Publications by authors named "David Antcliffe"

12 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

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

JAMA 2020 10;324(13):1317-1329

School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.

Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).

Main Outcomes And Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).

Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.

Conclusions And Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
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http://dx.doi.org/10.1001/jama.2020.17022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489418PMC
October 2020

Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial.

Intensive Care Med 2019 10 19;45(10):1392-1400. Epub 2019 Aug 19.

Section of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare NHS Trust, London, UK.

Purpose: Myocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects.

Methods: Two cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values.

Results: Levosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43-2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers.

Conclusion: Adding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.
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http://dx.doi.org/10.1007/s00134-019-05731-wDOI Listing
October 2019

Why Understanding Sepsis Endotypes Is Important for Steroid Trials in Septic Shock.

Crit Care Med 2019 12;47(12):1782-1784

Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.1097/CCM.0000000000003833DOI Listing
December 2019

Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial.

Am J Respir Crit Care Med 2019 04;199(8):980-986

1 Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.

Rationale: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration, but conflicting survival effects. Two transcriptomic sepsis response signatures (SRSs) have been identified. SRS1 is relatively immunosuppressed, whereas SRS2 is relatively immunocompetent.

Objectives: We aimed to categorize patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock.

Methods: A post hoc analysis was performed of a double-blind, randomized clinical trial in septic shock (VANISH [Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock]). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined by a previously established model using seven discriminant genes.

Measurements And Main Results: Samples were available from 176 patients: 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (P = 0.50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (P = 0.02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (odds ratio = 7.9; 95% confidence interval = 1.6-39.9).

Conclusions: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immunocompetent SRS2 endotype had significantly higher mortality when given corticosteroids compared with placebo. Clinical trial registered with www.clinicaltrials.gov (ISRCTN 20769191).
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http://dx.doi.org/10.1164/rccm.201807-1419OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467319PMC
April 2019

Profiling inflammatory markers in patients with pneumonia on intensive care.

Sci Rep 2018 10 3;8(1):14736. Epub 2018 Oct 3.

Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, UK.

Clinical investigations lack predictive value when diagnosing pneumonia, especially when patients are ventilated and develop ventilator associated pneumonia (VAP). New tools to aid diagnosis are important to improve outcomes. This pilot study examines the potential for a panel of inflammatory mediators to aid in the diagnosis. Forty-four ventilated patients, 17 with pneumonia and 27 with brain injuries, eight of whom developed VAP, were recruited. 51 inflammatory mediators, including cytokines and oxylipins, were measured in patients' serum using flow cytometry and mass spectrometry. The mediators could separate patients admitted to ICU with pneumonia compared to brain injury with an area under the receiver operating characteristic curve (AUROC) 0.75 (0.61-0.90). Changes in inflammatory mediators were similar in both groups over the course of ICU stay with 5,6-dihydroxyeicosatrienoic and 8,9-dihydroxyeicosatrienoic acids increasing over time and interleukin-6 decreasing. However, brain injured patients who developed VAP maintained inflammatory profiles similar to those at admission. A multivariate model containing 5,6-dihydroxyeicosatrienoic acid, 8,9-dihydroxyeicosatrienoic acid, intercellular adhesion molecule-1, interleukin-6, and interleukin-8, could differentiate patients with VAP from brain injured patients without infection (AUROC 0.94 (0.80-1.00)). The use of a selected group of markers showed promise to aid the diagnosis of VAP especially when combined with clinical data.
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http://dx.doi.org/10.1038/s41598-018-32938-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170441PMC
October 2018

Metabolic Profiling in Patients with Pneumonia on Intensive Care.

EBioMedicine 2017 Apr 29;18:244-253. Epub 2017 Mar 29.

Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, UK. Electronic address:

Clinical features and investigations lack predictive value when diagnosing pneumonia, especially when patients are ventilated and when patients develop ventilator associated pneumonia (VAP). New tools to aid diagnosis are important to improve outcomes. This pilot study examines the potential for metabolic profiling to aid the diagnosis in critical care. In this prospective observational study ventilated patients with brain injuries or pneumonia were recruited in the intensive care unit and serum samples were collected soon after the start of ventilation. Metabolic profiles were produced using 1D H NMR spectra. Metabolic data were compared using multivariate statistical techniques including Principal Component Analysis (PCA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA). We recruited 15 patients with pneumonia and 26 with brain injuries, seven of whom went on to develop VAP. Comparison of metabolic profiles using OPLS-DA differentiated those with pneumonia from those with brain injuries (RY=0.91, QY=0.28, p=0.02) and those with VAP from those without (RY=0.94, QY=0.27, p=0.05). Metabolites that differentiated patients with pneumonia included lipid species, amino acids and glycoproteins. Metabolic profiling shows promise to aid in the diagnosis of pneumonia in ventilated patients and may allow a more timely diagnosis and better use of antibiotics.
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http://dx.doi.org/10.1016/j.ebiom.2017.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405179PMC
April 2017

Metabonomics and intensive care.

