Delayed cerebral ischemia after SAH remains a

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1 J Neurosurg 112: , 2010 Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage Clinical article Ph i l i p p e Go m i s, M.D., 1 Je a n Pi e r r e Gr a f t i e a u x, M.D., 1 Ri c h a r d Se r c o m b e, Ph.D., 2 Do m i n i q u e He t t l e r, D.Ph a r m., 3 Be r n a r d Sc h e r p e r e e l, M.D., 4 a n d Pa s c a l Ro u s s e a u x, M.D. 4 1 Departement d Anesthésie-Réanimation et Biostatistiques, 3 Unité Médicaments et Pharmacotechnie, and 4 Service de Neurochirurgie, Centre Hospitalier Universitaire de Reims, Hôpital Maison Blanche, Reims; and 2 Laboratory of Microcirculation Research, Université Paris 7, France Object. The object of this study was to determine the efficacy of methylprednisolone in reducing symptomatic vasospasm and poor outcomes after subarachnoid hemorrhage (SAH). Methods. Ninety-five patients with proven SAH were recruited into a double-blind, placebo-controlled, randomized trial. Starting within 6 hours after angiographic diagnosis of aneurysm rupture, placebo or methylprednisolone, 16 mg/kg, was administered intravenously every day for 3 days to 46 and 49 patients, respectively. Deterioration, defined as development of a focal sign or decrease of more than 1 point on the Glasgow Coma Scale for more than 6 hours, was investigated by using clinical criteria and transcranial Doppler ultrasonography, cerebral angiography, or CT when appropriate. The end points were incidence of symptomatic vasospasm (delayed ischemic neurological deficits associated with angiographic arterial narrowing or accelerated flow on Doppler ultrasonography, or both) and outcome 1 year after entry into the study according to a simplified Rankin scale (Functional Outcome Scale [FOS]) in living patients and the Glasgow Outcome Scale in all patients included. Results. All episodes of deterioration and all living patients with a 1-year outcome were assessed by a review committee. In patients treated with methylprednisolone, the incidence of symptomatic vasospasm was 26.5% compared with 26.0% in those given placebo. Poor outcomes according to FOS were significantly reduced in the Methylprednisolone Group at 1 year of follow-up; the risk difference was 19.3% (95% CI %). The outcome was poor in 15% (6/40) of patients in the Methylprednisolone Group versus 34% (13/38) in the Placebo Group. Conclusions. A safe and simple treatment with methylprednisolone did not reduce the incidence of symptomatic vasospasm but improved ability and functional outcome at 1 year after SAH. (DOI: / JNS081377) Ke y Wo r d s methylprednisolone neuroprotection outcome subarachnoid hemorrhage inflammation Delayed cerebral ischemia after SAH remains a significant cause of death and continuing disability. 9,10,13 From the large database of patients who had participated in tirilazad trials, 30% of the 3567 patients were categorized as having an SV 17 through the presence Abbreviations used in this paper: ANOVA = analysis of variance; BI = benefit increase; DCI = delayed cerebral ischemia; DIND = delayed ischemic neurological deficit; FOS = Functional Outcome Scale; GCS = Glasgow Coma Scale; GOS = Glasgow Outcome Scale; mrs = modified Rankin Scale; NNT = number needed to treat; RD = risk difference; SAH = subarachnoid hemorrhage; SV = symptomatic vasospasm; WFNS = World Federation of Neurosurgical Societies. J Neurosurg / Volume 112 / March 2010 of DCI. Reducing the frequency and consequences of DCI will improve the outcome after SAH. Symptomatic vasospasm/dci occurs most frequently between 4 and 10 days after the hemorrhage. This time interval provides an opportunity for preventive treatment. The clinical symptoms associated with SV/DCI, although usually attributed essentially to vasospasm of the large arteries, probably include in their mechanisms an important phase of inflammation due to the presence of inflammatory cells (all categories of leukocytes), 14 inflammatory gene induction, 22 and the release of proinflammatory factors of various types. 25 Glucocorticoids possess several properties that have already stimulated investigations aimed at testing their clinical applications in SAH. 681

2 P. Gomis et al. They could be favorable in the course of SAH because of their antiinflammatory action, their proteinase-inhibiting effect (protection against smooth muscle protein degradation by calpains), 3 and their action on smooth muscle contraction by inhibition of protein kinase C. 5 Their antiinflammatory activity includes inhibition of transcription factors such as NF-κB and AP-1, 1,20 inhibition of cyclooxygenase expression, 15 and inhibition of lipid peroxidation and oxygen radical production. 18 High doses of glucocorticoids have been used in attempts to prevent vasospasm and improve outcome in experimental and clinical studies with some positive results. 6,16,27 Methylprednisolone in particular is readily available and inexpensive, and has a well-established clinical profile in steroid therapy for brain tumor. 