Publications
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Reddy K, Sinha P, O'Kane CM, et al., 2020, Subphenotypes in critical care: translation into clinical practice., The Lancet Respiratory Medicine, Vol: 8, Pages: 631-643, ISSN: 2213-2600
Despite progress in the supportive care available for critically ill patients, few advances have been made in the search for effective disease-modifying therapeutic options. The fact that many trials in critical care medicine have not identified a treatment benefit is probably due, in part, to the underlying heterogeneity of critical care syndromes. Numerous approaches have been proposed to divide populations of critically ill patients into more meaningful subgroups (subphenotypes), some of which might be more useful than others. Subclassification systems driven by clinical features and biomarkers have been proposed for acute respiratory distress syndrome, sepsis, acute kidney injury, and pancreatitis. Identifying the systems that are most useful and biologically meaningful could lead to a better understanding of the pathophysiology of critical care syndromes and the discovery of new treatment targets, and allow recruitment in future therapeutic trials to focus on predicted responders. This Review discusses proposed subphenotypes of critical illness syndromes and highlights the issues that will need to be addressed to translate subphenotypes into clinical practice.
Angus DC, Berry S, Lewis RJ, et al., 2020, The randomized embedded multifactorial adaptive platform for community-acquired pneumonia (REMAP-CAP) study: rationale and design, Annals of the American Thoracic Society, Vol: 17, Pages: 879-891, ISSN: 2329-6933
There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia (CAP). The trial uses a novel design entitled a randomized embedded multifactorial adaptive platform (REMAP). The design has 5 key features: i.) randomization, allowing robust causal inference; ii.) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; iii.) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; iv.) response-adaptive randomization with preferential assignment to those interventions that appear most favorable, and v.) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within 4 treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP was approved and enrolling patients in 52 ICUs in 13 countries in 3 continents. In February, it transitioned into pandemic mode wi
Nagendran M, Chen Y, Lovejoy C, et al., 2020, Artificial intelligence vs. clinicians – a systematic review of the design, reporting standards, and claims of deep learning studies in diagnostic medical imaging, BMJ: British Medical Journal, Vol: 368, ISSN: 0959-535X
Objective To systematically examine the design, reporting standards, risk of bias, and claims of studies comparing the performance of diagnostic deep learning algorithms for medical imaging with that of expert clinicians.Design Systematic review.Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, and the World Health Organization trial registry from 2010 to June 2019.Eligibility criteria for selecting studies Randomised trial registrations and non-randomised studies comparing the performance of a deep learning algorithm in medical imaging with a contemporary group of one or more expert clinicians. Medical imaging has seen a growing interest in deep learning research. The main distinguishing feature of convolutional neural networks (CNNs) in deep learning is that when CNNs are fed with raw data, they develop their own representations needed for pattern recognition. The algorithm learns for itself the features of an image that are important for classification rather than being told by humans which features to use. The selected studies aimed to use medical imaging for predicting absolute risk of existing disease or classification into diagnostic groups (eg, disease or non-disease). For example, raw chest radiographs tagged with a label such as pneumothorax or no pneumothorax and the CNN learning which pixel patterns suggest pneumothorax.Review methods Adherence to reporting standards was assessed by using CONSORT (consolidated standards of reporting trials) for randomised studies and TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) for non-randomised studies. Risk of bias was assessed by using the Cochrane risk of bias tool for randomised studies and PROBAST (prediction model risk of bias assessment tool) for non-randomised studies.Results Only 10 records were found for deep learning randomised clinical trials, two of which have been published (with low risk of bias, except for lack of bl
