Ventilator-induced Lung Injury Promotes Inflammation within the Pleural Cavity.

Mechanical ventilation contributes to the morbidity and mortality of patients in Intensive Care, likely through the exacerbation and dissemination of inflammation. Despite its proximity to the lungs and exposure to physical forces, little attention has been paid to the potential of the pleural cavity as an inflammatory source during ventilation. Here we investigate the pleural cavity as a novel site of inflammation during ventilator-induced lung injury. Mice were subjected to low or high tidal volume ventilation strategies for up to 3 hours. High tidal volume ventilation significantly increased cytokine and total protein levels in bronchoalveolar and pleural lavage fluid. In contrast acid aspiration, explored as an alternative model of injury, only promoted intra-alveolar inflammation with no effect on the pleural space. Resident pleural macrophages demonstrated enhanced activation following injurious ventilation, including upregulated ICAM-1 and interleukin-1ß expression, and release of extracellular vesicles. In vivo ventilation and in vitro stretch of pleural mesothelial cells promoted ATP secretion, while purinergic receptor inhibition substantially attenuated extracellular vesicles and cytokine levels in the pleural space. Finally, labelled protein rapidly translocated from the pleural cavity into the circulation during high tidal volume ventilation, to a significantly greater extent than protein translocation from the alveolar space. Overall we conclude that injurious ventilation induces pleural cavity inflammation mediated via purinergic pathway signaling, and likely enhances dissemination of mediators into the vasculature. This previously unidentified consequence of mechanical ventilation potentially implicates the pleural space as a focus of research and novel avenue for intervention in critical care.

Clinical practice, decision-making, and use of clinical decision support systems in invasive mechanical ventilation: a narrative review.

Invasive mechanical ventilation is a key supportive therapy for patients on intensive care. There is increasing emphasis on personalised ventilation strategies. Clinical decision support systems (CDSS) have been developed to support this. We conducted a narrative review to assess evidence that could inform device implementation. A search was conducted in MEDLINE (Ovid) and EMBASE. Twenty-nine studies met the inclusion criteria. Role allocation is well described, with interprofessional collaboration dependent on culture, nurse:patient ratio, the use of protocols, and perception of responsibility. There were no descriptions of process measures, quality metrics, or clinical workflow. Nurse-led weaning is well-described, with factors grouped by patient, nurse, and system. Physician-led weaning is heterogenous, guided by subjective and objective information, and 'gestalt'. No studies explored decision-making with CDSS. Several explored facilitators and barriers to implementation, grouped by clinician (facilitators: confidence using CDSS, retaining decision-making ownership; barriers: undermining clinician's role, ambiguity moving off protocol), intervention (facilitators: user-friendly interface, ease of workflow integration, minimal training requirement; barriers: increased documentation time), and organisation (facilitators: system-level mandate; barriers: poor communication, inconsistent training, lack of technical support). One study described factors that support CDSS implementation. There are gaps in our understanding of ventilation practice. A coordinated approach grounded in implementation science is required to support CDSS implementation. Future research should describe factors that guide clinical decision-making throughout mechanical ventilation, with and without CDSS, map clinical workflow, and devise implementation toolkits. Novel research design analogous to a learning organisation, that considers the commercial aspects of device design, is required.

Hypoxemia Trajectory of Non-COVID-19 Acute Respiratory Distress Syndrome Patients. An Observational Study Focusing on Hypoxemia Resolver Status.

