Tocilizumab is associated with reduced delirium and coma in critically ill patients with COVID-19.

Humans Antibodies, Monoclonal, Humanized / therapeutic use Delirium / drug therapy Male Female COVID-19 / complications Middle Aged Coma / etiology Critical Illness Aged COVID-19 Drug Treatment Intensive Care Units SARS-CoV-2 / isolation & purification Interleukin-6
COVID-19 Delirium ICU Interleukin-6 Sars-CoV-2 Tocilizumab

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
23 May 2024
Historique:
received: 29 11 2023
accepted: 17 05 2024
medline: 23 5 2024
pubmed: 23 5 2024
entrez: 22 5 2024
Statut: epublish

Résumé

Recent preclinical studies demonstrate a direct pathological role for the interleukin-6 (IL-6) pathway in mediating structural and functional delirium-like phenotypes in animal models of acute lung injury. Tocilizumab, an IL-6 pathway inhibitor, has shown reduced duration of ventilator dependency and mortality in critically ill patients with COVID-19. In this study, we test the hypothesis that tocilizumab is associated with reduced delirium/coma prevalence in critically ill patients with COVID-19. 253 patients were included in the study cohort, 69 in the tocilizumab group and 184 in the historical control group who did not receive tocilizumab. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with a positive score indicating delirium. Coma was defined as a Richmond Agitation-Sedation Scale score of - 4 or - 5. Tocilizumab was associated with significantly greater number of days alive without delirium/coma (tocilizumab [7 days (IQR: 3-9 days)] vs control [3 days (IQR: 1-8 days)]; p < 0.001). These results remained significant after adjusting for age, sex, sepsis, Charlson Comorbidity Index, Sequential Organ Failure Assessment score, and median daily dose of analgesics/sedatives (

Identifiants

DOI: 10.1038/s41598-024-62505-1 PMID: 38778074
pubmed: 38778074
doi: 10.1038/s41598-024-62505-1
pii: 10.1038/s41598-024-62505-1
doi:

Substances chimiques

Antibodies, Monoclonal, Humanized 0
tocilizumab I031V2H011
Interleukin-6 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

11738

Subventions

Organisme : NIH HHS
ID : R01 AG027472
Pays : United States
Organisme : NIH HHS
ID : R01 AG035117
Pays : United States
Organisme : NIH HHS
ID : R01 AG058639
Pays : United States
Organisme : NIH HHS
ID : I01RX002992
Pays : United States

Informations de copyright

© 2024. The Author(s).

