Fong, K

Harris, S

Palmer, E

English

UCL Discovery

  Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website.  Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.  e42 - COVID-19 CorrespondenceTrials in pandemics: here we go again?Steve Harris1,*, Ed Palmer2 and Kevin Fong31Critical Care Department, University College London Hospital, London, UK, 2Bloomsbury Institute of Intensive CareMedicine, University College London, London, UK and 3Department of Peri-operative Medicine, University CollegeLondon Hospital, London, UK*Corresponding author. E-mail: doc@steveharris.meKeywords: clinical trials; COVID-19; mechanical ventilation; pragmatic trials; randomised controlled trialsEditordCoronavirus disease 2019 (COVID-19) demanded thewholesale re-organisation of health services and supportivecare in the UK. And yet, heading into winter 2020 and facinga likely second surge, we remain unsure of how best to re-deploy resources to meet the needs of COVID-19 and non-COVID-19 patients alike. Simple and as yet unansweredclinical questions continue to impact the whole of healthservices around the world including the NHS in the UK.We face a stark choice in our approach to the managementof COVID-19. It is not the choice between drug A and drug B,but whether or not we are prepared to continue to derivepolicy without robust scientific evidence. There are pockets ofexcellence such as RECOVERY (arguably the most successfuldrug trial in COVID-19) and ISARIC (already reporting crucialobservational evidence), and pockets of hope such asRECOVERY-RS (a rapidly deployed trial of ventilation strategyfor COVID-19).1e3 But while both necessary and impressive,these trials are not sufficient.Take just one example: the limited question of ventilatorysupport for severe COVID-19 pneumonia. At University CollegeHospital London, our first COVID-19 patient arrived on March6, 2020. Reports from China and Italy indicated that our ICUwould be overrun. We contacted colleagues from thosecountries and designed a new care pathway overnight. Wetriaged patients after an ‘oxygen challenge’ to either CPAP forthose who responded, or invasive mechanical ventilation(IMV) for those who did not. In a neighbouring Londonteaching hospital, a different teammade the same phone callsbut came to very different conclusions. There, CPAP waslargely excluded in favour of early IMV. This latter approachbecame the organising principle for the Nightingale Hospitalin London. Nationally, the impact went further as we repur-posed production lines in the airline and motoring industriesto build new ventilators from scratch.4,5Neither the hypothesis that early IMV protected the lungs6nor our assertion that CPAP was safe have yet been tested.Both contributed to the shutdown of non-COVID-19 care ascritical care bedswere filled. And nearly 6months later, havingtreated many thousands of critically ill COVID-19 patients, westill do not know for which patients CPAP is sufficient, when toswitch from CPAP to IMV, or for whom early IMV is the rightchoice. The tragedy is that from the outset we had both thetools (RCTs) and the opportunity (the patient numbers) toanswer this and many other questions.The success of the RECOVERY drug trial shows that it ispossible to learn at pace and at scale. Just 6 days after SimonSteven’s ‘call to arms’,1 UK investigators submitted a protocolfor an RCT studying antiviral, steroid, and antibiotic treat-ments. By June 2020, more than 11 000 patients from 176hospitals had been recruited making it the ‘largest [RCT] … ofpotential COVID-19 treatments in the world.’ Early resultshave already debunked hydroxychloroquine and shown thatdexamethasone saved lives.7,8 What is RECOVERY doing tomake this work? It evaluates five treatment arms simulta-neously. Those sites can participate as long as they can delivertwo or more. Recruitment is excellent because clinicians arenot obliged to randomise to interventions they consider un-suitable for a specific patient. A simple case definition sufficesfor enrolment and, because hospital mortality is high, theoutcome is easy to capture. And finally, randomisation is donecentrally, and once the treatment has been allocated there isno further work for the bedside clinical team.RCTs require many patients in their numbers but we do notneed to rehearse the scale of the pandemic. Even a simplesimulation solely within the domain of critical care (Fig. 1)shows how quickly we could have answers with even a frac-tion of the resource that was spent on the Nightingale Hospi-tals, or the Ventilator Challenge.4,5 Ventilation strategy wasjust one speciality-specific example. The response to COVID-19 is much broader. It has forced us to modify and reducemany urgent, clinical services, from cancer to cardiac surgery.And we are now seeing worrying decreases in healthcare uti-lisation for non-COVID