Crit Care 2016 Mar 16;20:68. Epub 2016 Mar 16.

Department of Surgery & Cancer, Charing Cross Hospital / Imperial College London, Section of Anaesthetics, Pain Medicine & Intensive Care, London, UK.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
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http://dx.doi.org/10.1186/s13054-016-1222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794854PMC
March 2016

A meta-analysis of mini-open versus standard open and laparoscopic living donor nephrectomy.

Transpl Int 2009 Apr 20;22(4):463-74. Epub 2009 Jan 20.

Department of Biosurgery and Surgical Technology, Imperial College London, St Mary's Hospital, London, UK.

Mini-open donor nephrectomy (MODN) potentially combines advantages of standard open (SODN) and laparoscopic techniques (LDN). This article is a comparison of these techniques. A literature search was performed for studies comparing MODN with SODN or LDN. Nine studies met our selection criteria. Of the 1038 patients, 433 (42%) underwent MODN, 389 (37%) SODN and 216 (21%) LDN. MODN versus SODN: Operative time (P = 0.17), warm ischemia time (P = 0.20) and blood loss (P = 0.30) were not significantly different. Hospital stay and time to return to work were shorter for MODN by 1.67 days (P < 0.001) and 5 weeks (P = 0.03). Analgesia requirement and overall complications were less in the MODN group (P < 0.001) and (P = 0.03). Ureteric complications (P = 0.21) and 1-year graft survival (P = 0.28) were not significantly different. MODN versus LDN: Operative and warm ischemia times were significantly shorter for the MODN by 55 min (P = 0.005) and 147 s (P < 0.001). Analgesia requirement was greater for the MODN group by 9.62 mEq morphine (P = 0.04). No significant differences were found for blood loss (P = 0.8), hospital stay (P = 0.35), donor complications (P = 0.40) or ureteric complications (P = 0.83). MODN appears to provide advantages for the donor in comparison to SODN and also has a shorter operative time when compared with the LDN.
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http://dx.doi.org/10.1111/j.1432-2277.2008.00828.xDOI Listing
April 2009

Laparoscopic versus open live donor nephrectomy in renal transplantation: a meta-analysis.

Ann Surg 2008 Jan;247(1):58-70

Department of Biosurgery and Surgical Technology, Imperial College London, St Mary's Hospital, London, UK.

Objective: The aim of this study was to compare laparoscopic versus open live donor nephrectomy using meta-analytical techniques.

Summary Background Data: Laparoscopic live donor nephrectomy has gained widespread acceptance and is increasingly performed. The body of evidence assessing the safety and efficacy of laparoscopic compared with established open techniques is growing; however, very few randomized control trials exist and individual studies often have small patient numbers with varying results. We combined the available raw data to strengthen the current literature in comparing these techniques.

Methods: A literature search was performed and comparative studies published between 1997 and 2006 of open versus laparoscopic donor nephrectomy were included. Outcomes evaluated were operative and warm ischemia times, blood loss, donor complications, length of hospital stay, time to return to work, and delayed graft function.

Results: Seventy-three studies matched the selection criteria and included 6594 patients, 3751 (57%) had undergone laparoscopic surgery and 2843 (43%) open nephrectomy. The open nephrectomy group had shorter operative and warm ischemia times by 52 minutes (P < 0.001) and 102 seconds (P < 0.001), respectively. This did not translate into higher delayed graft function or graft loss rates between the 2 groups. Patients in the laparoscopic group had a shorter hospital stay and a faster return to work by 1.58 days (P < 0.001) and 2.38 weeks (P < 0.001), respectively. There was a significantly higher rate of overall donor complications in the open group (P = 0.007), a finding not reproduced in any subsequent sensitivity analyses. When only randomized control trials were considered, there were shorter operative times (P = 0.002) for the open group but nonsignificantly different warm ischemia times. In contrast to the main analysis there were no differences in the overall complication rate, postoperative analgesia, hospital stay, or time taken to return to work.