Références

Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506. https://doi.org/10.1016/s0140-6736(20)30183-5 (2020).
doi: 10.1016/s0140-6736(20)30183-5 pubmed: 31986264 pmcid: 7159299
Wang, D. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323, 1061–1069. https://doi.org/10.1001/jama.2020.1585 (2020).
doi: 10.1001/jama.2020.1585 pubmed: 32031570 pmcid: 7042881
Young, B. E. et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 323, 1488–1494. https://doi.org/10.1001/jama.2020.3204 (2020).
doi: 10.1001/jama.2020.3204 pubmed: 32125362 pmcid: 7054855
Chen, T. et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ 368, m1091. https://doi.org/10.1136/bmj.m1091 (2020).
doi: 10.1136/bmj.m1091 pubmed: 32217556 pmcid: 7190011
Mahase, E. Covid-19: Most patients require mechanical ventilation in first 24 hours of critical care. BMJ 368, m1201. https://doi.org/10.1136/bmj.m1201 (2020).
doi: 10.1136/bmj.m1201 pubmed: 32209544
Wu, Z. & McGoogan, J. M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 323, 1239–1242. https://doi.org/10.1001/jama.2020.2648 (2020).
doi: 10.1001/jama.2020.2648 pubmed: 32091533
Richardson, S. et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 323, 2052–2059. https://doi.org/10.1001/jama.2020.6775 (2020).
doi: 10.1001/jama.2020.6775 pubmed: 32320003 pmcid: 7177629
Guan, W. J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720. https://doi.org/10.1056/NEJMoa2002032 (2020).
doi: 10.1056/NEJMoa2002032 pubmed: 32109013
Grasselli, G. et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy. JAMA 323, 1574–1581. https://doi.org/10.1001/jama.2020.5394 (2020).
doi: 10.1001/jama.2020.5394 pubmed: 32250385 pmcid: 7136855
Grasselli, G., Pesenti, A. & Cecconi, M. Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: Early experience and forecast during an emergency response. JAMA 323, 1545–1546. https://doi.org/10.1001/jama.2020.4031 (2020).
doi: 10.1001/jama.2020.4031 pubmed: 32167538
Fan, E. et al. COVID-19-associated acute respiratory distress syndrome: Is a different approach to management warranted?. Lancet Respir. Med. 8, 816–821. https://doi.org/10.1016/S2213-2600(20)30304-0 (2020).
doi: 10.1016/S2213-2600(20)30304-0 pubmed: 32645311 pmcid: 7338016
Leisman, D. E. et al. Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir. Med. 8, 1233–1244. https://doi.org/10.1016/S2213-2600(20)30404-5 (2020).
doi: 10.1016/S2213-2600(20)30404-5 pubmed: 33075298 pmcid: 7567529
Del Valle, D. M. et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat. Med. 26, 1636–1643. https://doi.org/10.1038/s41591-020-1051-9 (2020).
doi: 10.1038/s41591-020-1051-9 pubmed: 32839624 pmcid: 7869028
Tang, Y. et al. Cytokine storm in COVID-19: The current evidence and treatment strategies. Front. Immunol. 11, 1708. https://doi.org/10.3389/fimmu.2020.01708 (2020).
doi: 10.3389/fimmu.2020.01708 pubmed: 32754163 pmcid: 7365923
Kotfis, K. et al. COVID-19: ICU delirium management during SARS-CoV-2 pandemic. Crit. Care 24, 176. https://doi.org/10.1186/s13054-020-02882-x (2020).
doi: 10.1186/s13054-020-02882-x pubmed: 32345343 pmcid: 7186945
Helms, J. et al. Delirium and encephalopathy in severe COVID-19: A cohort analysis of ICU patients. Crit. Care 24, 491. https://doi.org/10.1186/s13054-020-03200-1 (2020).
doi: 10.1186/s13054-020-03200-1 pubmed: 32771053 pmcid: 7414289
McLoughlin, B. C. et al. Functional and cognitive outcomes after COVID-19 delirium. Eur. Geriatr. Med. 11, 857–862. https://doi.org/10.1007/s41999-020-00353-8 (2020).
doi: 10.1007/s41999-020-00353-8 pubmed: 32666303 pmcid: 7358317
Pun, B. T. et al. Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): A multicentre cohort study. Lancet Respir. Med. 9, 239–250. https://doi.org/10.1016/S2213-2600(20)30552-X (2021).
doi: 10.1016/S2213-2600(20)30552-X pubmed: 33428871 pmcid: 7832119
Rashid, M. H. et al. Interleukin-6 mediates delirium-like phenotypes in a murine model of urinary tract infection. J. Neuroinflammation 18, 247. https://doi.org/10.1186/s12974-021-02304-x (2021).
doi: 10.1186/s12974-021-02304-x pubmed: 34711238 pmcid: 8554965
Anwar, F. et al. Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury. Crit. Care 26, 274. https://doi.org/10.1186/s13054-022-04159-x (2022).
doi: 10.1186/s13054-022-04159-x pubmed: 36100846 pmcid: 9469063
Sparrow, N. A. et al. IL-6 inhibition reduces neuronal injury in a murine model of ventilator-induced lung injury. Am. J. Respir. Cell. Mol. Biol. 65, 403–412. https://doi.org/10.1165/rcmb.2021-0072OC (2021).
doi: 10.1165/rcmb.2021-0072OC pubmed: 34014798 pmcid: 8525200
Choy, E. H. et al. Translating IL-6 biology into effective treatments. Nat. Rev. Rheumatol. 16, 335–345. https://doi.org/10.1038/s41584-020-0419-z (2020).
doi: 10.1038/s41584-020-0419-z pubmed: 32327746 pmcid: 7178926
Hermine, O. et al. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: A randomized clinical trial. JAMA Intern. Med. 181, 32–40. https://doi.org/10.1001/jamainternmed.2020.6820 (2021).
doi: 10.1001/jamainternmed.2020.6820 pubmed: 33080017
Salama, C. et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N. Engl. J. Med. 384, 20–30. https://doi.org/10.1056/NEJMoa2030340 (2021).
doi: 10.1056/NEJMoa2030340 pubmed: 33332779
Rosas, I. O. et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N. Engl. J. Med. 384, 1503–1516. https://doi.org/10.1056/NEJMoa2028700 (2021).
doi: 10.1056/NEJMoa2028700 pubmed: 33631066
Rosas, I. O. et al. Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: A randomized clinical trial. Intensive Care Med. 47, 1258–1270. https://doi.org/10.1007/s00134-021-06507-x (2021).
doi: 10.1007/s00134-021-06507-x pubmed: 34609549 pmcid: 8490137