emergencies, and early signs ofdecreasing cancer survival.9,10We urgently need to adopt the paradigm of the drug trial tothe broader questions of health services, and see specific non-drug interventions robustly evaluated. The rapid generation ofscientific evidence to inform policy and treatment needs to bepart of pandemic preparedness in the same way that weshould stockpile personal protective equipment, and builddepth to our testing infrastructure. We could and should gofurther and deploy ‘pandemic data officers’ to the frontline toassist with data collection, minimise logistical burden, andaccelerate learning. We could cluster randomise hospitals tostrategies that preserve surgical pathways for cancer to agreater or lesser extent.These are pared down solutions for extraordinary times,but could still be implemented for this winter with onlymodest resource. The pandemic is not over, and so the cost ofunanswered questions escalates. The sooner we optimise carepathways for COVID-19 patients, the sooner we can redeployresources to essential non-COVID-19 care. To restore the1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17300200National admissions to ICU1000Mar 01 Mar 15 Apr 01 Apr 15Detected benefit Detected harm EquivocalFig 1. A simulation to illustrate how we might have learnt, had all patients admitted to ICU for coronavirus disease 2019 (COVID-19) beenrecruited into trials for non-pharmacological interventions. The simulation runs trials in groups of 446 patients, which provides 80%power todetect an absolute risk reduction of 10% from a baseline mortality of 50%, at an alpha threshold of 0.2. This is an intentionally relaxed set ofthresholds to investigate a largenumber of candidate therapies,with the specific goal of identifying thosewith amaximumsignal for harmorbenefit. We use the daily admission numbers for COVID-19 to ICU as reported by the Intensive Care National Audit and Research Centre(ICNARC). The current best estimate ofmortality is ~50%, hence a reduction from50% to 40%mortality (10%actual risk reduction, 20% relativerisk reduction) would be a ‘big signal’. Assumingwe run one trial sequentially after another, we could expect 17 trials to complete during thefirst surge. This is without implementing an adaptive Bayesian framework, which would not only be more efficient, but would allow for ad-ditive learning to improve the grade of evidence to a confirmatory level should a signal appear.Wemade the following technical assumptions.(1) The true underlying treatment effect is drawn from a zero mean normal distribution with a standard deviation of 0.2. This means mostinterventions have a relatively small signal for harm or benefit, while a few will have a much larger effect size that is observable even withsmall samples. (2) Patients are recruited in accordance with the observed number of admissions to ICUs within the ICNARC network.COVID-19 Correspondence - e43health service for all, we must immediately learn from thesuccesses of clinical drug trials. We must not be content withretrospective policy review. We must not continue to createpolicy on the basis of phone calls to friends.Authors’ contributionsJointly contributed to the idea and the writing of the com-mentary: all authorsDeclarations of interestThe authors declare that they have no conflicts of interest.AcknowledgmentsSteve Harris is supported by a Health Foundation Improve-ment Science Fellowship, and by the Biomedical ResearchCentre at the University College Hospitals National HealthService (NHS) Foundation Trust and University College Lon-don. The views expressed are those of the authors and are notnecessarily those of the NIHR, the NHS, or the United KingdomDepartment of Health and Social Care.References1. RECOVERY trial rolled out across the UK 2020. Available from:https://www.recoverytrial.net/news/update. [Accessed 17May 2020]2. Docherty AB, Harrison EM, Green CA, et al. Features of20 133 UK patients in hospital with covid-19 using theISARIC WHO Clinical Characterisation Protocol: prospec-tive observational cohort study. BMJ 20 1985; 3693. Perkins GD, Couper K, Connolly B, et al. RECOVERY -respiratory support: respiratory strategies for patientswith suspected or proven COVID-19 respiratory failure;continuous positive airway pressure, high-flow nasaloxygen, and standard care: a structured summary of astudy protocol for a randomised controlled trial. Trials2020; 21: 6874. Tidman Z. Coronavirus: Government spent £220m creatingNightingale hospitals. The Independent; 20205. Balogun B. Coronavirus: ventilator availability in the UK.Briefing Paper 8904 2020. Available from: https://commonslibrary.parliament.uk/research-briefings/cbp-8904/. [Accessed 17 August 2020]6. Marini JJ, Gattinoni L. Management of COVID-19 respira-tory distress. JAMA 2020; 323: 2329e30e44 - COVID-19 Correspondence7. RECOVERY