Lamontagne F, Richards-Belle A, Thomas K, et al., 2020, Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension, JAMA, Vol: 323, Pages: 938-949, ISSN: 0098-7484
Importance Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.Objective To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.Design, Setting, and Participants A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.Interventions Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).Main Outcome and Measures The primary clinical outcome was all-cause mortality at 90 days.Results Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, –5.0; 95% CI, –7.8 to –2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, –8.7 mg; 95% CI, –12.8 to −4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, −2.85%; 95% CI, −6.75 to 1.05; P = .15) (unadjusted relative r
Patel PB, Brett S, O'Callaghan D, et al., 2020, A randomized clinical trial of methylnaltrexone for the treatment of opioid induced constipation & gastrointestinal stasis in intensive care patients; results from the MOTION trial, Intensive Care Medicine, Vol: 46, Pages: 747-755, ISSN: 0342-4642
PurposeConstipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid induced constipationMethodsThe MOTION trial is a multi-centre, double blind, randomised placebo controlled trial to investigate whether methylnaltrexone alleviatesopioid induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 hours) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day,escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficileinfection and finally 28 day, ICU and hospital mortality.ResultsA total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant differencein time to rescue-free laxation between the groups (Hazard ratio 1.42, 95%CI 0.82-2.46, p=0.22). There were no significant differencesin the majority of secondary outcomes, particularly days 1-3. However, during days 4-28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p=0.01) and a greater incidence of diarrhoea in the placebo group (p=0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group
Antcliffe DB, Gordon AC, 2019, Why Understanding Sepsis Endotypes Is Important for Steroid Trials in Septic Shock, Critical Care Medicine, Vol: 47, Pages: 1782-1784, ISSN: 0090-3493
Hajjar LA, Zambolim C, Belletti A, et al., 2019, Vasopressin versus norepinephrine for the management of septic shock in cancer patients: The VANCS II randomized clinical trial., Critical Care Medicine, Vol: 47, Pages: 1743-1750, ISSN: 0090-3493
OBJECTIVES: Previous trials suggest that vasopressin may improve outcomes in patients with vasodilatory shock. The aim of this study was to evaluate whether vasopressin could be superior to norepinephrine to improve outcomes in cancer patients with septic shock. DESIGN: Single-center, randomized, double-blind clinical trial, and meta-analysis of randomized trials. SETTING: ICU of a tertiary care hospital. PATIENTS: Two-hundred fifty patients 18 years old or older with cancer and septic shock. INTERVENTIONS: Patients were assigned to either vasopressin or norepinephrine as first-line vasopressor therapy. An updated meta-analysis was also conducted including randomized trials published until October 2018. MEASUREMENTS AND MAIN RESULTS: The primary outcome was all-cause mortality at 28 days after randomization. Prespecified secondary outcomes included 90-days all-cause mortality rate; number of days alive and free of advanced organ support at day 28; and Sequential Organ Failure Assessment score 24 hours and 96 hours after randomization. We also measure the prevalence of adverse effects in 28 days. A total of 250 patients were randomized. The primary outcome was observed in 71 patients (56.8%) in the vasopressin group and 66 patients (52.8%) in the norepinephrine group (p = 0.52). There were no significant differences in 90-day mortality (90 patients [72.0%] and 94 patients [75.2%], respectively; p = 0.56), number of days alive and free of advanced organ support, adverse events, or Sequential Organ Failure Assessment score. CONCLUSIONS: In cancer patients with septic shock, vasopressin as first-line vasopressor therapy was not superior to norepinephrine in reducing 28-day mortality rate.
Antcliffe DB, Santhakumaran S, Orme RML, et al., 2019, Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial, Intensive Care Medicine, Vol: 45, Pages: 1392-1400, ISSN: 0342-4642
PurposeMyocardial 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.MethodsTwo 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.ResultsLevosimendan 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.ConclusionAdding 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.
