Arulkumaran, N

Benhalim, S

Longobardo, A

Montanari, C

Shulman, R

Singer, M

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.  e44 - 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.2020.10.008Advance Access Publication Date: 10 October 2020© 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.Inhaled 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,COVID-19 Correspondence - e45pulmonary compliance, driving pressure, tidal volume, fluidbalance, or use of steroids in the 24 h from initiation of iNO.However, the increment in PaO2/FiO2 ratio after iNO wassignificantly lower in COVID-19 related ARDS patientscompared with ARDS not related to COVID-19 (3% [17% to26%] vs 47% [6e54%]; P<0.05) (Fig. 1; Supplementary Table S1).Venous thromboembolism (VTE) was diagnosed in seven(35%) COVID-19 patients. Seven patients underwent CT pul-monary angiography, of which two patients had evidence ofpulmonary emboli. A further 10 patients underwent lowerlimb Doppler ultrasonography, of whom five patients had adiagnosis of deep vein thrombosis.Only eight (40%) patients with COVID-19 related ARDS hadan increment in PaO2/FiO2 ratio >10% compared with 10 pa-tients (77%) with ARDS not related to ARDS (P¼0.07). BaselinePaO2/FiO2 ratio, dose of iNO, use of steroid, prone positionventilation, C-reactive protein, D-dimer levels, N-terminal B-type natriuretic peptide (NT-BNP) levels, fluid balance, drivingpressure, days from ICU admission to iNO, pulmonarycompliance, diagnosis of VTE, or BMI did not discriminatebetween COVID-19 patients who responded to iNO or not(Supplementary Fig. S1).10P682Tidal Vol (ml kg–1  IBW)40COVID ARDSNon-C30P=0.9612010Mean airway pressure (mm Hg)0COVID ARDSNon-COVID ARDS20P=0.1591510PEEP (cm H2O)50COVID ARDSNon-COVID ARDSa b c80P604020Days ICU admit to NO start0COVID ARDSNon-C800P=0.233600400200CRP (mg L–1 )0COVID ARDSNon-COVID ARDS4000P=0.461200030001000Fluid balance in 24 h (ml)0–1000–2000COVID ARDSNon-COVID ARDSf g hFig 1. Baseline patient characteristics, C-reactive protein (CRP), and PaOno differences in ventilatory parameters, CRP, or baseline PaO2/FiO2 rwith and without COVID-19 who received inhaled nitric oxide (iNO). Theto iNO was significantly lower compared with non-COVID ARDS. IBW,The potential benefit of iNO in reducing pulmonary shuntin COVID-19 related ARDS has been postulated.5 However, wefound that the increase in PaO2/FiO2 ratio in COVID-19 ARDSpatients in response to iNO was significantly lower comparedwith ARDS patients without ARDS, consistent with anotherpublished series.6 Pulmonary vascular endothelial dysfunc-tion and microthrombi are hallmarks of COVID-19-inducedlung damage, and this may impair iNO-induced pulmonaryvasodilation.4,7 In contrast, patients with coronavirus-relatedsevere acute respiratory syndrome, where increased throm-bosis was not a hallmark, demonstrated significant PaO2/FiO2ratio improvements in response to iNO.8Early in the COVID-19 disease process, hypoxaemia de-velops despite good pulmonary compliance, and a pulmonaryvasculopathy is implicated.9 Later on, compliance decreases tothat seenwith ‘classical’ ARDS.9,10 Our COVID-19 patients whoreceived iNO did so as a rescue treatment late in the disease, 12days after ICU admission. Although no differences were seenin D-dimer values between responders and non-responders,levels were significantly elevated in most patients. The bene-fits of iNO in COVID-19 related ARDS may extend beyond itseffects on pulmonary vasculature.11 However, the theoretical=0.981OVID ARDS40P=0.962203010Driving pressure (cm H2O)0COVID ARDSNon-COVID ARDS40P=0.983203010Compliance (ml cm H2O–1)0COVID ARDSNon-COVID ARDSd e=0.842OVID ARDS200P=0.27415010050Baseline P/F ratio (mm Hg)0COVID ARDSNon-COVID ARDS200P=0.0451000% Change in P/F ratio–100COVID ARDSNon-COVID ARDSi j2/FiO2 ratio in ARDS patients with and without COVID-19. There areatio between acute respiratory distress syndrome (ARDS) patientsincrease in PaO2/FiO2 ratio of COVID-19 ARDS patients in responseideal body weigh; PF ratio, PaO2/FiO2 ratio.e46 - COVID-19 Correspondencebenefits of iNO in inhibiting early-stage viral replication areunlikely to have benefited patients in whom iNO was admin-istered 12 (8e18) days after ICU admission.As with all retrospective analyses, we acknowledge the pos-sibility of residual confounding, and that results are associative.The small number of COVID-19 related ARDS patients includedalso warrants caution in interpreting the findings. CT imagingwas not performed on all patients