Conclusions: Laparoscopic nephrectomy in live donor transplantation is a safe alternative to the open technique. Although open nephrectomy may be associated with shorter operative and warm ischemia times, patients undergoing laparoscopic nephrectomy may benefit from a shorter hospital stay and faster return to work without compromising graft function.
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http://dx.doi.org/10.1097/SLA.0b013e318153fd13DOI Listing
January 2008

Outcome of kidney transplantation from nonheart-beating versus heart-beating cadaveric donors.

Transplantation 2007 May;83(9):1193-9

Imperial College London, Department of Biosurgery and Surgical Technology, St Mary's Hospital, London, United Kingdom.

Background: This study aimed to assess outcomes of kidney transplants from nonheart-beating (NHB) compared with heart-beating (HB) cadaveric donors with meta-analytical techniques.

Methods: A literature search was performed for studies comparing kidney transplants from NHB vs. HB cadaveric donors between 1992 and 2005. The following outcomes were evaluated: warm and cold ischemia times, primary nonfunction, delayed graft function, length of hospital stay, acute graft rejection, patient and graft survival, and post-transplant serum creatinine.

Results: Eighteen comparative studies of 114,081 patients matched the selection criteria; 1,858 received kidney from NHB and 112,223 from HB donor. Warm ischemia time was significantly longer for the NHB group by 24 min (P<0.001). Cold ischemia time was similar for the two groups (P=0.97). The incidence of primary nonfunction and delayed graft function was 2.4 times (P<0.001) and 3.6 times (P<0.001) greater, respectively, in the NHB group. Length of hospital stay was longer for the NHB group by 4.6 days (P<0.001). The 6-month, 2-year, and 5-year patient survival were similar between the two groups. The incidence of acute rejection was similar between the two groups whereas the initial graft survival advantage in favor of the HB group diminished gradually over the course of time. There was no statistically significant difference between the two groups for the recipient serum creatinine levels at 3 and 12 months after transplantation.

Conclusion: NHB donors carry the potential of expanding the cadaveric kidney pool. Although, transplants from NHB donors are associated with a greater incidence of early adverse events, long-term outcomes appear comparable with those of transplants from HB donors.
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http://dx.doi.org/10.1097/01.tp.0000261710.53848.51DOI Listing
May 2007

Comparison of laparoscopic versus hand-assisted live donor nephrectomy.

Transplantation 2007 Jan;83(1):41-7

Imperial College London, Department of Biosurgery and Surgical Technology, St. Mary's Hospital, London, United Kingdom.

Background: The aim of the present study was to compare hand-assisted laparoscopic live donor nephrectomy with the classic laparoscopic method, using meta-analytical techniques.

Methods: A literature search was performed for studies comparing hand-assisted laparoscopic nephrectomy with classic laparoscopic nephrectomy for live kidney donation between 1999 and 2005. The following end points were evaluated: operative time, warm ischemia time, intraoperative adverse events, donor and recipient postoperative complications, and length of hospital stay.

Results: Nine comparative studies matched the selection criteria, reporting on 376 patients, of whom 202 (53.7%) had hand-assisted laparoscopic nephrectomy and 174 (46.3%) had the classic laparoscopic technique. Conversion to open surgery was 2.97% in the hand-assisted group and 4.60% in the laparoscopic group (P=0.35). Total operative and warm ischemia times were significantly shorter for hand-assisted laparoscopy by 30.03 minutes (P=0.02) and 1.14 minutes (P<0.001), respectively. The intraoperative blood loss was less for the hand-assisted laparoscopy group by 34.16 mL (P=0.008), although intraoperative (3.46% vs. 7.47%; P=0.24) and postoperative (5.94% vs. 10.34%; P=0.30) donor complications and recipient complications (including delayed graft function and primary nonfunction, 8.41% vs. 7.42%; P=0.32) were similar between the hand-assisted and laparoscopic groups.

Conclusion: Hand-assisted laparoscopic nephrectomy appeared to have the same donor and recipient complication rate with standard laparoscopy but offered substantial advantages in terms of shortened operative and warm ischemia time as well as decreased intraoperative bleeding.
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http://dx.doi.org/10.1097/01.tp.0000248761.56724.9cDOI Listing
January 2007
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