Recovery Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet 397, 1637–1645. https://doi.org/10.1016/S0140-6736(21)00676-0 (2021).
doi: 10.1016/S0140-6736(21)00676-0
Investigators, R.-C. et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N. Engl. J. Med. 384, 1491–1502. https://doi.org/10.1056/NEJMoa2100433 (2021).
doi: 10.1056/NEJMoa2100433
Knorr, J. P., Colomy, V., Mauriello, C. M. & Ha, S. Tocilizumab in patients with severe COVID-19: A single-center observational analysis. J. Med. Virol. 92, 2813–2820. https://doi.org/10.1002/jmv.26191 (2020).
doi: 10.1002/jmv.26191 pubmed: 32628003 pmcid: 7323415
Mushtaq, M. Z., Mahmood, S. B. Z., Almas, A., Ather Wasti, S. & Ahsan Ali, S. Tocilizumab in critically ill COVID-19 patients: An observational study. Int. Immunopharmacol. 102, 108384. https://doi.org/10.1016/j.intimp.2021.108384 (2022).
doi: 10.1016/j.intimp.2021.108384 pubmed: 34838490
Tleyjeh, I. M. et al. Efficacy and safety of tocilizumab in COVID-19 patients: A living systematic review and meta-analysis. Clin. Microbiol. Infect. 27, 215–227. https://doi.org/10.1016/j.cmi.2020.10.036 (2021).
doi: 10.1016/j.cmi.2020.10.036 pubmed: 33161150
García-Grimshaw, M. et al. Delirium and associated factors in a cohort of hospitalized patients with coronavirus disease 2019. J. Acad. Consult. Liaison Psychiatry 63, 3–13. https://doi.org/10.1016/j.jaclp.2021.06.008 (2022).
doi: 10.1016/j.jaclp.2021.06.008 pubmed: 34242847
Girard, T. D. et al. Haloperidol and ziprasidone for treatment of delirium in critical illness. N. Engl. J. Med. 379, 2506–2516. https://doi.org/10.1056/NEJMoa1808217 (2018).
doi: 10.1056/NEJMoa1808217 pubmed: 30346242 pmcid: 6364999
Pandharipande, P. P. et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 298, 2644–2653. https://doi.org/10.1001/jama.298.22.2644 (2007).
doi: 10.1001/jama.298.22.2644 pubmed: 18073360
Ely, E. W. et al. Delirium in mechanically ventilated patients: Validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA 286, 2703–2710. https://doi.org/10.1001/jama.286.21.2703 (2001).
doi: 10.1001/jama.286.21.2703 pubmed: 11730446
Hills, T. E. et al. Simvastatin in critically ill patients with Covid-19. N. Engl. J. Med. 389, 2341–2354. https://doi.org/10.1056/NEJMoa2309995 (2023).
doi: 10.1056/NEJMoa2309995 pubmed: 37888913
Taori, G. et al. Landmark survival as an end-point for trials in critically ill patients—Comparison of alternative durations of follow-up: An exploratory analysis. Crit. Care 13, R128. https://doi.org/10.1186/cc7988 (2009).
doi: 10.1186/cc7988 pubmed: 19653888 pmcid: 2750185
Nolley, E. P. et al. Outcomes among mechanically ventilated patients with severe pneumonia and acute hypoxemic respiratory failure from SARS-CoV-2 and other etiologies. JAMA Netw. Open 6, e2250401. https://doi.org/10.1001/jamanetworkopen.2022.50401 (2023).
doi: 10.1001/jamanetworkopen.2022.50401 pubmed: 36626168 pmcid: 9856712
Brieghel, C. et al. Prognostic factors of 90-day mortality in patients hospitalised with COVID-19. Dan. Med. J. 68, A09200705 (2021).
pubmed: 33660609
Cilloniz, C. et al. Risk factors associated with mortality among elderly patients with COVID-19: Data from 55 intensive care units in Spain. Pulmonology 29, 362–374. https://doi.org/10.1016/j.pulmoe.2023.01.007 (2023).
doi: 10.1016/j.pulmoe.2023.01.007 pubmed: 36906462
Hol, L. et al. The effect of age on ventilation management and clinical outcomes in critically ill COVID-19 patients—Insights from the PRoVENT-COVID study. Aging (Albany NY) 14, 1087–1109. https://doi.org/10.18632/aging.203863 (2022).
doi: 10.18632/aging.203863 pubmed: 35100136
Hager, D. N. et al. Reducing deep sedation and delirium in acute lung injury patients: A quality improvement project. Crit. Care Med. 41, 1435–1442. https://doi.org/10.1097/CCM.0b013e31827ca949 (2013).
doi: 10.1097/CCM.0b013e31827ca949 pubmed: 23507716
Sasannejad, C., Ely, E. W. & Lahiri, S. Long-term cognitive impairment after acute respiratory distress syndrome: A review of clinical impact and pathophysiological mechanisms. Crit. Care 23, 352. https://doi.org/10.1186/s13054-019-2626-z (2019).
doi: 10.1186/s13054-019-2626-z pubmed: 31718695 pmcid: 6852966
Marra, A., Pandharipande, P. P. & Patel, M. B. Intensive care unit delirium and intensive care unit-related posttraumatic stress disorder. Surg. Clin. North Am. 97, 1215–1235. https://doi.org/10.1016/j.suc.2017.07.008 (2017).
doi: 10.1016/j.suc.2017.07.008 pubmed: 29132506 pmcid: 5747308
Bulic, D. et al. Cognitive and psychosocial outcomes of mechanically ventilated intensive care patients with and without delirium. Ann. Intensive Care 10, 104. https://doi.org/10.1186/s13613-020-00723-2 (2020).
doi: 10.1186/s13613-020-00723-2 pubmed: 32748298 pmcid: 7399009
Stone, J. H. et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N. Engl. J. Med. 383, 2333–2344. https://doi.org/10.1056/NEJMoa2028836 (2020).
doi: 10.1056/NEJMoa2028836 pubmed: 33085857
Duindam, H. B., Kessels, R. P. C., van den Borst, B., Pickkers, P. & Abdo, W. F. Long-term cognitive performance and its relation to anti-inflammatory therapy in a cohort of survivors of severe COVID-19. Brain Behav. Immun. Health 25, 100513. https://doi.org/10.1016/j.bbih.2022.100513 (2022).
doi: 10.1016/j.bbih.2022.100513 pubmed: 36159208 pmcid: 9482799
Andersen-Ranberg, N. C. et al. Agents intervening against delirium in the intensive care unit (AID-ICU)—Protocol for a randomised placebo-controlled trial of haloperidol in patients with delirium in the ICU. Acta Anaesthesiol. Scand. 63, 1426–1433. https://doi.org/10.1111/aas.13453 (2019).
doi: 10.1111/aas.13453 pubmed: 31350916