CG, Horby P, Lim WS, et al. Dexamethasone inhospitalized patients with Covid-19 - preliminary report.N Engl J Med 2020. https://doi.org/10.1056/NEJMoa2021436.Advance Access published on July 178. No clinical benefit from use of hydroxychloroquine in hospital-ised patients with COVID-19 2020. Available from: https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19. [Accessed 17 May 2020]9. Baum A, Schwartz MD. Admissions to Veterans Affairshospitals for emergency conditions during the COVID-19pandemic. JAMA 2020; 324: 96e910. Quilter-Pinner H. The hidden cost of Covid-19 on the NHS -and how to ‘build back better’ 2020. Available from: https://www.ippr.org/blog/the-hidden-cost-of-covid-19-on-the-nhs. [Accessed 17 August 2020]doi: 10.1016/j.bja.2020.10.0Advance Access Publication Date: 10 October 2020© 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.08Inhaled nitric oxide minimally improves oxygenation in COVID-19related acute respiratory distress syndromeAlessia Longobardo, Cecilia Montanari, Robert Shulman, Suzanne Benhalim,Mervyn Singer and Nishkantha Arulkumaran*Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK*Corresponding author. E-mail: nisharulkumaran@doctors.org.ukKeywords: ARDS; COVID-19; hypoxaemia; inhaled nitric oxide; mechanical ventilationEditordInhaled nitric oxide (iNO) diffuses across the alveolarcapillary membrane and acts on vascular smooth muscle toincrease vasodilation, resulting in increased blood flow toventilated alveoli and improved oxygenation. Despite the lackof conclusive evidence demonstrating survival benefit, iNO isused as a rescue strategy in refractory hypoxaemia.1,2 Patientswith coronavirus disease 2019 (COVID-19) related acuterespiratory distress syndrome (ARDS) have a significantburden of vascular endothelial injury and pulmonarymicrothrombi compared with patients with ARDS not causedby COVID-19.3,4 We therefore hypothesised that patientswith COVID-19 related ARDS would have a bluntedincrement in PaO2/FiO2 ratio in response to iNO comparedwith patients with ARDS not caused by COVID-19.We conducted a single-centre retrospective caseecontrolstudy of patients with ARDS treated with iNO at UniversityCollege London Hospital (UCLH) between March 1 and June 30,2020. Data on consecutive patients with ARDS not caused byCOVID-19 receiving iNO over the previous 2 yr were used forcomparison. Data were extracted from electronic healthcarerecords on patient characteristics, ventilatory parameters,highest iNO dose, fluid balance on the day of iNO initiation,steroiduse,andchange inPaO2/FiO2 ratioover24h.A24hperiodwaschosen tobothallowtime to titrate the iNOdose tomaximaleffect, and to assess whether there was sustained benefit. Dataandmaterials are available upon reasonable request.As this was a retrospective observational study, we did notdefine any sample size. Anonymised data were used foranalysis. Complete case analysis was used where there wasmissing data. Continuous and categorical variables arereported as median (inter-quartile range) and n (%), respec-tively. For comparison of continuous variables,ManneWhitney U-test was used for comparison between twogroups. Categorical data were compared using the c2 test.Statistical analysis was performed and graphs constructedusing Prism (GraphPad Software, version 5.0d; GraphPadSoftware, Inc., San Diego, CA, USA). Ethical reporting ofobservational data on critical care patients at UCLH is coveredby the National Research Ethics Service (14/LO/103).Of 154 patients admitted with COVID-19, 99 (64%) receivedinvasive mechanical ventilation (IMV). Of those requiring IMV,27 (27%) received inhaled NO. Comparison was made against91 patients with ARDS not caused by COVID-19, of whom 20(22%) received iNO. Seven (35%) patients with ARDS not causedby COVID-19 and six (22%) patients with COVID-19 relatedARDS who received iNO were excluded from the final analysisas they did not survive 24 h from iNO initiation.Among the patients with ARDS not caused by COVID-19,nine patients had bacterial pneumonia, one had intra-abdominal sepsis, one had fungal chest infection, and twohad viral influenza after chemotherapy. The time fromadmission to ICU to use of iNO was similar between patientswith COVID-19 and ARDS not caused by COVID-19(Supplementary data). Patients in both groups were treatedwith ARDS-net lung protective ventilation.Patients in both groups were of similar age and had asimilar PaO2/FiO2 ratio on initiation of iNO (SupplementaryTable 1). More males were in the COVID-19 related ARDSgroup. There were no differences between groups in maximaldose of iNO, mode of ventilation, mean airway pressure, PEEP,

Trials in pandemics: here we go again?

https://discovery.ucl.ac.uk/10139839/1/main%20%2814%29.pdf

Trials in pandemics: here we go again?

Abstract

Similar works

Full text

Available Versions

UCL Discovery