Nagendran M, Chen Y, Gordon AC, 2019, Real time self-rating of decision certainty by clinicians: a systematic review., Clinical medicine (London, England), Vol: 19, Pages: 369-374, ISSN: 1470-2118
BackgroundWe sought to establish to what extent decision certainty has been measured in real time and whether high or low levels of certainty correlate with clinical outcomes.MethodsOur pre-specified study protocol is published on PROSPERO, CRD42019128112. We identified prospective studies from Medline, Embase and PsycINFO up to February 2019 that measured real time self-rating of the certainty of a medical decision by a clinician.FindingsNine studies were included and all were generally at high risk of bias. Only one study assessed long-term clinical outcomes: patients rated with high diagnostic uncertainty for heart failure had longer length of stay, increased mortality and higher readmission rates at 1 year than those rated with diagnostic certainty. One other study demonstrated the danger of extreme diagnostic confidence - 7% of cases (24/341) labelled as having either 0% or 100% diagnostic likelihood of heart failure were made in error.ConclusionsThe literature on real time self-rated certainty of clinician decisions is sparse and only relates to diagnostic decisions. Further prospective research with a view to generating hypotheses for testable interventions that can better calibrate clinician certainty with accuracy of decision making could be valuable in reducing diagnostic error and improving outcomes.
Thomas K, Patel A, Sadique MZ, et al., 2019, Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Statistical and Health Economic Analysis Plan for the 65 trial, Journal of the Intensive Care Society, Vol: 21, Pages: 175114371986038-175114371986038, ISSN: 1751-1437
The 65 trial is a pragmatic, multicentre, parallel-group, open-label, randomised clinical trial of permissive hypotension (targeting a mean arterial pressure target of 60–65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial will recruit 2600 patients from 65 United Kingdom adult general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. This paper describes the proposed statistical and health economic analysis for the 65 trial.
Richards-Belle A, Mouncey P, Grieve R, et al., 2019, Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Statistical and Health Economic Analysis Plan for the 65 trial, Journal of the Intensive Care Society, Pages: 1-11, ISSN: 1751-1437
The 65 trial is a pragmatic, multicentre, parallel-group, open-label, randomised clinical trial of permissive hypotension (targeting a mean arterial pressure target of 60–65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial will recruit 2600 patients from 65 United Kingdom adult general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. This paper describes the proposed statistical and health economic analysis for the 65 trial.
Nagendran M, Russell JA, Brett S, et al., 2019, Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials, Intensive Care Medicine, Vol: 45, Pages: 844-855, ISSN: 0342-4642
PurposeWe performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups.MethodsOur pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses.ResultsFour trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86–1.12] or serious adverse events (RR 1.02, 95% CI 0.82–1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%–3.2%] but fewer arrhythmias (ARD − 2.8%, 95% CI − 0.2% to − 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74–0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion).ConclusionsVasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.
Peden CJ, Stephens T, Martin G, et al., 2019, Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial, Lancet, Vol: 393, Pages: 2213-2221, ISSN: 0140-6736
BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both t
Tridente A, Holloway PAH, Hutton P, et al., 2019, Methodological challenges in European ethics approvals for a genetic epidemiology study in critically ill patients: The GenOSept experience, BMC Medical Ethics, Vol: 20, ISSN: 1472-6939