IMPORTANCE: Most studies on acute respiratory distress syndrome (ARDS) group patients by severity based on their initial degree of hypoxemia. However, this grouping has limitations, including inconsistent hypoxemia trajectories and outcomes. OBJECTIVES: This study explores the benefits of grouping patients by resolver status based on their hypoxemia progression over the first 7 days. DESIGN SETTING AND PARTICIPANTS: This is an observational study from a large single-center database. Medical Information Mart for Intensive Care (MIMIC)-IV and MIMIC Chest X-ray JPEG databases were used. Mechanically ventilated patients that met the Berlin ARDS criteria were included. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of hypoxemia resolvers vs. nonresolvers in non-COVID-19 ARDS patients. Nonresolvers were defined as those whose hypoxemia worsened or remained moderate or severe over the first 7 days. Secondary outcomes included baseline admission characteristics, initial blood gases and ventilation settings, length of invasive mechanical ventilation, length of ICU stay, and ICU survival rates across resolver groups. RESULTS: A total of 894 ICU admissions were included in the study. Of these, 33.9% were hypoxemia nonresolvers. The resolver groups showed no significant difference in age, body mass index, comorbidities, or Charlson score. There was no significant difference in the percentage of those with initial severe hypoxemia between the two groups (8.1% vs. 9.2%; p = 0.126). The initial Pao2/Fio2 ratio did not significantly increase the odds ratio (OR) of being a nonresolver (OR, 0.84; 95% CI, 0.65-1.10). Nonresolver mortality was 61.4%, comparable to the survival rates seen in nonresolvers in a previous large COVID-19 ARDS study. CONCLUSIONS AND RELEVANCE: Our study shows that resolver status is a valuable grouping in ARDS. It has significant advantages over grouping by initial degree of hypoxemia, including better mapping of trajectory and comparable outcomes across other studies. While it may offer insights into disease-specific associations, future studies should include resolver status analysis for more definitive conclusions.

The metabolic cost of inspiratory muscle training in mechanically ventilated patients in critical care.

BACKGROUND: Diaphragmatic dysfunction is well documented in patients receiving mechanical ventilation. Inspiratory muscle training (IMT) has been used to facilitate weaning by strengthening the inspiratory muscles, yet the optimal approach remains uncertain. Whilst some data on the metabolic response to whole body exercise in critical care exist, the metabolic response to IMT in critical care is yet to be investigated. This study aimed to quantify the metabolic response to IMT in critical care and its relationship to physiological variables. METHODS: We conducted a prospective observational study on mechanically ventilated patients ventilated for ≥ 72 h and able to participate in IMT in a medical, surgical, and cardiothoracic intensive care unit. 76 measurements were taken on 26 patients performing IMT using an inspiratory threshold loading device at 4 cmH2O, and at 30, 50 and 80% of their negative inspiratory force (NIF). Oxygen consumption (VO2) was measured continuously using indirect calorimetry. RESULTS: First session mean (SD) VO2 was 276 (86) ml/min at baseline, significantly increasing to 321 (93) ml/min, 333 (92) ml/min, 351(101) ml/min and 388 (98) ml/min after IMT at 4 cmH2O and 30, 50 and 80% NIF, respectively (p = 0.003). Post hoc comparisons revealed significant differences in VO2 between baseline and 50% NIF and baseline and 80% NIF (p = 0.048 and p = 0.001, respectively). VO2 increased by 9.3 ml/min for every 1 cmH2O increase in inspiratory load from IMT. Every increase in P/F ratio of 1 decreased the intercept VO2 by 0.41 ml/min (CI - 0.58 to - 0.24 p < 0.001). NIF had a significant effect on the intercept and slope, with every 1 cmH2O increase in NIF increasing intercept VO2 by 3.28 ml/min (CI 1.98-4.59 p < 0.001) and decreasing the dose-response slope by 0.15 ml/min/cmH2O (CI - 0.24 to - 0.05 p = 0.002). CONCLUSIONS: IMT causes a significant load-dependent increase in VO2. P/F ratio and NIF impact baseline VO2. The dose-response relationship of the applied respiratory load during IMT is modulated by respiratory strength. These data may offer a novel approach to prescription of IMT. TAKE HOME MESSAGE: The optimal approach to IMT in ICU is uncertain; we measured VO2 at different applied respiratory loads to assess whether VO2 increased proportionally with load and found VO2 increased by 9.3 ml/min for every 1 cmH2O increase in inspiratory load from IMT. Baseline NIF has a significant effect on the intercept and slope, participants with a higher baseline NIF have a higher resting VO2 but a less pronounced increase in VO2 as the inspiratory load increases; this may offer a novel approach to IMT prescription. Trial registration ClinicalTrials.gov, registration number: NCT05101850. Registered on 28 September 2021, https://clinicaltrials.gov/ct2/show/NCT05101850.

Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study.

BACKGROUND: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. METHODS: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2-7 months after hospital discharge and a later time point 10-14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). FINDINGS: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4-6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5-8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (-19%; 95% CI -20 to -16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18-39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27-41% of this effect. INTERPRETATION: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. FUNDING: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council.

Upcoming and urgent challenges in critical care research based on COVID-19 pandemic experience.

While the coronavirus disease 2019 (COVID-19) pandemic placed a heavy burden on healthcare systems worldwide, it also induced urgent mobilisation of research teams to develop treatments preventing or curing the disease and its consequences. It has, therefore, challenged critical care research to rapidly focus on specific fields while forcing critical care physicians to make difficult ethical decisions. This narrative review aims to summarise critical care research -from organisation to research fields- in this pandemic setting and to highlight opportunities to improve research efficiency in the future, based on what is learned from COVID-19. This pressure on research revealed, i.e., (i) the need to harmonise regulatory processes between countries, allowing simplified organisation of international research networks to improve their efficiency in answering large-scale questions; (ii) the importance of developing translational research from which therapeutic innovations can emerge; (iii) the need for improved triage and predictive scores to rationalise admission to the intensive care unit. In this context, key areas for future critical care research and better pandemic preparedness are artificial intelligence applied to healthcare, characterisation of long-term symptoms, and ethical considerations. Such collaborative research efforts should involve groups from both high and low-to-middle income countries to propose worldwide solutions. As a conclusion, stress tests on healthcare organisations should be viewed as opportunities to design new research frameworks and strategies. Worldwide availability of research networks ready to operate is essential to be prepared for next pandemics. Importantly, researchers and physicians should prioritise realistic and ethical goals for both clinical care and research.

Investigation of Microvesicle Uptake by Mouse Lung-marginated Monocytes in vitro.

Extracellular microvesicles (MVs) are released into the circulation in large numbers during acute systemic inflammation, yet little is known of their intravascular cell/tissue-specific interactions under these conditions. We recently described a dramatic increase in the uptake of intravenously injected MVs by monocytes marginated within the pulmonary vasculature, in a mouse model of low-dose lipopolysaccharide-induced systemic inflammation. To investigate the mechanisms of enhanced MV uptake by monocytes, we developed an in vitro model using in vivo derived monocytes. Although mouse blood is a convenient source, monocyte numbers are too low for in vitro experimentation. In contrast, differentiated bone marrow monocytes are abundant, but they are rapidly mobilized during systemic inflammation, and thus no longer available. Instead, we developed a protocol using marginated monocytes from the pulmonary vasculature as an anatomically relevant and abundant source. Mice are sacrificed by terminal anesthesia, the lungs inflated and perfused via the pulmonary artery. Perfusate cell populations are evaluated by flow cytometry, combined with in vitro generated fluorescently labelled MVs, and incubated in suspension for up to one hour. Washed cells are analyzed by flow cytometry to quantify MV uptake and confocal microscopy to localize MVs within cells (O'Dea et al., 2020). Using this perfusion-based method, substantial numbers of marginated pulmonary vascular monocytes are recovered, allowing multiple in vitro tests to be performed from a single mouse donor. As MV uptake profiles were comparable to those observed in vivo, this method is suitable for physiologically relevant high throughput mechanistic studies on mouse monocytes under in vitro conditions. Graphic abstract: Figure 1. Schematic of lung perfusate cell harvest and co-incubation with in vitro generated MVs. Created with BioRender.com.

Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom.

