Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia

G Umberto Meduri, Mei-Chiung Shih, Lisa Bridges, Thomas J Martin, Ali El-Solh, Nitin Seam, Anne Davis-Karim, Reba Umberger, Antonio Anzueto, Peruvemba Sriram, Charlie Lan, Marcos I Restrepo, Juan J Guardiola, Teresa Buck, David P Johnson, Anthony Suffredini, W Andrew Bell, Julia Lin, Lan Zhao, Lauren Uyeda, Lori Nielsen, Grant D Huang, ESCAPe Study Group, Khalid Bashir, Octavian Ioachimescu, Theresa Buck, David Johnson, Ali El Solh, Michael Frye, Ralph Panos, Mohammad Shatat, Enoch Gray, Brian Smith, Myron Kung, James Cutrell, Roger Bedimo, Peruvemba Sriram, Charlie Lan, Padmashi Rastogi, John Callaghan, Chadi Hage, Mark Plautz, Takako Schaninger, Richard Greenberg, Lennard Specht, Catherine Sassoon, Juan Guardiola, Julio Ramirez, Muthiah P Muthiah, Roland Schein, Andreea Antonesu-Turcu, Kathryn Rice, Houssein Youness, Lee Morrow, Ware Kuschner, Lilibeth Pineda, Richard Allen Robbins, Sharon Camhi, Matthew Jankowich, Waseem Ahmed, Thomas Martin, Mitchell Horowitz, John Nord, Mark Elstad, Marcos I Restrepo, Antonio Anzueto, Timothy Bigby, William Rodriguez-Cintron, Vincent Fan, Pratibha Kaul, Michael Habib, Nitin Seam, Guy Soo Hoo, G Umberto Meduri, Mei-Chiung Shih, Lisa Bridges, Thomas J Martin, Ali El-Solh, Nitin Seam, Anne Davis-Karim, Reba Umberger, Antonio Anzueto, Peruvemba Sriram, Charlie Lan, Marcos I Restrepo, Juan J Guardiola, Teresa Buck, David P Johnson, Anthony Suffredini, W Andrew Bell, Julia Lin, Lan Zhao, Lauren Uyeda, Lori Nielsen, Grant D Huang, ESCAPe Study Group, Khalid Bashir, Octavian Ioachimescu, Theresa Buck, David Johnson, Ali El Solh, Michael Frye, Ralph Panos, Mohammad Shatat, Enoch Gray, Brian Smith, Myron Kung, James Cutrell, Roger Bedimo, Peruvemba Sriram, Charlie Lan, Padmashi Rastogi, John Callaghan, Chadi Hage, Mark Plautz, Takako Schaninger, Richard Greenberg, Lennard Specht, Catherine Sassoon, Juan Guardiola, Julio Ramirez, Muthiah P Muthiah, Roland Schein, Andreea Antonesu-Turcu, Kathryn Rice, Houssein Youness, Lee Morrow, Ware Kuschner, Lilibeth Pineda, Richard Allen Robbins, Sharon Camhi, Matthew Jankowich, Waseem Ahmed, Thomas Martin, Mitchell Horowitz, John Nord, Mark Elstad, Marcos I Restrepo, Antonio Anzueto, Timothy Bigby, William Rodriguez-Cintron, Vincent Fan, Pratibha Kaul, Michael Habib, Nitin Seam, Guy Soo Hoo

Abstract

Purpose: Severe community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clinical outcomes.

Methods: This double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72-96 h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40 mg loading bolus was followed by 40 mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1 year of follow-up.

Results: Between January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57-1.40). There were no significant differences in secondary outcomes or complications.

Conclusions: In patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications.

Trial registration: ClinicalTrials.gov NCT01283009.

Keywords: Community-acquired pneumonia; Glucocorticoids; Intensive care; Methylprednisolone; Randomized clinical trial.

Conflict of interest statement

No funding or other conflicts to report.

© 2022. This is a U.S. Goverment work and not under copyright protection in the US; foreign protection ma apply.