BackgroundDuring the set-up phase of an international study of genetic influences on outcomes from sepsis, we aimed to characterise potential differences in ethics approval processes and outcomes in participating European countries.MethodsBetween 2005 and 2007 of the FP6-funded international Genetics Of Sepsis and Septic Shock (GenOSept) project, we asked national coordinators to complete a structured survey of research ethic committee (REC) approval structures and processes in their countries, and linked these data to outcomes. Survey findings were reconfirmed or modified in 2017.ResultsEighteen countries participated in the study, recruiting 2257 patients from 160 ICUs. National practices differed widely in terms of composition of RECs, procedures and duration of the ethics approval process. Eight (44.4%) countries used a single centralised process for approval, seven (38.9%) required approval by an ethics committee in each participating hospital, and three (16.7%) required both. Outcomes of the application process differed widely between countries because of differences in national legislation, and differed within countries because of interpretation of the ethics of conducting research in patients lacking capacity. The RECs in four countries had no lay representation. The median time from submission to final decision was 1.5 (interquartile range 1–7) months; in nine (50%) approval was received within 1 month; six took over 6 months, and in one 24 months; had all countries been able to match the most efficient approvals processes, an additional 74 months of country or institution-level recruitment would have been available. In three countries, rejection of the application by some local RECs resulted in loss of centres; and one country rejected the application outright.ConclusionsThe potential benefits of the single application portal offered by the European Clinical Trials Regulation will not be realised without harmonisation of research
Santhakumaran S, Gordon AC, Prevost A, et al., 2019, Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials, Critical Care, Vol: 23, ISSN: 1364-8535
BackgroundRandomised controlled trials (RCTs) enrolling patients with sepsis or acute respiratory distress syndrome (ARDS) generate heterogeneous trial populations. Non-random variation in the treatment effect of an intervention due to differences in the baseline risk of death between patients in a population represents one form of heterogeneity of treatment effect (HTE). We assessed whether HTE in two sepsis and one ARDS RCTs could explain indeterminate trial results and inform future trial design.MethodsWe assessed HTE for vasopressin, hydrocortisone and levosimendan in sepsis and simvastatin in ARDS patients, on 28-day mortality, using the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing above (high) and below (low) the median score. Secondary risk measures were the acute physiology component of APACHE II and predicted risk of mortality using the APACHE II score. HTE was quantified both in additive (difference in risk difference (RD)) and multiplicative (ratio of relative risks (RR)) scales using estimated treatment differences from a logistic regression model with treatment risk as the interaction term.ResultsThe ratio of the odds of death in the highest APACHE II quartile was 4.9 to 7.4 times compared to the lowest quartile, across the three trials. We did not observe HTE for vasopressin, hydrocortisone and levosimendan in the two sepsis trials. In the HARP-2 trial, simvastatin reduced mortality in the low APACHE II group and increased mortality in the high APACHE II group (difference in RD = 0.34 (0.12, 0.55) (p = 0.02); ratio of RR 3.57 (1.77, 7.17) (p < 0.001). The HTE patterns were inconsistent across the secondary risk measures. The sensitivity analyses of HTE effects for vasopressin, hydrocortisone and levosimendan were consistent with the main analyses and attenuated for simvastatin.ConclusionsWe assessed HTE in three recent ICU RCTs, using m
Russell JA, Gordon AC, Walley KR, 2019, Early may be better – early low dose norepinephrine in septic shock, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 1049-1051, ISSN: 1073-449X
Antcliffe D, Burnham K, Al-Beidh F, et al., 2019, Transcriptomic signatures in sepsis and a differential response to steroids: from the VANISH randomized trial, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 980-986, ISSN: 1073-449X
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 (SRS) have been identified. SRS1 is relatively immunosuppressed whilst SRS2 is relatively immunocompetent. Objectives: We aimed to categorized 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). 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 using 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 (OR 7·9, 95%CI 1·6-39·9). Conclusions: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immuno-competent SRS2 endotype had significantly higher mortality when given corticosteroids compared to placebo. Clinical trial registration available at www.isrctn.com, ID ISRCTN20769191.
Rawson TM, Hernandez B, Moore L, et al., 2019, Supervised machine learning for the prediction of infection on admission to hospital: a prospective observational cohort study, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 1108-1115, ISSN: 0305-7453
BackgroundInfection diagnosis can be challenging, relying on clinical judgement and non-specific markers of infection. We evaluated a supervised machine learning (SML) algorithm for diagnosing bacterial infection using routinely available blood parameters on presentation to hospital.MethodsAn SML algorithm was developed to classify cases into infection versus no infection using microbiology records and six available blood parameters (C-reactive protein, white cell count, bilirubin, creatinine, ALT and alkaline phosphatase) from 160 203 individuals. A cohort of patients admitted to hospital over a 6 month period had their admission blood parameters prospectively inputted into the SML algorithm. They were prospectively followed up from admission to classify those who fulfilled clinical case criteria for a community-acquired bacterial infection within 72 h of admission using a pre-determined definition. Predictive ability was assessed using receiver operating characteristics (ROC) with cut-off values for optimal sensitivity and specificity explored.ResultsOne hundred and four individuals were included prospectively. The median (range) cohort age was 65 (21–98) years. The majority were female (56/104; 54%). Thirty-six (35%) were diagnosed with infection in the first 72 h of admission. Overall, 44/104 (42%) individuals had microbiological investigations performed. Treatment was prescribed for 33/36 (92%) of infected individuals and 4/68 (6%) of those with no identifiable bacterial infection. Mean (SD) likelihood estimates for those with and without infection were significantly different. The infection group had a likelihood of 0.80 (0.09) and the non-infection group 0.50 (0.29) (P < 0.01; 95% CI: 0.20–0.40). ROC AUC was 0.84 (95% CI: 0.76–0.91).ConclusionsAn SML algorithm was able to diagnose infection in individuals presenting to hospital using routinely available blood parameters.
Komorowski M, Celi LA, Badawi O, et al., 2019, Understanding the artificial intelligence clinician and optimal treatment strategies for sepsis in intensive care
In this document, we explore in more detail our published work (Komorowski,Celi, Badawi, Gordon, & Faisal, 2018) for the benefit of the AI in Healthcareresearch community. In the above paper, we developed the AI Clinician system,which demonstrated how reinforcement learning could be used to make usefulrecommendations towards optimal treatment decisions from intensive care data.Since publication a number of authors have reviewed our work (e.g. Abbasi,2018; Bos, Azoulay, & Martin-Loeches, 2019; Saria, 2018). Given the differenceof our framework to previous work, the fact that we are bridging two verydifferent academic communities (intensive care and machine learning) and thatour work has impact on a number of other areas with more traditionalcomputer-based approaches (biosignal processing and control, biomedicalengineering), we are providing here additional details on our recentpublication.
Mich V, Pho Y, Bory S, et al., 2019, Using research to prepare for outbreaks of severe acute respiratory infection, BMJ Global Health, Vol: 4, ISSN: 2059-7908
Severe acute respiratory infections (SARI) remain one of the leading causes of mortality around the world in all age groups. There is large global variation in epidemiology, clinical management and outcomes, including mortality. We performed a short period observational data collection in critical care units distributed globally during regional peak SARI seasons from 1 January 2016 until 31 August 2017, using standardised data collection tools. Data were collected for 1 week on all admitted patients who met the inclusion criteria for SARI, with follow-up to hospital discharge. Proportions of patients across regions were compared for microbiology, management strategies and outcomes. Regions were divided geographically and economically according to World Bank definitions. Data were collected for 682 patients from 95 hospitals and 23 countries. The overall mortality was 9.5%. Of the patients, 21.7% were children, with case fatality proportions of 1% for those less than 5 years. The highest mortality was in those above 60 years, at 18.6%. Case fatality varied by region: East Asia and Pacific 10.2% (21 of 206), Sub-Saharan Africa 4.3% (8 of 188), South Asia 0% (0 of 35), North America 13.6% (25 of 184), and Europe and Central Asia 14.3% (9 of 63). Mortality in low-income and low-middle-income countries combined was 4% as compared with 14% in high-income countries. Organ dysfunction scores calculated on presentation in 560 patients where full data were available revealed Sequential Organ Failure Assessment (SOFA) scores on presentation were significantly associated with mortality and hospital length of stay. Patients in East Asia and Pacific (48%) and North America (24%) had the highest SOFA scores of >12. Multivariable analysis demonstrated that initial SOFA score and age were independent predictors of hospital survival. There was variability across regions and income groupings for the critical care management and outcomes of SARI. Intensive care unit-sp
