Non-COVID-19

PurposeThere may be a difference in respiratory mechanics, inflammatory markers, and pulmonary emboli in COVID-19 associated ARDS vs. ARDS from other etiologies. Our purpose was to determine differences in respiratory mechanics, inflammatory markers, and incidence of pulmonary embolism in patients with and without COVID-19 associated ARDS admitted in the same period and treated with a similar ventilation strategy.MethodsA cohort study of COVID-19 associated ARDS and non COVID-19 patients in a Saudi Arabian center between June 1 and 15, 2020. We measured respiratory mechanics (ventilatory ratio (VR), recruitability index (RI), markers of inflammation, and computed tomography pulmonary angiograms.ResultsForty-two patients with COVID-19 and 43 non-COVID patients with ARDS comprised the cohort. The incidence of “recruitable” patients using the recruitment/inflation ratio was slightly lower in COVID-19 patients (62 vs. 86%; p = 0.01). Fifteen COVID-19 ARDS patients (35.7%) developed a pulmonary embolism as compared to 4 (9.3%) in other ARDS patients (p = 0.003). In COVID-19 patients, a D-Dimer ≥ 5.0 mcg/ml had a 73% (95% CI 45–92%) sensitivity and 89% (95% CI 71–98%) specificity for predicting pulmonary embolism. Crude 60-day mortality was higher in COVID-19 patients (35 vs. 15%; p = 0.039) but three multivariate analysis showed that independent predictors of 60-day mortality included the ventilatory ratio (OR 3.67, 95% CI 1.61–8.35), PaO2/FIO2 ratio (OR 0.93; 95% CI 0.87–0.99), IL-6 (OR 1.02, 95% CI 1.00–1.03), and D-dimer (OR 7.26, 95% CI 1.11–47.30) but not COVID-19 infection.ConclusionCOVID-19 patients were slightly less recruitable and had a higher incidence of pulmonary embolism than those with ARDS from other etiologies. A high D-dimer was predictive of pulmonary embolism in COVID-19 patients. COVID-19 infection was not an independent predictor of 60-day mortality in the presence of ARDS.

Inhaled pulmonary vasodilators are not associated with improved gas exchange in mechanically ventilated patients with COVID-19: A retrospective cohort study.

PurposeMeasure the effect of inhaled pulmonary vasodilators on gas exchange in mechanically ventilated patients with COVID-19.MethodsA retrospective observational cohort study at three New York University Hospitals was performed including eighty-four mechanically ventilated SARS Cov-2 nasopharyngeal PCR positive patients, sixty nine treated with inhaled nitric oxide (iNO) and fifteen with inhaled epoprostenol (iEPO). The primary outcomes were change in PAO2:FIO2 ratio, oxygenation Index (OI), and ventilatory ratio (VR) after initiation of inhaled pulmonary vasodilators.ResultsThere was no significant change in PAO2:FIO2ratio after initiation of iNO (mean − 4.1, 95% CI -17.3-9.0, P = 0.54) or iEPO (mean − 3.4, 95% CI -19.7-12.9, P = 0.66), in OI after initiation of iNO (mean 2.1, 95% CI-0.04-4.2, P = 0.054) or iEPO (mean − 3.4, 95% CI -19.7-12.9, P = 0.75), or in VR after initiation of iNO (mean 0.17, 95% CI -0.03-0.36, P = 0.25) or iEPO (mean 0.33, 95% CI -0.0847-0.74, P = 0.11). PAO2:FIO2, OI and VR did not significantly change over a five day period starting the day prior to drug initiation in patients who received either iNO or iEPO assessed with a fixed effects model.ConclusionInhaled pulmonary vasodilators were not associated with significant improvement in gas exchange in mechanically ventilated patients with COVID-19.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Positive end-expiratory pressure in COVID-19 acute respiratory distress syndrome: the heterogeneous effects

