Published online before print December 18, 2003, doi: 10.1161/01.STR.0000105931.81723.26
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2004;35:229.)
© 2004 American Heart Association, Inc.
Controversies in Stroke |
Steroids Have No Role in Stroke Therapy
From the Division of Medicine, Department of Neurology, Siriraj Hospital Medical School, Mahidol University, Bangkok, Thailand.
Correspondence to Prof Niphon Poungvarin, Mahidol University - Thailand, Siriraj Hospital Medical School, Dept of Medicine/Division of Neurology, Bangkok, 1070 Thailand. E-mail sinpg{at}mucc.mahidol.ac.th
Key Words: brain edema • corticosteroids • dexamethasone • stroke, acute
Steroids are considered as a group of the magic drugs and have been widely used in neurology for more than 40 years. Theoretically, steroids are immunosuppressive agents, lessen the damaging effects of vasogenic cerebral edema, decrease intracranial pressure, and strengthen the blood-brain barrier. However, these possible benefits have to be weighed against potentially serious steroid-related side effects such as immunosuppression and infection, diabetic exacerbation, gastrointestinal hemorrhage, and compromised wound healing.
The place of steroids in the management of stroke is still controversial. As stroke is a heterogeneous condition, it is therefore unlikely that a single agent would be beneficial in any treatment plan. Perhaps the only general agreement on the use of steroids in stroke is where vasculitis is suspected or proven. As a cause of stroke, vasculitis is very rare (<1% of all strokes), but treatment with steroids should be started whenever it is suspected.1 The effectiveness of steroids as one of the options for the treatment of acute stroke, either hemorrhagic or infarction, has never been shown. So far only 2 randomized, controlled trials concerning the use of dexamethasone in primary supratentorial intracerebral hemorrhage have been reported.2,3
Tellez and Bauer in 1973 did a trial on 40 patients presumed to have intracerebral hemorrhage and found no beneficial effects of dexamethasone.2 There were no CT brain scans available at that period, and 22 patients were later verified to have hemorrhagic infarction or posterior fossa hemorrhage. Poungvarin et al in 1987 conducted a well-designed double-blind controlled trial of dexamethasone in patients with primary supratentorial intracerebral hemorrhage confirmed by CT brain scan.3 This study was terminated after the second interim analysis (total of 93 patients) due to lack of a demonstrated benefit of steroids but showed an overwhelming number of clinically important adverse effects (ie, local and systemic infections, gastrointestinal bleeding, and diabetogenic effects). Recently, Desai and Prasad did a double-blind, randomized, placebo-controlled trial of dexamethasone as a pilot project of 26 patients (12 with steroids and 14 placebo) with primary supratentorial intracerebral hemorrhage.4 They found no beneficial effect of dexamethasone in terms of mortality and morbidity, but the adverse effects were more in the placebo group (not statistically significant). In conclusion, evidence-based data on clinical trials of dexamethasone in primary intracerebral hemorrhage showed no beneficial effects of steroids.
In the past, steroid treatment had been widely used in acute cerebral infarction, yet its value was controversial. Thus Norris and Hachinski in 1986 did a double-blind controlled trial of high-dose dexamethasone (480 mg over 12 days) in 113 patients within 48 hours of onset.5 Fifty-four patients received a high dose of dexamethasone and 59 matched patients were on placebo. The 2 groups did not differ significantly in death rate or quality of survivorship. There was a small difference in mortality between the 2 groups, with marginal therapeutic effect. The authors concluded that the widespread use of steroids in response to such a marginal therapeutic gain would expose large numbers of patients with stroke to more serious hazards of steroid treatment and convert patients who would otherwise have died into neurovegetative survivors, which is considered worse than death. High-dose steroid treatment was ineffective in ischemic stroke, and the data suggest that further evaluation by a large multicenter trial is not justified. In 1988, De Reuck et al analyzed 556 ischemic stroke patients.6 They found 271 patients with steroid treatment and 279 patients without steroids. Comparison of the whole group showed that the steroid-treated patients had less improvement of their disability and a higher mortality rate than the nonsteroid group. However, this study was not a double-blind controlled trial, thus the patients with steroids were more severe than the placebo group. Thus, data from previous clinical trials showed no beneficial effect of steroids for patients with acute cerebral infarction.