Figures

Fig. 1
Fig. 1
Enrollment, randomization, and follow-up. ¥Participants who were consented improperly are not included in this diagram. §The reasons for failing eligibility criteria were “select all that apply,” so one patient may have more than one reason for exclusion. Five patients who did not meet eligibility criteria (three did not meet inclusion criteria and two met exclusion criteria) were randomized. *Reasons for study drug withdrawal were check all that apply. ¶Active gastrointestinal bleeding requiring transfusion of at least 5 units of PRBC’s. ¶¶Such as exacerbation of COPD or asthma, and vasculitis
Fig. 2
Fig. 2
Kaplan–Meier estimate of survival. Kaplan–Meier estimates of survival are shown in the overall population (A), in patients who were receiving mechanical ventilation at randomization (Patients on MV; B), and in those not receiving mechanical ventilation at randomization (Patients not on MV; C). The inset in each panel shows the same data on an enlarged y axis and up to day 60
Fig. 2
Fig. 2
Kaplan–Meier estimate of survival. Kaplan–Meier estimates of survival are shown in the overall population (A), in patients who were receiving mechanical ventilation at randomization (Patients on MV; B), and in those not receiving mechanical ventilation at randomization (Patients not on MV; C). The inset in each panel shows the same data on an enlarged y axis and up to day 60
Fig. 3
Fig. 3
60-day all-cause mortality according to subgroup. The odds ratios and 95% confidence intervals are based on logistic regression with treatment as the single covariate. The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects

References

    1. Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014;5:4–11. doi: 10.4161/viru.27372.
    1. Kang C-I, Song J-H, Kim SH, Chung DR, Peck KR, Thamlikitkul V, Wang H, So TM-K, Hsueh P-R, Yasin RM. Risk factors and pathogenic significance of bacteremic pneumonia in adult patients with community-acquired pneumococcal pneumonia. J Infect. 2013;66:34–40. doi: 10.1016/j.jinf.2012.08.011.
    1. Cillóniz C, Polverino E, Ewig S, Aliberti S, Gabarrús A, Menéndez R, Mensa J, Blasi F, Torres A. Impact of age and comorbidity on cause and outcome in community-acquired pneumonia. Chest. 2013;144:999–1007. doi: 10.1378/chest.13-0062.
    1. Hsu JL, Siroka AM, Smith MW, Holodniy M, Meduri GU. One-year outcomes of community-acquired and healthcare-associated pneumonia in the Veterans Affairs Healthcare System. Int J Infect Dis. 2011;15:e382–387. doi: 10.1016/j.ijid.2011.02.002.
    1. Musher DM, Montoya R, Wanahita A. Diagnostic value of microscopic examination of Gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2004;39:165–169. doi: 10.1086/421497.
    1. Corrales-Medina VF, Musher DM. Immunomodulatory agents in the treatment of community-acquired pneumonia: a systematic review. J Infect. 2011;63:187–199. doi: 10.1016/j.jinf.2011.06.009.
    1. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA, J Am Med Assoc. 2010;304:1787–1794. doi: 10.1001/jama.2010.1553.
    1. Wang HE, Szychowski JM, Griffin R, Safford MM, Shapiro NI, Howard G. Long-term mortality after community-acquired sepsis: a longitudinal population-based cohort study. BMJ Open. 2014;4:e004283. doi: 10.1136/bmjopen-2013-004283.
    1. Confalonieri M, Meduri GU. Glucocorticoid treatment in community-acquired pneumonia. Lancet. 2011;377:1982–1984. doi: 10.1016/S0140-6736(11)60777-0.
    1. Yende S, Kellum JA, Talisa VB, Palmer OMP, Chang C-CH, Filbin MR, Shapiro NI, Hou PC, Venkat A, LoVecchio F. Long-term host immune response trajectories among hospitalized patients with sepsis. JAMA Netw Open. 2019;2:e198686–e198686. doi: 10.1001/jamanetworkopen.2019.8686.
    1. Siemieniuk RA, Meade MO, Alonso-Coello P, Briel M, Evaniew N, Prasad M, Alexander PE, Fei Y, Vandvik PO, Loeb M, Guyatt GH. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:519–528. doi: 10.7326/M15-0715.
    1. Briel M, Spoorenberg SM, Snijders D, Torres A, Fernandez-Serrano S, Meduri GU, Gabarrús A, Blum CA, Confalonieri M, Kasenda B. Corticosteroids in patients hospitalized with community-acquired pneumonia: systematic review and individual patient data metaanalysis. Clin Infect Dis. 2017;66:346–354. doi: 10.1093/cid/cix801.
    1. Meduri GU, Chrousos GP (2020) General adaptation in critical illness: glucocorticoid receptor-alpha master regulator of homeostatic corrections. Front Endocrinol (Lausanne) 11
    1. Nawab Q, Golden E, Confalonieri M, Umberger R, Meduri G. Corticosteroid treatment in severe community-acquired pneumonia: duration of treatment affects control of systemic inflammation and clinical improvement. Intensive Care Med. 2011;37:1153–1554. doi: 10.1007/s00134-011-2274-5.
    1. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Jr, Musher DM, Niederman MS, Torres A, Whitney CG. Infectious diseases society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–72. doi: 10.1086/511159.
    1. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. 2008;34:17–60. doi: 10.1007/s00134-007-0934-2.
    1. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286:1754–1758. doi: 10.1001/jama.286.14.1754.
    1. Kazis LE, Selim AJ, Rogers W, Ren XS, Lee A, Miller D, Veterans RAND 12 item Health Survey (VR-12): a white paper summary
    1. Selim AJ, Rogers W, Fleishman JA, Qian SX, Fincke BG, Rothendler JA, Kazis LE. Updated US population standard for the Veterans RAND 12-item Health Survey (VR-12) Qual Life Res. 2009;18:43–52. doi: 10.1007/s11136-008-9418-2.
    1. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9:179–186. doi: 10.1093/geront/9.3_Part_1.179.
    1. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The Index of Adl: a standardized measure of biological and psychosocial function. JAMA. 1963;185:914–919. doi: 10.1001/jama.1963.03060120024016.
    1. Lai TL, Shih M-C. Power, sample size and adaptation considerations in the design of group sequential clinical trials. Biometrika. 2004;91:507–528. doi: 10.1093/biomet/91.3.507.
    1. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, Coley CM, Marrie TJ, Kapoor WN. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243–250. doi: 10.1056/NEJM199701233360402.
