Publications by authors named "Brijesh V Patel"

22 Publications

  • Page 1 of 1

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

Intensive Care Med 2021 05 11;47(5):549-565. Epub 2021 May 11.

Brain & Behaviour Lab, Dept. Of Computing, Imperial College London, London, UK.

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 PaO/FiO 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 PaO/FiO 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 30cmHO. 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.
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http://dx.doi.org/10.1007/s00134-021-06389-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111053PMC
May 2021

Secreted Extracellular Cyclophilin A is a Novel Mediator of Ventilator Induced Lung Injury.

Am J Respir Crit Care Med 2021 Apr 13. Epub 2021 Apr 13.

Imperial College London, Anaesthetics & Intensive Care, London, United Kingdom of Great Britain and Northern Ireland;

Rationale: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator induced lung injury. Extracellular Cyclophilin A is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to COVID-19 infection.

Objectives: Here we explore the involvement of extracellular Cyclophilin A in the pathophysiology of ventilator-induced lung injury.

Methods: Mice were ventilated with low or high tidal volume for up to 3 hours, with or without blockade of extracellular Cyclophilin A signalling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretch to explore the cellular source of extracellular Cyclophilin A, and Cyclophilin A levels were measured in bronchoalveolar lavage fluid from acute respiratory distress syndrome patients, to evaluate clinical relevance.

Measurements And Main Results: High tidal volume ventilation in mice provoked a rapid increase in soluble Cyclophilin A levels in the alveolar space, but not plasma. In vivo ventilation and in vitro stretch experiments indicated alveolar epithelium as the likely major source. In vivo blockade of extracellular Cyclophilin A signalling substantially attenuated physiological dysfunction, macrophage activation and matrix metalloproteinases. Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated levels of extracellular Cyclophilin A within bronchoalveolar lavage.

Conclusions: Cyclophilin A is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. Extracellular Cyclophilin A represents an exciting novel target for pharmacological intervention.
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http://dx.doi.org/10.1164/rccm.202009-3545OCDOI Listing
April 2021

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

Radiol Cardiothorac Imaging 2020 Oct 29;2(5):e200428. Epub 2020 Oct 29.

Department of Imaging, Royal Brompton Hospital, London, UK (C.A.R., S.R.D., C.M., D.L.L., S.M., T.S., E.S., S.P.P, A.D.); Imperial College London, London, UK (N.J.); Anaesthesia and Critical Care, Royal Brompton Hospital, London, UK (S.P., C.B., B.V.P.); Department of Haematology, Imperial College London, London, UK and Department of Haematology, Royal Brompton Hospital, London, UK (D.J.A).

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 (β = 0.13, p = 0.04), and inversely correlated with RVD (β = -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.
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http://dx.doi.org/10.1148/ryct.2020200428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605077PMC
October 2020

Potential for personalised application of inhaled nitric oxide in COVID-19 pneumonia.

Br J Anaesth 2021 02 14;126(2):e72-e75. Epub 2020 Nov 14.

National Heart and Lung Institute, Imperial College London, London, UK; National Pulmonary Hypertension Service, Royal Brompton Hospital, UK. Electronic address:

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http://dx.doi.org/10.1016/j.bja.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666572PMC
February 2021

Right ventricular dysfunction in critically ill COVID-19 ARDS.

Int J Cardiol 2021 03 23;327:251-258. Epub 2020 Nov 23.

Department of Cardiology, Royal Brompton Hospital, Sydney Street, London, UK; Department of Adult Critical Care, Royal Brompton Hospital, Sydney Street, London, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681038PMC
March 2021

Reply to Sanfilippo and to Caviedes

Am J Respir Crit Care Med 2021 01;203(2):261-263

Imperial College London London, United Kingdom and.

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http://dx.doi.org/10.1164/rccm.202008-3340LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874410PMC
January 2021

Contrast Echocardiography in VV-ECMO-Dependent Patients with COVID-19.

J Am Soc Echocardiogr 2020 11 17;33(11):1419-1420. Epub 2020 Jul 17.

Department of Cardiology, Royal Brompton Hospital, London, United Kingdom; Department of Adult Critical Care, Royal Brompton Hospital, London, United Kingdom.

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http://dx.doi.org/10.1016/j.echo.2020.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366993PMC
November 2020

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

Thorax 2020 11 24;75(11):1009-1016. Epub 2020 Aug 24.

Aintree University Hospitals NHS Foundation Trust, Liverpool, UK

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.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447111PMC
November 2020

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

Am J Respir Crit Care Med 2020 09;202(5):690-699

Department of Haematology.

Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology. To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia. Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [ = 39] and dual-energy CT [DECT,  = 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. In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29-79 yr]; Black and minority ethnic,  = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm HO; 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,  = 3; mottled,  = 9; mixed pattern,  = 6). 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.
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http://dx.doi.org/10.1164/rccm.202004-1412OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462405PMC
September 2020

Anticoagulation with argatroban in patients with acute antithrombin deficiency in severe COVID-19.

Br J Haematol 2020 09 30;190(5):e286-e288. Epub 2020 Jun 30.

Royal Brompton &, Harefield NHS Foundation Trust and Imperial College London, London, UK.

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http://dx.doi.org/10.1111/bjh.16927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300519PMC
September 2020

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.

Crit Care Med 2020 05;48(5):e371-e379

Department of Intensive Care Medicine, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.

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.
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http://dx.doi.org/10.1097/CCM.0000000000004261DOI Listing
May 2020

Monocytes mediate homing of circulating microvesicles to the pulmonary vasculature during low-grade systemic inflammation.

J Extracell Vesicles 2020 5;9(1):1706708. Epub 2020 Jan 5.

Section of Anaesthetics, Pain Medicine & Intensive Care, Imperial College London, Chelsea & Westminster Hospital, London, UK.

Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6C and Ly6C monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6C monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6C monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6C monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6C subset monocytes, become a dominant target cell population for MVs during systemic inflammation, with significant implications for the function and targeting of endogenous and therapeutically administered MVs, lending novel insights into the pathophysiology of pulmonary vascular inflammation.
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http://dx.doi.org/10.1080/20013078.2019.1706708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968433PMC
January 2020

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

Semin Thromb Hemost 2018 Apr 22;44(3):276-286. Epub 2018 Mar 22.

Adult Intensive Care Unit, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.

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 ( = 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];  = 0.03 and 43.7% [7/16] vs 26.3% [35/133];  = 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.
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http://dx.doi.org/10.1055/s-0038-1636840DOI Listing
April 2018

Extracorporeal Circulatory Support in Acute Coronary Syndromes: A Systematic Review and Meta-Analysis.

Crit Care Med 2017 Nov;45(11):e1173-e1183

1Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Cona (FE), Italy. 2Dipartimento di Scienze Cardiotoraciche, II università degli Studi di Napoli, Neaples, Italy. 3Hospital Universitario de Santa Maria, CHLN, CAML, CCUL, Facultade de Medicina, Universitade de Lisboa, Lisbon, Portugal. 4Maria Cecilia Hospital, GVM Care & Research, Cotignola (RA), Italy. 5Anaesthetics, Pain Medicine & Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, United Kingdom. 6Adult Intensive Care Unit, Royal Brompton Hospital, London, United Kingdom.

Objectives: Extracorporeal circulatory support is a life-saving technique, and its use is increasing in acute coronary syndromes. A meta-analysis on pooled event rate of short-term mortality and complications of acute coronary syndrome patients treated with extracorporeal circulatory support was performed.

Data Sources: Articles were searched in MEDLINE, Cochrane Library, Google Scholar, and Biomed Central.

Study Selection: Inclusion criteria were observational studies on acute coronary syndrome patients treated with extracorporeal circulatory support. Primary outcome was short-term mortality. Secondary outcomes were extracorporeal circulatory support-related complications, causes of death, long-term mortality, and bridge therapy.

Data Extraction: Sixteen articles were selected. Data about clinical characteristics, acute coronary syndrome diagnosis and treatment, extracorporeal circulatory support setting, outcome definitions, and event rate were retrieved from the articles. Random effect meta-analytic pooling was performed reporting results as a summary point estimate and 95% CI.

Data Synthesis: A total of 739 patients were included (mean age, 59.8 ± 2.9). The event rate of short-term mortality was 58% (95% CI, 51-64%), 6-month mortality was affecting 24% (95% CI, 5-63%) of 1-month survivors, and 1-year mortality 17% (95% CI, 6-40%) of 6-month survivors. The event rates of extracorporeal circulatory support-related complications were acute renal failure 41%, bleeding 25%, neurologic damage in survivors 21%, sepsis/infections 21%, and leg ischemia 12%. Between causes of death, multiple organ failure and brain death affected respectively 40% and 27% of patients. Bridge to ventricular assistance device was offered to 14% of patients, and 7% received a transplant.

Conclusions: There is still a high rate of short-term mortality and complications in acute coronary syndrome patients treated with extracorporeal circulatory support. New studies are needed to optimize and standardize extracorporeal circulatory support.
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http://dx.doi.org/10.1097/CCM.0000000000002692DOI Listing
November 2017

High-Fat Feeding Protects Mice From Ventilator-Induced Lung Injury, Via Neutrophil-Independent Mechanisms.

Crit Care Med 2017 Aug;45(8):e831-e839

All authors: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.

Objective: Obesity has a complex impact on acute respiratory distress syndrome patients, being associated with increased likelihood of developing the syndrome but reduced likelihood of dying. We propose that such observations are potentially explained by a model in which obesity influences the iatrogenic injury that occurs subsequent to intensive care admission. This study therefore investigated whether fat feeding protected mice from ventilator-induced lung injury.

Design: In vivo study.

Setting: University research laboratory.

Subjects: Wild-type C57Bl/6 mice or tumor necrosis factor receptor 2 knockout mice, either fed a high-fat diet for 12-14 weeks, or age-matched lean controls.

Interventions: Anesthetized mice were ventilated with injurious high tidal volume ventilation for periods up to 180 minutes.

Measurements And Main Results: Fat-fed mice showed clear attenuation of ventilator-induced lung injury in terms of respiratory mechanics, blood gases, and pulmonary edema. Leukocyte recruitment and activation within the lungs were not significantly attenuated nor were a host of circulating or intra-alveolar inflammatory cytokines. However, intra-alveolar matrix metalloproteinase activity and levels of the matrix metalloproteinase cleavage product soluble receptor for advanced glycation end products were significantly attenuated in fat-fed mice. This was associated with reduced stretch-induced CD147 expression on lung epithelial cells.

Conclusions: Consumption of a high-fat diet protects mice from ventilator-induced lung injury in a manner independent of neutrophil recruitment, which we postulate instead arises through blunted up-regulation of CD147 expression and subsequent activation of intra-alveolar matrix metalloproteinases. These findings may open avenues for therapeutic manipulation in acute respiratory distress syndrome and could have implications for understanding the pathogenesis of lung disease in obese patients.
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http://dx.doi.org/10.1097/CCM.0000000000002403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511730PMC
August 2017

Inhibition of TNF Receptor p55 By a Domain Antibody Attenuates the Initial Phase of Acid-Induced Lung Injury in Mice.

Front Immunol 2017 13;8:128. Epub 2017 Feb 13.

Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital , London , UK.

Background: Tumor necrosis factor-α (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator-induced lung injury. In the current study, we explored the efficacy of this antibody in mouse models of acid-induced lung injury to investigate the longer consequences of treatment.

Methods: We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting "dummy" dAb, 1 or 4 h before acid instillation.

Results: Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation, and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase.

Conclusion: These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24 h. Together with our previous data, the current study lends support toward the clinical targeting of p55 for patients with, or at risk of ARDS.
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http://dx.doi.org/10.3389/fimmu.2017.00128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304467PMC
February 2017

New Consensus Definitions for Sepsis and Septic Shock: Implications for Treatment Strategies and Drug Development?

Drugs 2017 Mar;77(4):353-361

Section of Anaesthesia, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, UK.

Sepsis continues to escape a precise diagnostic definition. The most recent consensus definition, termed Sepsis-3, highlights the importance of the maladaptive and potentially life-threatening host response to infection. After briefly reviewing the history and epidemiology of sepsis, we go on to describe some of the challenges encountered when classifying such a heterogenous disease state. In the context of these new definitions for sepsis and septic shock, we explore current and potentially novel therapies, and conclude by mentioning some of the controversies of this most recent framework.
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http://dx.doi.org/10.1007/s40265-017-0698-0DOI Listing
March 2017

In vivo compartmental analysis of leukocytes in mouse lungs.

Am J Physiol Lung Cell Mol Physiol 2015 Oct 7;309(7):L639-52. Epub 2015 Aug 7.

Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom

The lung has a unique structure consisting of three functionally different compartments (alveolar, interstitial, and vascular) situated in an extreme proximity. Current methods to localize lung leukocytes using bronchoalveolar lavage and/or lung perfusion have significant limitations for determination of location and phenotype of leukocytes. Here we present a novel method using in vivo antibody labeling to enable accurate compartmental localization/quantification and phenotyping of mouse lung leukocytes. Anesthetized C57BL/6 mice received combined in vivo intravenous and intratracheal labeling with fluorophore-conjugated anti-CD45 antibodies, and lung single-cell suspensions were analyzed by flow cytometry. The combined in vivo intravenous and intratracheal CD45 labeling enabled robust separation of the alveolar, interstitial, and vascular compartments of the lung. In naive mice, the alveolar compartment consisted predominantly of resident alveolar macrophages. The interstitial compartment, gated by events negative for both intratracheal and intravenous CD45 staining, showed two conventional dendritic cell populations, as well as a Ly6C(lo) monocyte population. Expression levels of MHCII on these interstitial monocytes were much higher than on the vascular Ly6C(lo) monocyte populations. In mice exposed to acid aspiration-induced lung injury, this protocol also clearly distinguished the three lung compartments showing the dynamic trafficking of neutrophils and exudative monocytes across the lung compartments during inflammation and resolution. This simple in vivo dual-labeling technique substantially increases the accuracy and depth of lung flow cytometric analysis, facilitates a more comprehensive examination of lung leukocyte pools, and enables the investigation of previously poorly defined "interstitial" leukocyte populations during models of inflammatory lung diseases.
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http://dx.doi.org/10.1152/ajplung.00140.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593833PMC
October 2015

TNF-induced death signaling triggers alveolar epithelial dysfunction in acute lung injury.

J Immunol 2013 Apr 13;190(8):4274-82. Epub 2013 Mar 13.

Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, United Kingdom.

The ability of the alveolar epithelium to prevent and resolve pulmonary edema is a crucial determinant of morbidity and mortality in acute lung injury (ALI). TNF has been implicated in ALI pathogenesis, but the precise mechanisms remain undetermined. We evaluated the role of TNF signaling in pulmonary edema formation in a clinically relevant mouse model of ALI induced by acid aspiration and investigated the effects of TNF p55 receptor deletion, caspase-8 inhibition, and alveolar macrophage depletion on alveolar epithelial function. We found that TNF plays a central role in the development of pulmonary edema in ALI through activation of p55-mediated death signaling, rather than through previously well-characterized p55-mediated proinflammatory signaling. Acid aspiration produced pulmonary edema with significant alveolar epithelial dysfunction, as determined by alveolar fluid clearance (AFC) and intra-alveolar levels of the receptor for advanced glycation end-products. The impairment of AFC was strongly correlated with lung caspase-8 activation, which was localized to type 1 alveolar epithelial cells by flow cytometric analysis. p55-deficient mice displayed markedly attenuated injury, with improved AFC and reduced caspase-8 activity but no differences in downstream cytokine/chemokine production and neutrophil recruitment. Caspase-8 inhibition significantly improved AFC and oxygenation, whereas depletion of alveolar macrophages attenuated epithelial dysfunction with reduced TNF production and caspase-8 activity. These results provide in vivo evidence for a novel role for TNF p55 receptor-mediated caspase-8 signaling, without substantial apoptotic cell death, in triggering alveolar epithelial dysfunction and determining the early pathophysiology of ALI. Blockade of TNF-induced death signaling may provide an effective early-phase strategy for ALI.
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http://dx.doi.org/10.4049/jimmunol.1202437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701855PMC
April 2013

Ventilation with "clinically relevant" high tidal volumes does not promote stretch-induced injury in the lungs of healthy mice.

Crit Care Med 2012 Oct;40(10):2850-7

Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.

Objective: Ventilator-induced lung injury is a crucial determinant of the outcome of mechanically ventilated patients. Increasing numbers of mouse studies have identified numerous pathways and mediators that are modulated by ventilation, but it is conceptually difficult to reconcile these into a single paradigm. There is substantial variability in tidal volumes used in these studies and no certainty about the pathophysiology that such varied models actually represent. This study was designed to investigate whether ventilation strategies ranging from "very high" to more "clinically relevant" tidal volumes induce similar pathophysiologies in healthy mice or represent distinct entities.

Design: In vivo study.

Setting: University research laboratory.

Subjects: C57/Bl6 mice.

Interventions: Anesthetized mice were ventilated with various tidal volumes up to 40 mL/kg.

