Efficacy and safety of low-dose corticosteroids for acute respiratory distress syndrome: A systematic review and meta-analysis

doi:10.5847/wjem.j.1920-8642.2021.03.008

Abstract

Abstract:

BACKGROUND: There are conflicting results regarding whether corticosteroids have better efficacy than placebo in acute respiratory distress syndrome (ARDS) patients. Therefore, we aim to further evaluate the efficacy and safety of corticosteroids in adult ARDS patients.

METHODS: The databases, including Medline, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, were searched from their inception to May 2, 2020. Randomized controlled trials (RCTs) and observational cohort studies were selected to assess the use of corticosteroids in adult ARDS patients. The quality of the results was judged by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The inverse-variance method with random or fixed effects modeling was used to compute pooled odds ratio (OR), standardized mean difference (SMD), and their 95% confidence interval (CI).

RESULTS: Eight eligible RCTs and six cohort studies were included. The use of corticosteroids was associated with reduced mortality (OR 0.57, 95% CI 0.43-0.76, I²=35.1%, P=0.148) in ARDS patients, and the result was confirmed in the included cohort studies (OR 0.51, 95% CI 0.27-0.95, I²=66.7%, P=0.010). The subgroup analysis stratified by the initiation time and duration of corticosteroid use showed that early ARDS and prolonged corticosteroid use had significant survival benefits in the RCTs. The low-dose corticosteroid use was also associated with significantly more ventilator-free days and a reduced rate of new infections in ARDS patients.

CONCLUSIONS: The low-dose corticosteroid therapy may be safe and reduce mortality, especially in patients with prolonged treatment and early ARDS.

Key words: Low-dose, Corticosteroid, Acute respiratory distress syndrome, Mortality, Systematic review, Meta-analysis

Yu-qing Cui, Xian-fei Ding, Huo-yan Liang, Dong Wang, Xiao-juan Zhang, Li-feng Li, Quan-cheng Kan, Le-xin Wang, Tong-wen Sun. Efficacy and safety of low-dose corticosteroids for acute respiratory distress syndrome: A systematic review and meta-analysis[J]. World Journal of Emergency Medicine, 2021, 12(3): 207-213.

Figures/Tables 3

Table 1

Figure 1.

Figure 2.

References 36

1	ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012; 307(23):2526-33. doi: 10.1001/jama.2012.5669 pmid: 22797452
2	Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016; 315(8):788-800. doi: 10.1001/jama.2016.0291
3	Bein T, Grasso S, Moerer O, Quintel M, Guerin C, Deja M, et al. The standard of care of patients with ARDS: ventilatory settings and rescue therapies for refractory hypoxemia. Intensive Care Med. 2016; 42(5):699-711. doi: 10.1007/s00134-016-4325-4
4	Fan YW, Jiang SW, Chen JM, Wang HQ, Liu D, Pan SM, et al. A pulmonary source of infection in patients with sepsis-associated acute kidney injury leads to a worse outcome and poor recovery of kidney function. World J Emerg Med. 2020; 11(1):18-26. doi: 10.5847/wjem.j.1920-8642.2020.01.003
5	Wan YD, Sun TW, Liu ZQ, Zhang SG, Wang LX, Kan QC. Efficacy and safety of corticosteroids for community-acquired pneumonia: a systematic review and meta-analysis. Chest. 2016; 149(1):209-19. doi: 10.1378/chest.15-1733
6	Fang F, Zhang Y, Tang J, Lunsford LD, Li T, Tang R, et al. Association of corticosteroid treatment with outcomes in adult patients with sepsis: a systematic review and meta-analysis. JAMA Intern Med. 2019; 179(2):213-23. doi: 10.1001/jamainternmed.2018.5849 pmid: 30575845
7	Song LC, Chen XX, Meng JG, Hu M, Huan JB, Wu J, et al. Effects of different corticosteroid doses and durations on smoke inhalation-induced acute lung injury and pulmonary fibrosis in the rat. Int Immunopharmacol. 2019; 71:392-403. doi: 10.1016/j.intimp.2019.03.051
8	Yu Z, Ouyang JP, Li YP. Dexamethasone attenuated endotoxin-induced acute lung injury through inhibiting expression of inducible nitric oxide synthase. Clin Hemorheol Microcirc. 2009; 41(2):117-25. doi: 10.3233/CH-2009-1162
9	Thompson BT. Corticosteroids for ARDS. Minerva Anestesiol. 2010; 76(6):441-7. pmid: 20473257
10	Wiegers GJ, Reul JMHM. Induction of cytokine receptors by glucocorticoids: functional and pathological significance. Trends Pharmacol Sci. 1998; 19(8):317-21. pmid: 9745359
11	Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007; 131(4):954-63. doi: 10.1378/chest.06-2100
12	Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998; 280(2):159-65. doi: 10.1001/jama.280.2.159
13	Rezk NA, Ibrahim AM. Effects of methyl prednisolone in early ARDS. Egyptian Journal of Chest Diseases and Tuberculosis. 2013; 62(1):167-72. doi: 10.1016/j.ejcdt.2013.02.013
14	Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020; 8(3):267-76. doi: S2213-2600(19)30417-5 pmid: 32043986
15	Tongyoo S, Permpikul C, Mongkolpun W, Vattanavanit V, Udompanturak S, Kocak M, et al. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care. 2016; 20(1):329. pmid: 27741949
16	Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. Int J Surg. 2010; 8(5):336-41. doi: 10.1016/j.ijsu.2010.02.007
17	Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ, et al. What is “quality of evidence” and why is it important to clinicians? BMJ. 2008; 336(7651):995-8. doi: 10.1136/bmj.39490.551019.BE
18	Chou R, Fu R, Carson S, Saha S, Helfand M. Methodological shortcomings predicted lower harm estimates in one of two sets of studies of clinical interventions. J Clin Epidemiol. 2007; 60(1):18-28. doi: 10.1016/j.jclinepi.2006.02.021
19	Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analyses. Available at: www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
20	Wetterslev J, Jakobsen JC, Gluud C. Trial sequential analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017; 17(1):39. doi: 10.1186/s12874-017-0315-7 pmid: 28264661
21	Annane D, Sebille V, Bellissant E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med. 2006; 34(1):22-30. doi: 10.1097/01.CCM.0000194723.78632.62
22	Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006; 354(16):1671-84. doi: 10.1056/NEJMoa051693
23	Liu L, Li J, Huang YZ, Liu SQ, Yang CS, Guo FM, et al. The effect of stress dose glucocorticoid on patients with acute respiratory distress syndrome combined with critical illness-related corticosteroid insufficiency. Zhonghua Nei Ke Za Zhi. 2012; 51(8):599-603.
24	Keel JB, Hauser M, Stocker R, Baumann PC, Speich R. Established acute respiratory distress syndrome: benefit of corticosteroid rescue therapy. Respiration. 1998; 65(4):258-64. pmid: 9730790
25	Lee HS, Lee JM, Kim MS, Kim HY, Hwangbo B, Zo JI. Low-dose steroid therapy at an early phase of postoperative acute respiratory distress syndrome. Ann Thorac Surg. 2005; 79(2):405-10. doi: 10.1016/j.athoracsur.2004.07.079
26	Seam N, Meduri GU, Wang H, Nylen ES, Sun J, Schultz MJ, et al. Effects of methylprednisolone infusion on markers of inflammation, coagulation, and angiogenesis in early acute respiratory distress syndrome. Crit Care Med. 2012; 40(2):495-501. doi: 10.1097/CCM.0b013e318232da5e
27	Varpula T, Pettila V, Rintala E, Takkunen O, Valtonen V. Late steroid therapy in primary acute lung injury. Intensive Care Med. 2000; 26(5):526-31. doi: 10.1007/s001340051199
28	Zhao JN, Liu Y, Li HC. Corticosteroids in treatment of aspiration-related acute respiratory distress syndrome: results of a retrospective cohort study. BMC Pulm Med. 2016; 16:29. doi: 10.1186/s12890-016-0194-4
29	Baek MS, Lee Y, Hong SB, Lim CM, Koh Y, Huh JW. Effect of corticosteroid therapy in the early phase of acute respiratory distress syndrome: a propensity-matched cohort study. Korean J Intern Med. 2021; 36(1):145-53. doi: 10.3904/kjim.2019.153
30	Chen LP, Chen JH, Chen Y, Wu C, Yang XH. Efficacy and safety of glucocorticoids in the treatment of community-acquired pneumonia: a meta-analysis of randomized controlled trials. World J Emerg Med. 2015; 6(3):172-8. doi: 10.5847/wjem.j.1920-8642.2015.03.002
31	Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019; 5(1):18. doi: 10.1038/s41572-019-0069-0
32	Meduri GU, Eltorky MA. Understanding ARDS-associated fibroproliferation. Intensive Care Med. 2015; 41(3):517-20. doi: 10.1007/s00134-014-3613-0
33	Meduri GU, Chinn AJ, Leeper KV, Wunderink RG, Tolley E, Winer-Muram HT, et al. Corticosteroid rescue treatment of progressive fibroproliferation in late ARDS. Chest. 1994; 105(5):1516-27. pmid: 8181346
34	Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007; 167(15):1655-63. pmid: 17698689
35	Lekkou A, Karakantza M, Mouzaki A, Kalfarentzos F, Gogos CA. Cytokine production and monocyte HLA-DR expression as predictors of outcome for patients with community-acquired severe infections. Clin Diagn Lab Immunol. 2004; 11(1):161-7. pmid: 14715564
36	Meduri GU, Yates CR. Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS. Ann N Y Acad Sci. 2004; 1024:24-53. doi: 10.1196/annals.1321.004

Study	Country	Center	Number of patients		Female/ male	Age, years (mean±SD)		Initial daily dose^a	Time of treatment initiation	Duration of treatment (days)	Primary outcome			Secondary outcomes
			Number of patients			Age, years (mean±SD)					Mortality		MV free days (mean±SD)		New infection rate
			SG	NG		SG	NG				SG	NG	SG	NG	SG	NG
Meduri et al^[11] (2007)	USA	M	63	28	44/47	50.1±15.3	53.2±15.3	Infusion of Me 1 mg/(kg·d)	Early severe ARDS	Up to 28	15/63	12/28	16.5±10.1	8.7±10.2	27/63	16/28
Meduri et al^[12] (1998)	USA	M	16	8	15/9	47.0±39.0	51.0±6.6	Intravenous pushing Me 2 mg/(kg·d)	Unresolving ARDS	Up to 32	2/16	5/8	NA	NA	12/16	6/8
Rezk et al^[13] (2013)	Egypt	M	18	9	4/23	NA	NA	Infusion of Me 1 mg/(kg·d)	Early ARDS	Up to 28	0/18	3/9	NA	NA	NA	NA
Villar et al^[14] (2020)	Spain	M	139	138	86/191	56.0±14.0	58.0±15.0	Intravenously receiving Dex 20 mg/d	Early ARDS	Up to 10	29/139	50/138	12.3±9.9	7.5±9.0	33/139	35/138
Tongyoo et al^[15] (2016)	Thailand	S	98	99	96/101	64.5±17.3	64.3±16.0	Intravenous bolus Hy 200 mg/d	Early ARDS	7	22/98	27/99	12.0±9.7	9.7±10.0	34/98	41/99
Annane et al^[21] (2006)	France	M	85	92	NA	NA	NA	Hy 200 mg/d and Flu 50 μg	Early ARDS	7	54/85	67/92	4.9±8.4	3.1±6.9	12/85	12/92
Steinberg et al^[22](2006)	USA	M	89	91	82/98	49.0±19.0	49.2±16.5	Intravenously receivng Me 2 mg/(kg·d)	Unresolving ARDS	Up to 25	26/89	26/91	11.2±9.4	6.8±8.5	25/89	43/91
Liu et al^[23](2012)	China	S	12	14	7/19	69.8±14.9	55.9±15.3	Intravenous bolus Hy 300 mg/d	Early ARDS	7	3/12	6/14	13.9±11.3	12.8±11.3	3/12	2/14

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