PURPOSE: The trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions. METHODS: We included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget ( https://www.CovidUK.ICU ). RESULTS: Data for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P < 0.001; median PaO2/FiO2 on the day of death was 12.3(8.9-18.4) kPa] and non-response to proning (69.5% vs.31.1%; P < 0.001). Two ML models using weeklong data demonstrated an increased predictive accuracy for mortality compared to admission data (74.5% and 76.3% vs 60%, respectively). XAI models highlighted the increasing importance, over the first week, of PaO2/FiO2 in predicting mortality. Prone positioning improved oxygenation only in 45% of patients. A higher peak pressure (OR 1.42[1.06-1.91]; P < 0.05), raised respiratory component (OR 1.71[ 1.17-2.5]; P < 0.01) and cardiovascular component (OR 1.36 [1.04-1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33 [0.99-1.79]; P = 0.057) immediately prior to application of prone positioning were associated with lack of oxygenation response. Prone positioning was not applied to 76% of patients with moderate hypoxemia and 45% of those with severe hypoxemia and patients who died without receiving proning interventions had more missed opportunities for prone intervention [7 (3-15.5) versus 2 (0-6); P < 0.001]. Despite the severity of gas exchange deficit, most patients received lung-protective ventilation with tidal volumes less than 8 mL/kg and plateau pressures less than 30cmH2O. This was despite systematic errors in measurement of height and derived ideal body weight. CONCLUSIONS: Refractory hypoxaemia remains a major association with mortality, yet evidence based ARDS interventions, in particular prone positioning, were not implemented and had delayed application with an associated reduced responsiveness. Real-time service evaluation techniques offer opportunities to assess the delivery of care and improve protocolised implementation of evidence-based ARDS interventions, which might be associated with improvements in survival.

Secreted Extracellular Cyclophilin A Is a Novel Mediator of Ventilator-induced Lung Injury.

Rationale: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator-induced lung injury. eCypA (extracellular CypA [cyclophilin A]) is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to coronavirus disease (COVID-19). Objectives: To explore the involvement of eCypA in the pathophysiology of ventilator-induced lung injury. Methods: Mice were ventilated with a low or high Vt for up to 3 hours, with or without blockade of eCypA signaling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretching to explore the cellular source of eCypA, and CypA concentrations were measured in BAL fluid from patients with acute respiratory distress syndrome to evaluate the clinical relevance. Measurements and Main Results: High-Vt ventilation in mice provoked a rapid increase in soluble CypA concentration in the alveolar space but not in plasma. In vivo ventilation and in vitro stretching experiments indicated the alveolar epithelium as the likely major source. In vivo blockade of eCypA signaling substantially attenuated physiological dysfunction, macrophage activation, and MMPs (matrix metalloproteinases). Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated concentrations of eCypA within BAL fluid. Conclusions: CypA is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. eCypA represents an exciting novel target for pharmacological intervention.

Right ventricular dysfunction in critically ill COVID-19 ARDS.

AIMS: Comprehensive echocardiography assessment of right ventricular (RV) impairment has not been reported in critically ill patients with COVID-19. We detail the specific phenotype and clinical associations of RV impairment in COVID-19 acute respiratory distress syndrome (ARDS). METHODS: Transthoracic echocardiography (TTE) measures of RV function were collected in critically unwell patients for associations with clinical, ventilatory and laboratory data. RESULTS: Ninety patients (25.6% female), mean age 52.0 ± 10.8 years, veno-venous extracorporeal membrane oxygenation (VVECMO) (42.2%) were studied. A significantly higher proportion of patients were identified as having RV dysfunction by RV fractional area change (FAC) (72.0%,95% confidence interval (CI) 61.0-81.0) and RV velocity time integral (VTI) (86.4%, 95 CI 77.3-93.2) than by tricuspid annular plane systolic excursion (TAPSE) (23.8%, 95 CI 16.0-33.9), RVS' (11.9%, 95% CI 6.6-20.5) or RV free wall strain (FWS) (35.3%, 95% CI 23.6-49.0). RV VTI correlated strongly with RV FAC (p ≤ 0.01). Multivariate regression demonstrated independent associations of RV FAC with NTpro-BNP and PVR. RV-PA coupling correlated with PVR (univariate p < 0.01), as well as RVEDAi (p < 0.01), and RVESAi (p < 0.01), and was associated with P/F ratio (p 0.026), PEEP (p 0.025), and ALT (p 0.028). CONCLUSIONS: Severe COVID-19 ARDS is associated with a specific phenotype of RV radial impairment with sparing of longitudinal function. Clinicians should avoid interpretation of RV health purely on long-axis parameters in these patients. RV-PA coupling potentially provides important additional information above standard measures of RV performance in this cohort.