    1. Moreno RP, Metnitz PG, Almeida E, Jordan B, Bauer P, Campos RA, Iapichino G, Edbrooke D, Capuzzo M, Le Gall JR. SAPS 3–from evaluation of the patient to evaluation of the intensive care unit. Part 2: development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med. 2005;31:1345–1355. doi: 10.1007/s00134-005-2763-5.
    1. Zhao L, Tian L, Uno H, Solomon SD, Pfeffer MA, Schindler JS, Wei LJ. Utilizing the integrated difference of two survival functions to quantify the treatment contrast for designing, monitoring, and analyzing a comparative clinical study. Clin Trials. 2012;9:570–577. doi: 10.1177/1740774512455464.
    1. Pastores SM, Annane D, Rochwerg B. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 2018;44:474–477. doi: 10.1007/s00134-017-4951-5.
    1. Briel M, Spoorenberg SMC, Snijders D, Torres A, Fernandez-Serrano S, Meduri GU, Gabarrus A, Blum CA, Confalonieri M, Kasenda B, Siemieniuk RAC, Boersma W, Bos WJW, Christ-Crain M, Ovidius Study G, Capisce Study G, Group SS Corticosteroids in patients hospitalized with community-acquired pneumonia: systematic review and individual patient data metaanalysis. Clin Infect Dis. 2018;66:346–354. doi: 10.1093/cid/cix801.
    1. Coelho LM, Salluh JI, Soares M, Bozza FA, Verdeal JC, Castro-Faria-Neto HC, Lapa-e-Silva JR, Bozza PT, Povoa P. Patterns of c-reactive protein RATIO response in severe community-acquired pneumonia: a cohort study. Crit Care. 2012;16:R53. doi: 10.1186/cc11291.
    1. Monedero P, Gea A, Castro P, Candela-Toha AM, Hernandez-Sanz ML, Arruti E, Villar J, Ferrando C, Network C-SI. Early corticosteroids are associated with lower mortality in critically ill patients with COVID-19: a cohort study. Crit Care. 2021;25:2. doi: 10.1186/s13054-020-03422-3.
    1. Meduri GU, Annane D, Confalonieri M, Chrousos GP, Rochwerg B, Busby A, Ruaro B, Meibohm B. Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med. 2020;46:2284–2296. doi: 10.1007/s00134-020-06289-8.
    1. Torres A, Sibila O, Ferrer M, Polverino E, Menendez R, Mensa J, Gabarrus A, Sellares J, Restrepo MI, Anzueto A, Niederman MS, Agusti C. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA. 2015;313:677–686. doi: 10.1001/jama.2015.88.
    1. Rodriguez JM, Monsalves-Alvarez M, Henriquez S, Llanos MN, Troncoso R. Glucocorticoid resistance in chronic diseases. Steroids. 2016;115:182–192. doi: 10.1016/j.steroids.2016.09.010.
    1. Cangemi R, Falcone M, Taliani G, Calvieri C, Tiseo G, Romiti GF, Bertazzoni G, Farcomeni A, Violi F, Group SS Corticosteroid use and incident myocardial infarction in adults hospitalized for community-acquired pneumonia. Ann Am Thorac Soc. 2019;16:91–98. doi: 10.1513/AnnalsATS.201806-419OC.
    1. Annane D, Pastores S, Rochwerg B, Arlt W, Balk R, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper M. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017;45:2078–2088. doi: 10.1097/CCM.0000000000002737.
    1. Odeyemi YE, Herasevich S, Chalmers SJ, Barreto EF, Frank RD, Gajic OO, Yadav H. Biomarker-concordant steroid use in critically ill patients with pneumonia. Mayo Clin Proc Innov Qual Outcomes. 2020;4:649–656. doi: 10.1016/j.mayocpiqo.2020.07.011.
    1. Li J, Liao X, Zhou Y, Wang L, Yang H, Zhang W, Zhang Z, Kang Y. Comparison of associations between glucocorticoids treatment and mortality in COVID-19 patients and SARS patients: a systematic review and meta-analysis. Shock. 2021;56:215–228. doi: 10.1097/SHK.0000000000001738.
    1. Recovery Collaborative Group. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384:693–704. doi: 10.1056/NEJMoa2021436.
    1. World Health Organization (2020) Corticosteroids for COVID-19: living guidance, 2 September 2020. In: Book corticosteroids for COVID-19: living guidance, 2 September 2020. World Health Organization, City
    1. Villar J, Ferrando C, Martinez D, Ambros A, Munoz T, Soler JA, Aguilar G, Alba F, Gonzalez-Higueras E, Conesa LA, Martin-Rodriguez C, Diaz-Dominguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Anon JM, Fernandez RL, Gonzalez-Martin JM, Dexamethasone in AN Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8:267–276. doi: 10.1016/S2213-2600(19)30417-5.
    1. Yates CR, Vysokanov A, Mukherjee A, Ludden TM, Tolley EA, Meduri GU, Dalton JT. Time-variant increase in methylprednisolone clearance in patients with acute respiratory distress syndrome: a population pharmocokinetic study. J Clin Pharmacol. 2001;41:1–10. doi: 10.1177/00912700122010276.
    1. Chriguer RS, Elias LLK, da Silva Jr IM, Vieira JGH, Moreira AC, de Castro M. Glucocorticoid sensitivity in young healthy individuals: in vitro and in vivo studies. J Clin Endocrinol Metab. 2005;90:5978–5984. doi: 10.1210/jc.2005-0067.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir