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Corticosteroids in late ARDS
Lead author: Kenneth Steinberg Three-part Clinical Question: Patients: Patients with late stage ARDS Intervention: High dose methylprednisolone Outcome: (Primary) Mortality, (Secondary) ventilator-free days, organ-failure-free days.
Search Terms: ARDS; therapy.
The Study: Single-blinded randomised controlled trial with intention-to-treat.
The Study Patients: Late
stage ARDS according to American European Consensus Conference criteria still
requiring mechanical ventilation for 7-28 days after onset of ARDS. Control group (N = 91; 91 analysed): No specified ventilatory strategy (probably not controlled) until 1999 then standard ARDSnet ventilation strategy after 1999 and weaned according to a standardised weaning protocol.
Experimental group (N = 89; 89 analysed): No specified ventilatory strategy (probably not controlled) until 1999 then standard ARDSnet ventilation strategy after 1999 and weaned according to a standard weaning protocol plus the addition of corticosteroids. Methylprednisolone 2mg/kg as one off dose followed by 0.5mg/kg six hourly for 14 days, 0.5mg/kg twelve hourly for 7 days then tapered to off over 4 days if still ventilated or over 2 days if not ventilated or patient had developed fungal infection or septic shock.
The Evidence:
Comments: 1) Do the methods allow accurate testing of the hypothesis? This is in question. The study ran for 7 years partly due to factors outside the control of the authors and clinical practice changed markedly in this time (i.e. the publication of the ARDSnet study in 2000). Study patients were changed to ARDSnet ventilation after 1999 and their ventilation was not protocolised before this time. Further, the patient number for the entire study and for all subgroups is far below the original power calculation. Although not fully explained they probably relate to poor recruitment rather than any genuine change in estimated mortality. The trial only recruited 5% of available patients so limiting the trial results applicability. The late treatment subgroup (14-28 days) was clearly post-hoc as it was not stated in the trial protocol with all the problems associated with such analysis. With a total of 48 patients in the 14-28 day subgroup (2 deaths in control group and 8 in treatment) this result should not be considered valid as it is grossly underpowered. One extra death in control group would make this non-significant.
2) Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes.
3) Are conclusions valid in light of the results? They conclude that the results do not support the routine use of methlyprednisolone in prolonged ARDS. This is a reasonable conclusion. They also conclude that starting methylprednisolone more than two weeks after onset of ARDS may increase mortality. This may lack validity due to very small event numbers.
4) Did results get omitted, and why? No.
5) Did they suggest areas of further research? No. 6) Did they make any recommendations based on the results and were they appropriate? Yes. They concluded that results did not support the routine use of methyprednisolone in ARDS. This seems a reasonable recommendation. 7) Is the study relevant to my clinical practice? They recruited from a group of all comers with ARDS who are still ventilated after 7 days but they only recruited 5% of the available patients thus limiting the generalisability of the result. Extrapolating the lack of clinical benefit in such a highly selected group of patients to all ARDS patients may be questionable. 8) What level of evidence does this study represent? 1+.
9) What grade of recommendation can I make on this result alone? B. Steroids do not improve mortality in late (>7 days) ARDS who still require mechanical ventilation. There appears to be some benefit in terms of the secondary outcomes of duration of ventilation and ICU stay although late readmission to ICU in the treatment group makes this non-significant at 180 days.
10) What grade of recommendation can I make when this study is considered along with other available evidence? B also as this study is the only valid randomised controlled trial in this group of patients. The previous study by Meduri et al was extremely small and lacked internal or external validity.
11) Should I change my practice because of these results? Yes. If you use steroids in late ARDS you should review your practice. The further use of this therapy depends on the interpretation of the importance of the effects on duration of ventilation at 28 days. In light of the lack of effect on other clinically important outcomes and the presence of some serious side effects such as myopathies (which may lead to an increased requirement for re-ventilation during the study period), this reviewer suggests that this treatment should not be used for this indication.
12) Should I audit my current practice because of these results? Yes. If you use steroids you should consider auditing your results. If you intend to start using steroids for the ventilatory benefits you should also audit your results prospectively including the presence of side effects such as weakness syndromes, sepsis, hyperglycaemia etc. and longer term outcomes such a 180 day mortality, ventilatory status and ICU stay.
Appraised by: BH Cuthbertson,
Intensive Care Unit, Aberdeen Royal Infirmary, Aberdeen, Scotland. 44 (0)1224
554580; 08 May 2006
Citation: EBM Critical Appraisals. Scottish Intensive Care Society EBM Group. 2006 & JICS 2006 Vol7(2). Cuthbertson BH: 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. NEJM 2006; 354: 1671-1684.
©SICS EBM 2006
Reviewer & edited by CC & BT
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