Respiratory follow-up of patients with COVID-19 pneumonia.

The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.

Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging, and Hematologic Observations.

Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology.Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia.Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography.Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29-79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic "shutdown". The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6).Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.

Frequency of Thrombocytopenia and Heparin-Induced Thrombocytopenia in Patients Receiving Extracorporeal Membrane Oxygenation Compared With Cardiopulmonary Bypass and the Limited Sensitivity of Pretest Probability Score.

OBJECTIVES: To ascertain: 1) the frequency of thrombocytopenia and heparin-induced thrombocytopenia; 2) positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia; and 3) clinical outcome of heparin-induced thrombocytopenia in adult patients receiving venovenous- or venoarterial-extracorporeal membrane oxygenation, compared with cardiopulmonary bypass. DESIGN: A single-center, retrospective, observational cohort study from January 2016 to April 2018. SETTING: Tertiary referral center for cardiac and respiratory failure. PATIENTS: Patients who received extracorporeal membrane oxygenation for more than 48 hours or had cardiopulmonary bypass during specified period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and laboratory data were collected retrospectively. Pretest Probability Score and heparin-induced thrombocytopenia testing results were collected prospectively. Mean age (± SD) of the extracorporeal membrane oxygenation and cardiopulmonary bypass cohorts was 45.4 (± 15.6) and 64.9 (± 13), respectively (p < 0.00001). Median duration of cardiopulmonary bypass was 4.6 hours (2-16.5 hr) compared with 170.4 hours (70-1,008 hr) on extracorporeal membrane oxygenation. Moderate and severe thrombocytopenia were more common in extracorporeal membrane oxygenation compared with cardiopulmonary bypass throughout (p < 0.0001). Thrombocytopenia increased in cardiopulmonary bypass patients on day 2 but was normal in 83% compared with 42.3% of extracorporeal membrane oxygenation patients at day 10. Patients on extracorporeal membrane oxygenation also followed a similar pattern of platelet recovery following cessation of extracorporeal membrane oxygenation. The frequency of heparin-induced thrombocytopenia in extracorporeal membrane oxygenation and cardiopulmonary bypass were 6.4% (19/298) and 0.6% (18/2,998), respectively (p < 0.0001). There was no difference in prevalence of heparin-induced thrombocytopenia in patients on venovenous-extracorporeal membrane oxygenation (8/156, 5.1%) versus venoarterial-extracorporeal membrane oxygenation (11/142, 7.7%) (p = 0.47). The positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia in patients post cardiopulmonary bypass and on extracorporeal membrane oxygenation was 56.25% (18/32) and 25% (15/60), respectively. Mortality was not different with (6/19, 31.6%) or without (89/279, 32.2%) heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation (p = 0.79). CONCLUSIONS: Thrombocytopenia is already common at extracorporeal membrane oxygenation initiation. Heparin-induced thrombocytopenia is more frequent in both venovenous- and venoarterial-extracorporeal membrane oxygenation compared with cardiopulmonary bypass. Positive predictive value of Pretest Probability Score in identifying heparin-induced thrombocytopenia was lower in extracorporeal membrane oxygenation patients. Heparin-induced thrombocytopenia had no effect on mortality.

