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Three Part Question

In [adults with ARDS] do [corticosteroids] improve [outcome]?

Clinical Scenario

You are treating a middle-aged man with severe pancreatitis. It is apparent that he is hypoxic, deteriorating, and will need to be ventilated. A chest X ray shows bilateral shadowing. There is no clinical indication to suggest either infection or pulmonary oedema. Your colleague from Intensive Care decides that the patient has Adult Respiratory Distress Syndrome and should be given high dose steroids. You wonder what evidence there is to support this treatment.

Search Strategy

Medline: 1966 to Sept 2006
Cochrane Database
[(exp Respiratory Distress Syndrome, Adult/ or ARDS.mp.)] AND [(steroids.mp. or exp Steroids/) OR (corticosteroids.mp. or exp Adrenal Cortex Hormones/) OR (glucocorticoids.mp. or exp Glucocorticoids/)]
limit to (humans and english language) and "all adult (19 plus years)"

Search Outcome

Medline search brought up 261 citations. 24 appeared relevant to the question. 7 were critically appraised the other 13 were excluded (2 letters, 5 reviews, 1 ex-vivo study, 2 pathophysiology studies, and 3 case series). 1 other study was found from the references.
Cochrane Database: 1 citation (no new evidence).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bernard 1987 USA	99 patients with ARDS. 50 received methyprednisolone (MP) at 30 mg/kg every 6 hrs for 24 hrs, 49 received placebo.	Multi-centre, randomised, double-blind, placebo-controlled trial	45 day mortality	MP group 30/50 = 60%, placebo: 31/49 = 63%, P = 0.74	24 hrs of steroids only
			Infectious complications	MP 16%, placebo 10%, P = 0.60
Meduri 1998 USA	24 patients with severe ARDS who had failed to improve despite mechanical ventilation for more than 7 days. 16 received methylprednisolone (2 mg/kg loading dose then 2mg/kg/day for 14 days and then tapered until day 32), 8 received placebo.	Multi-centre, randomised, double-blind, placebo-controlled trial with 2:1 randomisation. A cross-over was designed if patients failed to improve after 10 days.	ICU mortality	MP 0/16, placebo 5/8 = 62%, P=0.002	Sequential analysis. Only 22 patients completed the trial (1 had a GI bleed after crossing over, 1 candidaemia on steroids).
			Hospital mortality	MP 2/16 = 12%, placebo 5/16 = 62%, P=0.03
Varpula 2000 Finland	31 patients with acute lung injury (ALI), mechanically ventilated for more than 10 days. 16 received methyprednisolone (80 mg mane, 40 mg nocte and tapered according to response)	Retrospective chart analysis	30-day mortality	MP 3/16 = 19%, placebo 3/15 = 20%, P=0.82	Retrospective analysis. Corticosteroids had been adopted as an empirical treatment for ALI but not consistently applied. Lacked power to assess survival.
			Days mechanical ventilation	MP 20.5, placebo 20.1, P = 0.70
			Days ICU	MP 20.9, placebo 20.8, P = 0.63
Keel 1998 Switzerland	31 non-trauma ARDS patients who had been on mechanical ventilation at least 7 days.13 received methylprednisolone (100-250 mg for 1-3 days and then tapered), 18 did not.	Retrospective chart analysis	Mortality	MP 5/13 = 38%, placebo 12/18 = 67%	Retrospective analysis. Steroid treatment based on physician preference.
Lee 2005 Korea	20 patients with ARDS after major thoracic operations. 12 received methylprednisolone (2 mg/kg loading dose, then 2 mg/kg/day. Dose tapered according to clinical response), 8 did not.	Prospective observation with historical controls.	Mortality rate	MP 1/12 = 8.3%, control 7/8 = 87.5%	Observational study. No randomisation. Historical controls. Outcomes not defined a priori.
Annane 2006 France	Patients enrolled in a study of steroids in septic shock. Post-hoc analysis of 177 patients with ARDS. 85 received hydrocortisone 50 mg QDS and fludrocortisone 50 mug OD for 7 days, 92 received placebo. Patients were stratified as to their response to an ACTH stimulation test.	Multi-centre, randomised, double-blind, placebo-controlled trial	28-day survival in non-responders to ACTH testing	Steroid gp 33/62 = 53%, placebo 50/67 = 75% (RR 0.71, 95% CI 0.54-0.94, P=0.011)	Post-hoc analysis from another study
			28-day survival in responders	No significant difference in survival
ARDSnet 2006 USA	180 patient swith ARDS for at least 7 days. 98 received methylprednisolone (2 mg/kg loading dose and then 2 mg/kg/day tapering after 14 days), 91 received placebo.	Multi-centre, randomised, double-blind, placebo-controlled trial	60-day mortality	MP 26/89 = 29.2%, placebo 26/91 = 28.6%	Originally planned to recruit 400 patients. Re-sized the power calculation after 2 years because of low enrollment. Study lasted 7 years, during which there were major changes in critical care.
			180-day mortality	MP 28/89 = 31.9%, placebo 29/91 = 31.5%
Luce 1988 USA	87 patients with septic shock (75 had positive cultures). 38 received methylprednisolone (30mg/kg in 4 divided doses), 37 received placebo.	Randomised, double-blind, placebo-controlled trial. Prophylaxis trial.	Development of ARDS	MP 13/38 = 34%, placebo 14/37 =38%	3 year recruitment period. 24 hrs of steroids.
			Hospital mortality	MP 22/38 = 58%, placebo 20/37 =54%
van der Merwe 1985 South Africa	92 trauma patients. 47 received methylprednisolone (MP) 45 did not.	Prophylaxis trial.	Development of ARDS	MP 3/47 = 6%, control 11/45 = 24%.	Definition of ARDS has since changed. Patients may not have met current criteria for ARDS.
Weigelt JA 1985 USA	81 acutely ill ventilated patients at high risk for ARDS. 39 treated with methylprednisolone (MP) at 30 mg/kg 6 hourly for 48 hours, 42 given mannitol placebo.	Randomised, double-blind, placebo-controlled trial. Prophylaxis trial.	Development of ARDS	MP 25/39 (64%), placebo 14/42 (33%)	Definition of ARDS did not include chest X ray changes. Randomisation method not specified.
			Infection	MP 30/39 (77%), placebo 18/42 (43%)
Bone 1987 USA	304 patients with septic syndrome. 152 received methylprednisolone (MP) at 30 mg/kg 4 doses every 6 hours, 152 received placebo.	Randomised, double-blind, placebo-controlled trial. Prophylaxis trial.	Development of ARDS	MP 50/152 = 32%, placebo 38/152 = 25%, p=0.10	Data collected from a study of steroids in early sepsis
			Reversal of ARDS	MP 15/50 = 31%, placebo 23/38 = 61%, p=0.005
			14 day mortality	MP 26/50 = 52%, placebo 8/22 = 22%, p=0.004
du Toit 1984 South Africa	22 patients for total hip replacement under general anaethesia. 10 were pre-treated with methylprednisolone (MP) at 30 mg/kg, 12 acted as controls.	Prophylaxis trial.	Development of ARDS	1 of the 10 in the MP group developed ARDS. 5 of the 12 controls developed ARDS.	This was not ARDS by current standards. Chest X ray changes did not form part of the ARDS definition.