because of clinical instabilityor lack of a clear indication; thus, the presence of major embolimay have been missed in some patients. Alternatively, lack ofidentification by CT does not exclude the presence of multiplepulmonary microthrombi contributing to increased pulmonaryvascular resistance and right heart dysfunction. Echocardiog-raphy was not performed systematically to assess impact oncardiac anatomy and function, but NT-BNP levels were signifi-cantly elevated and raised pulmonary pressures werecommonplace findings when measured. NT-BNP and D-dimervalues were not routinely collected in ARDS patients before theCOVID-19 pandemic so comparisons cannot be made.In summary, more than half of patients with refractoryhypoxaemia secondary to COVID-19 ARDS did not show anincrease in PaO2/FiO2 ratio in response to iNO. This responsewas much lower compared with a cohort with ARDS notrelated to COVID-19. Further work is required to ascertain ifthis lack of response to iNO is diagnostic for degree of pul-monary thromboembolism.Authors’ contributionsStudy design: NAData collection: AL, CM, RS, SBStatistics: NADrafting manuscript: NAFinalising manuscript: MS, NADeclarations of interestThe authors declare that they have no conflicts of interest.Appendix A. Supplementary dataSupplementary data to this article can be found online athttps://doi.org/10.1016/j.bja.2020.10.011.References1. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled ni-tric oxide for acute respiratory distress syndrome (ARDS)in children and adults. Cochrane Database Syst Rev 2016; 6:CD0027872. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patternsof care, and mortality for patients with acute respiratorydistress syndrome in intensive care units in 50 countries.JAMA 2016; 315: 788e8003. Helms J, Tacquard C, Severac F, et al. High risk ofthrombosis in patients with severe SARS-CoV-2 infection:a multicenter prospective cohort study. Intensive Care Med2020; 46: 1089e984. Menter T, Haslbauer JD, Nienhold R, et al. Postmortemexamination of COVID-19 patients reveals diffuse alveolardamage with severe capillary congestion and variegatedfindings in lungs and other organs suggesting vasculardysfunction. Histopathology 2020 May 4; 77: 198e2095. Hedenstierna G, Chen L, Hedenstierna M, Scaramuzzo G.Treatment of COVID-19 by inhaled NO to reduce shunt?Am J Respir Crit Care Med 2020; 202: 6186. Tavazzi G, Marco P, Mongodi S, Dammassa V, Romito G,Mojoli F. Inhaled nitric oxide in patients admitted tointensive care unit with COVID-19 pneumonia. Crit Care2020; 24: 5087. Patel BV, Arachchillage DJ, Ridge CA, et al. Pulmonaryangiopathy in severe COVID-19: physiologic, imaging andhematologic observations. Am J Respir Crit Care Med 2020;202: 690e98. Chen L, Liu P, Gao H, et al. Inhalation of nitric oxide in thetreatment of severe acute respiratory syndrome: a rescuetrial in Beijing. Clin Infect Dis 2004; 39: 1531e59. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S,Chiumello D. Covid-19 does not lead to a "typical" acuterespiratory distress syndrome. Am J Respir Crit Care Med2020; 201: 1299e30010. Gattinoni L, Chiumello D, Caironi P, et al. COVID-19pneumonia: different respiratory treatments for differentphenotypes? Intensive Care Med 2020; 46: 1099e10211. Hedenstierna G, Chen L, Hedenstierna M, Lieberman R,Fine DH. Nitric oxide dosed in short bursts at high con-centrations may protect against Covid 19. Nitric Oxide2020; 103: 1e3doi: 10.1016/j.bja.2020.10.011Advance Access Publication Date: 14 October 2020© 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.Response of US hospitals to elective surgical cases in the COVID-19pandemicRomain Pirracchio1, Orestes Mavrothalassitis1, Michael Mathis2,3,Sachin Kheterpal2,3 and Matthieu Legrand1,4,*1Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA, 2Department ofAnesthesiology, University of Michigan, Ann Arbor, MI, USA, 3Institute for Healthcare Policy and Innovation, Universityof Michigan, Ann Arbor, MI, USA and 4F-CRIN INI-CRCT Network, Nancy, France*Corresponding author. E-mail: Matthieu.legrand@ucsf.edu

Inhaled nitric oxide minimally improves oxygenation in COVID-19 related acute respiratory distress syndrome

https://discovery.ucl.ac.uk/10128472/1/Inhaled%20nitric%20oxide%20minimally%20improves%20oxygenation%20in%20COVID-19%20related%20acute%20respiratory%20distress%20syndrome.pdf

Inhaled nitric oxide minimally improves oxygenation in COVID-19 related acute respiratory distress syndrome

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