Scheeren TWL, Bakker J, De Backer D, et al., 2019, Current use of vasopressors in septic shock, Annals of Intensive Care, Vol: 9, ISSN: 2110-5820
BackgroundVasopressors are commonly applied to restore and maintain blood pressure in patients with sepsis. We aimed to evaluate the current practice and therapeutic goals regarding vasopressor use in septic shock as a basis for future studies and to provide some recommendations on their use.MethodsFrom November 2016 to April 2017, an anonymous web-based survey on the use of vasoactive drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 17 questions focused on the profile of respondents, triggering factors, first choice agent, dosing, timing, targets, additional treatments, and effects of vasopressors. We investigated whether the answers complied with current guidelines. In addition, a group of 34 international ESICM experts was asked to formulate recommendations for the use of vasopressors based on 6 questions with sub-questions (total 14).ResultsA total of 839 physicians from 82 countries (65% main specialty/activity intensive care) responded. The main trigger for vasopressor use was an insufficient mean arterial pressure (MAP) response to initial fluid resuscitation (83%). The first-line vasopressor was norepinephrine (97%), targeting predominantly a MAP > 60–65 mmHg (70%), with higher targets in patients with chronic arterial hypertension (79%). The experts agreed on 10 recommendations, 9 of which were based on unanimous or strong (≥ 80%) agreement. They recommended not to delay vasopressor treatment until fluid resuscitation is completed but rather to start with norepinephrine early to achieve a target MAP of ≥ 65 mmHg.ConclusionReported vasopressor use in septic shock is compliant with contemporary guidelines. Future studies should focus on individualized treatment targets including earlier use of vasopressors.
Lambden S, Tomlinson J, Piper S, et al., 2018, Evidence for a protective role for the rs805305 single nucleotide polymorphism of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in septic shock through the regulation of DDAH activity, Critical Care, Vol: 22, ISSN: 1364-8535
BackgroundDimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the synthesis of nitric oxide (NO) through the metabolism of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA). Pilot studies have associated the rs805305 SNP of DDAH2 with ADMA concentrations in sepsis. This study explored the impact of the rs805305 polymorphism on DDAH activity and outcome in septic shock.MethodsWe undertook a secondary analysis of data and samples collected during the Vasopressin versus noradrenaline as initial therapy in septic shock (VANISH) trial. Plasma and DNA samples isolated from 286 patients recruited into the VANISH trial were analysed. Concentrations of L-Arginine and the methylarginines ADMA and symmetric dimethylarginine (SDMA) were determined from plasma samples. Whole blood and buffy-coat samples were genotyped for polymorphisms of DDAH2. Clinical data collected during the study were used to explore the relationship between circulating methylarginines, genotype and outcome.ResultsPeak ADMA concentration over the study period was associated with a hazard ratio for death at 28 days of 3.3 (95% CI 2.0–5.4), p < 0.001. Reduced DDAH activity measured by an elevated ADMA:SDMA ratio was associated with a reduced risk of death in septic shock (p = 0.03). The rs805305 polymorphism of DDAH2 was associated with reduced DDAH activity (p = 0.004) and 28-day mortality (p = 0.02). Mean SOFA score and shock duration were also reduced in the less common G:G genotype compared to heterozygotes and C:C genotype patients (p = 0.04 and p = 0.02, respectively).ConclusionsPlasma ADMA is a biomarker of outcome in septic shock, and reduced DDAH activity is associated with a protective effect. The polymorphism rs805305 SNP is associated with reduced mortality, which is potentially mediated by reduced DDAH2 activity.
Gordon AC, Russell JA, 2018, Innovation and safety in critical care: should we collaborate with the industry? Yes, Intensive Care Medicine, Vol: 44, Pages: 2276-2278, ISSN: 0342-4642
As clinicians we all want to improve care for our patients. We can do that in two ways. We can do what we currently do better, or we can do new things (better). The development of large clinical academic trials groups and networks has enabled clinicians to understand what particular clinical care leads to better patient-centred outcomes. Ironically, we have learnt that many of our “usual” interventions either provided no benefit or were even harmful. Thus, clinicians, can improve the safety and effectiveness of critical care practice. But when it comes to innovation - new therapeutics and novel diagnostics - then it is hard to imagine that we could achieve this without input from or partnership with industry. Furthermore, a brief walk around an ICU illustrates cogently the vast number of devices used and drugs being infused, all of which originated in industry, some with much and some with little clinician scientist input. We argue herein that such collaboration is not only acceptable, it is necessary and can be done ethically, using established guidelines and conflict of interest disclosure.