Comment(s)

5 studies looked at prevention of ARDS using steroids. The study in trauma patients (3) showed some apparent benefit, but the patients may not have had ARDS by current standards. The definition of ARDS in the hip replacement study is also out of date (1) . The studies in septic patients (2, 4, 6) showed either no benefit, or an increased incidence of ARDS, mortality and infection rates. The 2 retrospective analyses (7, 9) showed no benefit from steroids, while Lee et al (10) used only historical controls, and was not a randomised study. The 4 randomised trials for treatment of ARDS spanned 16 years: a long time in critical care, and used different steroid doses. The ARDSnet study (180 patients) seems to lay to rest the 2mg/kg/day methylprednisolone regime, showing no benefit in early ARDS and increased mortality in late ARDS. The post-hoc analysis by Annane confirms the importance of low dose steroids in septic shock and associated ARDS.

Clinical Bottom Line

High dose steroids do not prevent ARDS in septic patients. There is no convincing evidence that using methylprednisolone at 2 mg/kg/day in the treatment of ARDS reduces mortality. Low dose steroids (hydrocortisone 200-300 mg) for 7 days may have a role independent of their benefit for septic shock.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Bernard G, Luce J, Sprung C, Rinaldo J, Tate R, Sibbald W, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. New England Journal of Medicine 1987;317(25):1565-1570.
2. 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 Journal of American Medical Association 1998;280(2):159-165.
3. Varpula T, Pettila V, Nieminen H, Takkunen O. Late steroid therapy in primary acute lung injury Intensive Care Medicine 2000;26:526-531.
4. Keel JBP, Hauser M, Stocker R, Baumann PC, Speich R. Established Acute Respiratory Distress Syndrome: Benefit of Corticosteroid Rescue Therapy. Respiration 1998;65(4):258-264.
5. Lee H-S, Lee JM, Kim MS, Kim HY, Hwangbo B, Zo JI. Low-Dose Steroid Therapy at an Early Phase of Postoperative Acute Respiratory Distress Syndrome. Annals of Thoracic Surgery 2005;79(2):405-410.
6. Annane D, Sebille V, Bellissant E, for the Ger-Inf-05 Study group. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Critical Care Medicine 2006;34:22-30.
7. The National Heart Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome New England Journal of Medicine 2006;354(16):1671-1684.
8. Luce J, Montgomery A, Marks J, Turner J, Metz C, Murray J. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. American Review of Respiratory Disease 1988;138:62-68.
9. van der Merwe CJ, Louw AF, Welthagen D, Schoeman HS Adult respiratory distress syndrome in cases of severe trauma - the prophylactic value of methylprednisolone sodium succinate. South African Medical Journal 1985, 67: 279-284.
10. Weigelt JA, Norcross JF, Borman KR, Snyder WH. Early steroid therapy for respiratory failure. Archives of Surgery 1985, 120: 536-540
11. Bone RC, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA and the Methylprednisolone Severe Sepsis Study Group A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock New England Journal of Medicine 1987, 317: 653-658
12. du Toit HJ, Erasmus FR, Macfarlane CM, Taljaard JJ, King JB, de Klerk AJ, Elk E. Methylprednisolone and the adult respiratory distress syndrome. South Africa Medical Journal 1984, 65: 1049-53