Measurements And Main Results: Respiratory system compliance and arterial blood gases were used to evaluate physiological variables of injury. Lung wet:dry weight ratio, lavage fluid protein, and cytokines were used to assess pulmonary edema and inflammation. All ventilation strategies induced changes in respiratory system compliance, although the pattern of change was unique for each strategy. Ventilation with 10 mL/kg and 40 mL/kg also induced decreases in arterial PO2 and blood pressure. Any physiological changes induced during the 10, 20, and 30 mL/kg strategies were largely reversed by recruitment maneuvers at the end of the protocol. Markers of pulmonary edema and inflammation indicated that only 40 mL/kg induced substantial increases in both, consistent with development of lung injury.

Conclusions: Tidal volumes up to 20 mL/kg are unlikely to induce substantial lung overstretch in models using healthy, young mice. Signs of injury/inflammation using such models are likely to result from other factors, particularly alveolar derecruitment and atelectasis. The results of such studies may need to be reevaluated before clinical relevance can be accurately determined.
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http://dx.doi.org/10.1097/CCM.0b013e31825b91efDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698535PMC
October 2012

Resolution of acute lung injury and inflammation: a translational mouse model.

Eur Respir J 2012 May 17;39(5):1162-70. Epub 2011 Oct 17.

Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK.

Previous animal models of acute lung injury (ALI) are limited as they only reproduce part of the complex pathobiology of clinical ALI. Here we develop a translational mouse model of ALI, which not only reflects the major clinical and pathological features but also enables investigation into ALI resolution. Anaesthetised mice underwent orotracheal instillation of hydrochloric acid. During the immediate period after instillation, mice were carefully maintained with supplemental oxygen to avoid mortality. At specified time-points, lung injury was assessed by analysis of blood gases, respiratory mechanics, bronchoalveolar lavage fluid, alveolar fluid clearance and lung histology. Animals exhibited significant weight loss, decreased oxygenation, increased respiratory elastance and pulmonary inflammation (intra-alveolar leukocyte influx/cytokine levels and histological injury scores). Moreover, mice displayed alveolar-capillary barrier dysfunction/epithelial injury as reflected by increased alveolar protein, lung wet/dry weight ratio and soluble receptor for advanced glycation end-products, as well as reduced alveolar fluid clearance. These injury parameters peaked between days 1 and 3, followed by almost complete recovery over days 5-10. Histology showed evidence of fibrosis on day 10. The results indicate that this resolving model of acid aspiration represents a powerful experimental tool to investigate the injurious, inflammatory, fibrotic, and resolving and reparative processes of ALI.
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http://dx.doi.org/10.1183/09031936.00093911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568398PMC
May 2012

Sources of alveolar soluble TNF receptors during acute lung injury of different etiologies.

J Appl Physiol (1985) 2011 Jul 21;111(1):177-84. Epub 2011 Apr 21.

Section of Anaesthetics, Pain Medicine, and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Rd., London SW10 9NH, UK.

Elevated soluble tumor necrosis factor-α receptor (sTNFR) levels in bronchoalveolar lavage fluid (BALF) are associated with poor patient outcome in acute lung injury (ALI). The mechanisms underlying these increases are unknown, but it is possible that pulmonary inflammation and increased alveolar epithelial permeability may individually contribute. We investigated mechanisms of elevated BALF sTNFRs in two in vivo mouse models of ALI. Anesthetized mice were challenged with intratracheal lipopolysaccharide or subjected to injurious mechanical ventilation. Lipopolysaccharide instillation produced acute intra-alveolar inflammation, but minimal alveolar epithelial permeability changes, with increased BALF sTNFR p75, but not p55. Increased p75 levels were markedly attenuated by alveolar macrophage depletion. In contrast, injurious ventilation induced substantial alveolar epithelial permeability, with increased BALF p75 and p55, which strongly correlated with total protein. BALF sTNFRs were not increased in isolated buffer-perfused lungs (devoid of circulating sTNFRs) subjected to injurious ventilation. These results suggest that lipopolysaccharide-induced intra-alveolar inflammation upregulates alveolar macrophage-mediated production of sTNFR p75, whereas enhanced alveolar epithelial permeability following mechanical ventilation leads to increased BALF p75 and p55 via plasma leakage. These data provide new insights into differential regulation of intra-alveolar sTNFR levels during ALI and may suggest sTNFRs as potential markers for evaluating the pathophysiology of ALI.
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http://dx.doi.org/10.1152/japplphysiol.00007.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137530PMC
July 2011