Published online before print December 18, 2003, doi: 10.1161/01.STR.0000105932.01846.7B
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(Stroke. 2004;35:230.)
© 2004 American Heart Association, Inc.
Controversies in Stroke |
Steroids for Stroke: Another Potential Therapy Discarded Prematurely?
From the Department of Neurology (S.M.D.), Royal Melbourne Hospital and University of Melbourne; and The National Stroke Research Institute (G.A.D.), Austin and Repatriation Medical Centre and University of Melbourne, Australia.
Corresponence to Prof Stephen M. Davis, Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, Australia 3050. E-mail stephen.davis{at}mh.org.au
Key Words: corticosteroids • stroke, acute • stroke, ischemic
Why do we discard potentially promising therapies so easily? First, the perception that the evidence has been adequately assessed becomes ingrained in the thought processes of everyday practitioners. Second, there is no commercial imperative to drive new trials of therapy. In virtually any modern review of acute stroke therapy, a statement is included that corticosteroids are disproven. However, when the evidence for use of steroids in stroke is examined in more detail, the data seem to be disturbingly sparse. For example, the Cochrane Review of steroids for acute ischemic stroke could identify only 7 trials that met their criteria for evaluation, and these involved only 453 patients.1 Furthermore, the last of these trials was published in 1986, by Norris and Hachinski.2 In intracerebral hemorrhage (ICH), there appear to be only 3 randomized control trials targeting ICH alone, involving only 159 patients.3–5 However, it should be noted that Poungvarin, one of our protagonists, performed the most rigorous and most often cited study of steroids in ICH in 1987.4 To date, the amount of evidence is minimal and there have been no recent large trials. Methodological problems also include long time windows, uncertainty about dose, protracted steroid treatment, and lack of rigorous monitoring and correction of potential steroid side effects, particularly hyperglycemia.
The theoretical constructs involved here are important, as outlined by Norris. He nicely draws attention to the important differences between vasogenic and cytotoxic edema and their temporal relationships. Practicing clinicians would be well aware that the edema surrounding ICH, commonly seen on CT and MR images, includes vasogenic as well as cytotoxic components. In ICH, the perihematomal edema volume substantially increases in the first 24 hours after onset and is independently predictive of functional outcome.6 Hence, it would seem more logical to study the effects of steroids in cases of hemorrhage rather than infarction, where it is generally considered that cytotoxic edema predominates.
Modern trial principles for any re-evaluation of steroids in stroke would require administration of therapy during an earlier time window, use of high-dose intravenous steroids (such as methylprednisolone), a shorter duration of therapy to avoid potential side effects, and adequate sample size. Adverse effects of steroid therapy, such as hyperglycemia, infections, and gastrointestinal hemorrhage, have offset any trend to improvement in ICH in previous trials.4 These would need to be considered in trial design. For example, with the modern understanding of the adverse effects of hyperglycemia in acute stroke, rigorous glycemic monitoring and insulin therapy would be required. Both of our protagonists have published widely quoted negative studies concerning steroids in stroke.2,4 Norris points out that steroid use remains prevalent, nonetheless, in many countries. This is an ideal scenario for a high-quality investigator-driven trial to be generated. Clearly, this has no commercial attraction, as is the case with many potentially promising but prematurely discarded therapies. We will watch with interest.
References
1. Qizilbash N, Lewington SL, Lopez-Arrieta JM. Corticosteroids for acute ischemic stroke (Cochrane Review) The Cochrane Library, Issue 1, 2003. Oxford: Update Software; 2003.
2. Norris JW, Hachinski VC. High dose steroid therapy in cerebral infarction. BMJ. 1986; 292: 21–23.
3. Tellez H, Bauer RB. Dexamethasone as treatment in cerebrovascular disease, I: a controlled study in intracerebral hemorrhage. Stroke. 1973; 4: 541–546.
4. Poungvarin N, Bhoopat W, Viriyavejakul A, Rodprasert P, Buranasiri P, Sukondhabhant S, Hensley MJ, Strom BL. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med. 1987; 316: 1229–1233.[Abstract]
5. Desai P, Prasad K. Dexamethasone is not necessarily unsafe in primary supratentorial cerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1998; 65: 799–800.
6. Gebel JM Jr, Jauch EC, Brott TG, Khoury J, Sauerbeck L, Salisbury S, Spilker J, Tomsick TA, Duldner J, Broderick JP. Relative edema volume is a predictor of outcome in patients with hyperacute spontaneous intracerebral hemorrhage. Stroke. 2002; 33: 2636–2641.
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