Davies R, ODea K, Gordon A, 2018, Immune therapy in sepsis; are we ready to try again?, Journal of the Intensive Care Society, Vol: 19, Pages: 326-344, ISSN: 1751-1437
Immune-therapy to ease the burden of sepsis has thus far failed to consistently improve patient outcomes. Advances in cancer immune-therapy and awareness that prolonged immune suppression in sepsis can leave patients vulnerable to secondary infection and death, have driven resurgence in the field of sepsis immune-therapy investigation. As we develop and evaluate these novel therapies, we must learn from past experiences where single-mediator targeted immune-therapies were blindly delivered to heterogeneous patient cohorts with complex and evolving immune responses. Advances in genomics, proteomics, metabolomics, and point-of-care technology, coupled with a better understanding of sepsis pathogenesis have meant that personalised immune-therapy is on the horizon. Here we review the complex immune pathogenesis in sepsis and the contemporary immune therapies that are being investigated to manipulate this response. An outline of the immune biomarkers that may be used to support this approach is also provided.
Gordon AC, Santhakumaran S, Al-Beidh F, et al., 2018, Levosimendan to prevent acute organ dysfunction in sepsis: the LeoPARDS RCT, Efficacy and Mechanism Evaluation, Vol: 5, Pages: 1-124, ISSN: 2050-4365
Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial
Mårtensson J, Gordon AC, 2018, Terlipressin or norepinephrine, or both in septic shock?, Intensive Care Medicine, Vol: 44, Pages: 1964-1966, ISSN: 0342-4642
Komorowski M, Celi LA, Badawi O, et al., 2018, The Artificial Intelligence Clinician learns optimal treatment strategies for sepsis in intensive care, Nature Medicine, Vol: 24, Pages: 1716-1720, ISSN: 1078-8956
Sepsis is the third leading cause of death worldwide and the main cause of mortality in hospitals1–3, but the best treatment strategy remains uncertain. In particular, evidence suggests that current practices in the administration of intravenous fluids and vasopressors are suboptimal and likely induce harm in a proportion of patients1,4–6. To tackle this sequential decision-making problem, we developed a reinforcement learning agent, the artificial intelligence (AI) Clinician, which learns from data to predict patient dynamics given specific treatment decisions. Our agent extracted implicit knowledge from an amount of patient data that exceeds many-fold the life-time experience of human clinicians and learned optimal treatment by having analysed myriads of (mostly sub-optimal) treatment decisions. We demonstrate that the value of the AI Clinician’s selected treatment is on average reliably higher than the human clinicians. In a large validation cohort independent from the training data, mortality was lowest in patients where clinicians’ actual doses matched the AI policy. Our model provides individualized and clinically interpretable treatment decisions for sepsis that could improve patient outcomes.
Fiorini F, Antcliffe D, Al-Beidh F, et al., 2018, Analysis of lipoproteins in septic shock, European Society of Intensive Care Medicine Congress, Publisher: SpringerOpen, ISSN: 2197-425X
Antcliffe D, Ward J, Marshall T, et al., 2018, Multivariate analysis of cytokines in septic shock predicts outcome, European Society of Intensive Care Medicine Congress, Publisher: SpringerOpen, ISSN: 2197-425X
Antcliffe D, Al-Beidh F, Gordon A, 2018, Metabolic profiles in sepsis evolve over time, European Society of Intensive Care Medicine Congress, Publisher: SpringerOpen, ISSN: 2197-425X
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