Auteurs

Tuqa Alkhateeb (T)

The Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Joanna L Stollings (JL)

The Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN, USA.

Ine Sohn (I)

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.

Dandan Liu (D)

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.

L Montana Fleenor (LM)

The Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN, USA.

E Wesley Ely (EW)

The Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Geriatric Research, Education and Clinical Center (GRECC) Service, Department of Veterans Affairs Medical Center Tennessee Valley Healthcare System, Nashville, TN, USA.

Shouri Lahiri (S)

Departments of Neurology, Neurosurgery, and Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA. shouri.lahiri@csmc.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Tocilizumab is associated with reduced...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps monoclonaux › Anticorps monoclonaux humanisés › Tocilizumab is associated with reduced...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Délire avec confusion › Tocilizumab is associated with reduced...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Pneumopathie infectieuse › Pneumopathie virale › COVID-19 › Tocilizumab is associated with reduced...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Tocilizumab is associated with reduced...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Perte de conscience › Coma › Tocilizumab is associated with reduced...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie grave › Tocilizumab is associated with reduced...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Tocilizumab is associated with reduced...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Traitements médicamenteux de la COVID-19 › Tocilizumab is associated with reduced...
questionsmedicales.fr › Établissements, main d'oeuvre et services de soins de santé › Établissements de santé › Unités hospitalières › Unités de soins intensifs › Tocilizumab is associated with reduced...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Virus du SRAS › SARS-CoV-2 › Tocilizumab is associated with reduced...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-6 › Tocilizumab is associated with reduced...