BackgroundWe hypothesized that as CARDS may present different pathophysiological features than classic ARDS, the application of high levels of end-expiratory pressure is questionable. Our first aim was to investigate the effects of 5–15 cmH2O of PEEP on partitioned respiratory mechanics, gas exchange and dead space; secondly, we investigated whether respiratory system compliance and severity of hypoxemia could affect the response to PEEP on partitioned respiratory mechanics, gas exchange and dead space, dividing the population according to the median value of respiratory system compliance and oxygenation. Thirdly, we explored the effects of an additional PEEP selected according to the Empirical PEEP-FiO2 table of the EPVent-2 study on partitioned respiratory mechanics and gas exchange in a subgroup of patients.MethodsSixty-one paralyzed mechanically ventilated patients with a confirmed diagnosis of SARS-CoV-2 were enrolled (age 60 [54–67] years, PaO2/FiO2 113 [79–158] mmHg and PEEP 10 [10–10] cmH2O). Keeping constant tidal volume, respiratory rate and oxygen fraction, two PEEP levels (5 and 15 cmH2O) were selected. In a subgroup of patients an additional PEEP level was applied according to an Empirical PEEP-FiO2 table (empirical PEEP). At each PEEP level gas exchange, partitioned lung mechanics and hemodynamic were collected.ResultsAt 15 cmH2O of PEEP the lung elastance, lung stress and mechanical power were higher compared to 5 cmH2O. The PaO2/FiO2, arterial carbon dioxide and ventilatory ratio increased at 15 cmH2O of PEEP. The arterial–venous oxygen difference and central venous saturation were higher at 15 cmH2O of PEEP. Both the mechanics and gas exchange variables significantly increased although with high heterogeneity. By increasing the PEEP from 5 to 15 cmH2O, the changes in partitioned respiratory mechanics and mechanical power were not related to hypoxemia or respiratory compliance. The empirical PEEP was 18 ± 1 cmH2O. The empirical PEEP significantly increased the PaO2/FiO2 but also driving pressure, lung elastance, lung stress and mechanical power compared to 15 cmH2O of PEEP.ConclusionsIn COVID-19 ARDS during the early phase the effects of raising PEEP are highly variable and cannot easily be predicted by respiratory system characteristics, because of the heterogeneity of the disease.

Effect of Different Corticosteroid Regimens on the Outcome of Severe COVID-19-Related Acute Respiratory Failure. A Retrospective Analysis.

Background: Systemic corticosteroids are associated with reduced mortality in COVID-19-related acute respiratory failure; however, the type and dose has not yet been established. Objectives: To compare the outcomes of dexamethasone vs. methylprednisolone, along with the effects of rescue, short-term, high-dose boluses of corticosteroids. Methods: Before/after and case/control retrospective analysis of consecutive critically ill COVID-19 subjects. Subjects were initially given dexamethasone; however, after review of the local protocol, methylprednisolone was suggested. A three-day course of 1000 mg/day of methylprednisolone was administered in the case of refractory hypoxemia within the first 10 days of treatment. Propensity score-adjusted comparisons were performed. Results: A total of 81 consecutive subjects were included (85% males, 60 ± 10 years, SAPS II 27 ± 7, SOFA 4 [IQR 3, 6] points) and 51 of these subjects (62.9%) received dexamethasone and 29 (35.8%) had methylprednisolone. The groups were well matched for age, comorbidities, and severity at admission. No differences were found in the duration of ICU stay, hospital mortality, or infectious complications between the groups. A total of 22 subjects (27.2%) received a rescue bolus; these subjects had a significantly lower oxygenation, a higher driving pressure, and an increased ventilatory ratio during the first ten days. Short-term/high-dose boluses were associated with higher hospital mortality, longer mechanical ventilation and ICU and hospital stay, and more infectious complications. A subgroup of subjects who received the boluses had significantly improved oxygenation and lower hospital mortality. Conclusions: We were unable to find any difference between dexamethasone or methylprednisolone on the explored outcomes; high-dose boluses of corticosteroids were associated with a worse outcome. However, a subgroup of subjects was identified in whom the high-dose boluses seemed beneficial.

Phenotyping in acute respiratory distress syndrome: state of the art and clinical implications.

Decades of research in acute respiratory distress syndrome (ARDS) have led to few interventions that impact clinical outcomes. The pandemic of patients with ARDS due to the novel SARS-CoV-2 infection has stressed the need for more effective therapies in ARDS. Phenotyping may enable successful trials and precision therapeutics in this patient population. Clinical phenotypes that group patients by shared cause, time-course or radiographic presentation are of prognostic value, but their use is limited by misclassification. Physiological phenotypes, including the P/F ratio, ventilatory ratio and dead space fraction, predict poor outcomes but can rapidly change, making them unstable over time. Biologic phenotypes have prognostic value with composite clinical and biomarker sub-phenotypes additionally impacting treatment response but are yet to be prospectively validated. Although much progress has been made in ARDS phenotyping, implementation of precision medicine practices will depend on conducting phenotype-aware trials using rapid point of care assays or machine learning algorithms. Omics studies will enhance our understanding of biologic determinants of clinical outcomes in ARDS sub-phenotypes. Whether biologic ARDS sub-phenotypes are specific to this syndrome or rather more broadly identify endotypes of critical illness remains to be determined.

Some Patients Are More Equal Than Others: Variation in Ventilator Settings for Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.

As coronavirus disease 2019 is a novel disease, treatment strategies continue to be debated. This provides the intensive care community with a unique opportunity as the population of coronavirus disease 2019 patients requiring invasive mechanical ventilation is relatively homogeneous compared with other ICU populations. We hypothesize that the novelty of coronavirus disease 2019 and the uncertainty over its similarity with noncoronavirus disease 2019 acute respiratory distress syndrome resulted in substantial practice variation between hospitals during the first and second waves of coronavirus disease 2019 patients. Multicenter retrospective cohort study. Twenty-five hospitals in the Netherlands from February 2020 to July 2020, and 14 hospitals from August 2020 to December 2020. One thousand two hundred ninety-four critically ill intubated adult ICU patients with coronavirus disease 2019 were selected from the Dutch Data Warehouse. Patients intubated for less than 24 hours, transferred patients, and patients still admitted at the time of data extraction were excluded. We aimed to estimate between-ICU practice variation in selected ventilation parameters (positive end-expiratory pressure, Fio2, set respiratory rate, tidal volume, minute volume, and percentage of time spent in a prone position) on days 1, 2, 3, and 7 of intubation, adjusted for patient characteristics as well as severity of illness based on Pao2/Fio2 ratio, pH, ventilatory ratio, and dynamic respiratory system compliance during controlled ventilation. Using multilevel linear mixed-effects modeling, we found significant (p ≤ 0.001) variation between ICUs in all ventilation parameters on days 1, 2, 3, and 7 of intubation for both waves. This is the first study to clearly demonstrate significant practice variation between ICUs related to mechanical ventilation parameters that are under direct control by intensivists. Their effect on clinical outcomes for both coronavirus disease 2019 and other critically ill mechanically ventilated patients could have widespread implications for the practice of intensive care medicine and should be investigated further by causal inference models and clinical trials.

Longitudinal respiratory subphenotypes in patients with COVID-19-related acute respiratory distress syndrome: results from three observational cohorts

BackgroundPatients with COVID-19-related acute respiratory distress syndrome (ARDS) have been postulated to present with distinct respiratory subphenotypes. However, most phenotyping schema have been limited by sample size, disregard for temporal dynamics, and insufficient validation. We aimed to identify respiratory subphenotypes of COVID-19-related ARDS using unbiased data-driven approaches.MethodsPRoVENT–COVID was an investigator-initiated, national, multicentre, prospective, observational cohort study at 22 intensive care units (ICUs) in the Netherlands. Consecutive patients who had received invasive mechanical ventilation for COVID-19 (aged 18 years or older) served as the derivation cohort, and similar patients from two ICUs in the USA served as the replication cohorts. COVID-19 was confirmed by positive RT-PCR. We used latent class analysis to identify subphenotypes using clinically available respiratory data cross-sectionally at baseline, and longitudinally using 8-hourly data from the first 4 days of invasive ventilation. We used group-based trajectory modelling to evaluate trajectories of individual variables and to facilitate potential clinical translation. The PRoVENT-COVID study is registered with ClinicalTrials.gov, NCT04346342.FindingsBetween March 1, 2020, and May 15, 2020, 1007 patients were admitted to participating ICUs in the Netherlands, and included in the derivation cohort. Data for 288 patients were included in replication cohort 1 and 326 in replication cohort 2. Cross-sectional latent class analysis did not identify any underlying subphenotypes. Longitudinal latent class analysis identified two distinct subphenotypes. Subphenotype 2 was characterised by higher mechanical power, minute ventilation, and ventilatory ratio over the first 4 days of invasive mechanical ventilation than subphenotype 1, but PaO2/FiO2, pH, and compliance of the respiratory system did not differ between the two subphenotypes. 185 (28%) of 671 patients with subphenotype 1 and 109 (32%) of 336 patients with subphenotype 2 had died at day 28 (p=0·10). However, patients with subphenotype 2 had fewer ventilator-free days at day 28 (median 0, IQR 0–15 vs 5, 0–17; p=0·016) and more frequent venous thrombotic events (109 [32%] of 336 patients vs 176 [26%] of 671 patients; p=0·048) compared with subphenotype 1. Group-based trajectory modelling revealed trajectories of ventilatory ratio and mechanical power with similar dynamics to those observed in latent class analysis-derived trajectory subphenotypes. The two trajectories were: a stable value for ventilatory ratio or mechanical power over the first 4 days of invasive mechanical ventilation (trajectory A) or an upward trajectory (trajectory B). However, upward trajectories were better independent prognosticators for 28-day mortality (OR 1·64, 95% CI 1·17–2·29 for ventilatory ratio; 1·82, 1·24–2·66 for mechanical power). The association between upward ventilatory ratio trajectories (trajectory B) and 28-day mortality was confirmed in the replication cohorts (OR 4·65, 95% CI 1·87–11·6 for ventilatory ratio in replication cohort 1; 1·89, 1·05–3·37 for ventilatory ratio in replication cohort 2).InterpretationAt baseline, COVID-19-related ARDS has no consistent respiratory subphenotype. Patients diverged from a fairly homogenous to a more heterogeneous population, with trajectories of ventilatory ratio and mechanical power being the most discriminatory. Modelling these parameters alone provided prognostic value for duration of mechanical ventilation and mortality.FundingAmsterdam UMC.