For practical purposes, if steroids are beneficial for acute stroke patients, there is no need to perform CT brain scan to differentiate cerebral infarction from hemorrhage. Steroids could be used in any acute stroke patients. To prove this hypothesis, Kumar et al in 1989 performed a clinical trial of dexamethasone in 40 patients with acute stroke (both infarction and hemorrhage) of <48 hours.7 Twenty-five patients were given dexamethasone and 15 patients placebo. They found no significant difference in mortality between the study and control groups (36% versus 33%). There was also no significant difference in the outcome of patients with cerebral hemorrhage or cerebral infarction whether treated with dexamethasone or not. In 2001, Ogun and Odusote performed a prospective double-blind, placebo-controlled, randomized clinical trial to determine the effectiveness of a short course of high-dose dexamethasone on mortality and neurological recovery in acute stroke patients.8 Forty patients were eligible for the study (27 were presumed to have hemorrhagic stroke and 13 patients had cerebral infarction). Of the 27 hemorrhagic stroke patients, 15 were treated with 100 mg dexamethasone immediately and 16 mg every 6 hours for 2 days, and 12 patients were given placebo. Of the 13 patients with cerebral infarction, 5 were in the steroid group and 8 in the placebo group. At 1 month, 16 patients (80%) in the dexamethasone group and 17 (85%) in the placebo group had died. In conclusion, this study failed to demonstrate any benefit of a short-term course of high-dose steroids in improving the mortality of acute stroke patients, and the use of these steroids should be discouraged.
Subarachnoid hemorrhage (SAH) accounts for 7% to 8% of all strokes and leads to early death (1 month) in about 30% to 35%.9 There is evidence that decreasing plasma volume, hyponatremia, impaired autoregulation of cerebral blood flow, and reactive inflammation are important contributing factors to the development of delayed cerebral ischemia after aneurysmal SAH. Moreover, mineralocorticoid treatment with fludrocortisone acetate prevents plasma volume depletion, and glucocorticoid treatment has an anti-inflammatory effect and results in cerebral vasodilation and improvement of cerebral blood flow after SAH. However, a beneficial effect of steroids on the clinical outcome in patients with SAH has not been proven by any well-conducted clinical trial.10
In summary, steroids have a very limited role in stroke therapy. The only definite proven indication of steroids in stroke is in patients with vasculitis. Steroid use in acute stroke, caused by either cerebral infarction or hemorrhage, has been confirmed by several well-controlled clinical trials to be of no benefit. With regard to SAH, it is still debatable whether steroids are beneficial and further studies are necessary to document their benefit.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
References
1. Zuber M. Isolated angiitis of the central nervous system. In: Bogousslavsky J, Caplan L, eds. Uncommon Causes of Stroke. Cambridge, UK: Cambridge University Press; 2001: 1–9.
2. Tellez H, Bauer RB. Dexamethasone as treatment in cerebrovascular disease, I: a controlled study in intracerebral hemorrhage. Stroke. 1973; 4: 541–546.
3. Poungvarin N, Bhoopat W, Viriyavejakul A, Rodprasert P, Buranasiri P, Sukondhabhant S, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med. 1987; 316: 1229–1233.[Abstract]
4. Desai P, Prasad K. Dexamethasone is not necessarily unsafe in primary supratentorial intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1998; 65: 799–800.
5. Norris JW, Hachinski VC. High dose steroid treatment in cerebral infarction. BMJ. 1986; 292: 21–23.
6. De Reuck J, Vandekerchove T, Bosma G, De Meulemeester K, Van Landegem W, De Waele J, et al. Steroid treatment in acute ischaemic stroke: a comparative retrospective study of 556 cases. Eur Neurol. 1988; 28: 70–72.[CrossRef][Medline] [Order article via Infotrieve]
7. Kumar N, Jain S, Maheshwari MC. Role of dexamethasone in the outcome from acute stroke. J Assoc Physicians India. 1989; 37: 315–317.[Medline] [Order article via Infotrieve]
8. Ogun SA, Odusote KA. Effectiveness of high dose dexamethasone in the treatment of acute stroke. West Afr J Med. 2001; 20: 1–6.[Medline] [Order article via Infotrieve]
9. Feigin VJL, Lawes CMM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003; 2: 43–53.[CrossRef][Medline] [Order article via Infotrieve]
10. Meyer FB, Morita A, Puumala MR, Nichols DA. Medical and surgical management of intracranial aneurysms. Mayo Clin Proc. 1995; 70: 153–172.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  P. A. Fraser Can a broken barrier be repaired? J. Physiol., June 1, 2006; 573(2): 287 - 287. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||