Dual-Energy CT Pulmonary Angiography (DECTPA) Quantifies Vasculopathy in Severe COVID-19 Pneumonia.

BACKGROUND: The role of dual energy computed tomographic pulmonary angiography (DECTPA) in revealing vasculopathy in coronavirus disease 2019 (COVID-19) has not been fully explored. PURPOSE: To evaluate the relationship between DECTPA and disease duration, right ventricular dysfunction (RVD), lung compliance, D-dimer and obstruction index in COVID-19 pneumonia. MATERIALS AND METHODS: This institutional review board approved this retrospective study, and waived the informed consent requirement. Between March-May 2020, 27 consecutive ventilated patients with severe COVID-19 pneumonia underwent DECTPA to diagnose pulmonary thrombus (PT); 11 underwent surveillance DECTPA 14 ±11.6 days later. Qualitative and quantitative analysis of perfused blood volume (PBV) maps recorded: i) perfusion defect 'pattern' (wedge-shaped, mottled or amorphous), ii) presence of PT and CT obstruction index (CTOI) and iii) PBV relative to pulmonary artery enhancement (PBV/PAenh); PBV/PAenh was also compared with seven healthy volunteers and correlated with D-Dimer and CTOI. RESULTS: Amorphous (n=21), mottled (n=4), and wedge-shaped (n=2) perfusion defects were observed (M=20; mean age=56 ±8.7 years). Mean extent of perfusion defects=36.1%±17.2. Acute PT was present in 11/27(40.7%) patients. Only wedge-shaped defects corresponded with PT (2/27, 7.4%). Mean CTOI was 2.6±5.4 out of 40. PBV/PAenh (18.2 ±4.2%) was lower than in healthy volunteers (27 ±13.9%, p = 0.002). PBV/PAenh correlated with disease duration (ß = 0.13, p = 0.04), and inversely correlated with RVD (ß = -7.2, p = 0.001), persisting after controlling for confounders. There were no linkages between PBV/PAenh and D-dimer or CTOI. CONCLUSION: Perfusion defects and decreased PBV/PAenh are prevalent in severe COVID-19 pneumonia. PBV/PAenh correlates with disease duration and inversely correlates with RVD. PBV/PAenh may be an important marker of vasculopathy in severe COVID-19 pneumonia even in the absence of arterial thrombus.

Intracranial Hemorrhage and Early Mortality in Patients Receiving Extracorporeal Membrane Oxygenation for Severe Respiratory Failure.

Intracranial hemorrhage (ICH) is a serious complication in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) and is associated with high mortality. It is unknown whether ICH may be a consequence of the ECMO or of an underlying disease. The authors first aimed to assess the incidence of ICH at initiation and during the course of VV-ECMO and its associated mortality. The second aim was to identify clinical and laboratory measures that could predict the development of ICH in severe respiratory failure. Data were collected from a total number of 165 patients receiving VV-ECMO from January, 2012 to December, 2016 in a single tertiary center and treated according to a single protocol. Only patients who had a brain computed tomography within 24 hours of initiation of ECMO (n = 149) were included for analysis. The prevalence and incidence of ICH at initiation and during the course of VV-ECMO (at median 9 days) were 10.7% (16/149) and 5.2% (7/133), respectively. Thrombocytopenia and reduced creatinine clearance (CrCL) were independently associated with increased risk of ICH on admission; odds ratio (95% confidence interval): 22.6 (2.6-99.5), and 10.8 (5.6-16.2). Only 30-day (not 180-day) mortality was significantly higher in patients with ICH on admission versus those without (37.5% [6/16] vs 16.4% [22/133]; p = 0.03 and 43.7% [7/16] vs 26.3% [35/133]; p = 0.15, respectively). Reduced CrCL and thrombocytopenia were associated with ICH at initiation of VV-ECMO. The higher incidence of ICH at initiation suggests it is more closely related to the severity of the underlying lung injury than to the VV-ECMO itself. ICH at VV-ECMO initiation was associated with early mortality.