21 In the current study, we therefore aimed to assess whether intravenous methylprednisolone treatment, started within 1 or 2 days after SAH onset, could reduce the frequency of SV and improve outcome in patients with aneurysmal SAH. This report provides statistical evidence of the clinical efficacy of methylprednisolone in significantly improving the overall outcome of patients suffering from aneurysmal SAH. Methods Patient Population This study was conducted in the neurosurgical unit of a French university hospital. The eligible patients had suffered SAH from aneurysm rupture proven by cerebral CT and angiography. Patients were included independent of time of ictus, GCS score, 26 Hunt and Hess grade, 11 Fisher grade, 8 or WFNS classification. 7 The following conditions were exclusion criteria: pregnancy; age < 18 years; major cardiopulmonary, hepatorenal, or metabolic disease; SAH without aneurysm on cerebral arteriography; and allergy to corticosteroids. In fact, with the exception of 1 pregnant woman, who was excluded, none of the patients admitted with SAH met any of the exclusion criteria, so all of the admitted patients except for that 1 woman were included in the study. Randomization Protocol This study was designed as a randomized, doubleblind, placebo-controlled trial, with adherence to the principles of the World Medical Association Declaration of Helsinki. The ethics committee of the hospital approved the protocol of the trial and informed consent was obtained from the patients or from their closest relative. The human subjects assurance number was (SHAM, Lyon, France), and this interventional study was registered as a PHRC (Program Hospitalier de Recherche Clinique) under the number 15A98. The ward pharmacy was supplied with coded packs containing 3 doses (10 ml each) of either methylprednisolone (16 mg/kg dissolved in 10 ml of distilled water) or placebo (2 g glucose dissolved in distilled water), which were assigned to eligible patients. Treatment was started within 6 hours of arteriographic diagnosis of the aneurysm. Each dose was administered intravenously over a 1 2-hour period once per day; treatment was continued for 3 days. Monitoring and Treatment Protocol Although the protocol of acute surgical treatment and acute endovascular coil embolization was standard, delayed surgery and delayed coil placement were allowed depending on the condition of the patient. All patients received intravenous nimodipine (5 10 mg/hour) according to blood pressure tolerance followed by oral nimodipine at a dose of 60 mg every 4 hours for an overall period of 3 weeks. The temporary use of clonidine, labetalol, or urapidil to control hypertension as well as the use of hypertensionhypervolemia therapy and other treatments was left to the discretion of the surgeon and the intensivist in charge. On admission and immediately before surgical clipping or coil embolization, the severity of SAH was graded according to the GCS and Hunt and Hess, WFNS, and Fisher scales. Neurological observations, including those made according to the Hunt and Hess scale, the GCS, and the WFNS scale, were recorded every day until Day 21. The severity of motor paresis and aphasia was scored according to a motor paresis scale, in which the function of each limb was classified into 4 categories by the use of an objective scale. Deterioration of the neurological condition during the course of treatment, objectively defined as an alteration of any of the GCS or motor paresis scale scores by more than 1 point for at least 6 hours, was regarded as a DIND when other possible causes, such as brain damage inflicted at surgery, rebleeding, or thromboembolic strokes related to the endovascular coiling procedure, seizure, infection, cardiopulmonary dysfunction, hydrocephalus, electrolyte imbalance, or metabolic disorders, could be excluded. To avoid unnecessary interventions, postoperative radiological investigations such as angiography were not performed unless diagnostically necessary. All patients were required to undergo repeat CT scans at approximately Day 14 and Day 30, in addition to those obtained on exacerbation of neurological deficits. The findings of each CT scan and the presumed cause of the postoperative appearance of low-density areas were documented according to the surgeon s and radiologist s judgment. Patients were also required to undergo detailed neurological assessment at 1 and 3 months and 1 year post-sah. The objective evaluation of the outcome at 1 year was assessed by means of a simplified version of the mrs, which is a 6-point handicap scale with a strong accent on physical abilities and activities of daily living, 23 and by means of the GOS 12 (in which the outcome is divided into 5 categories including death). Our simplified mrs, the Functional Outcome Scale (FOS), combined into the same grade the first 2 mrs grades (namely, no symptom and minor symptoms with no restrictions of lifestyle; see Table 3) because of the difficulty of distinguishing these first 2 grades without neuropsychological assessment. 9,10 Prior to key code breaking, the review committee, composed of 6 senior neurosurgeons and the controller, checked the eligibility of each patient, the appropriateness of each surgeon s judgment regarding the occurrence of DINDs, the presumed cause of low-density areas in the CT scans, and the outcome in view of the data documented in each protocol. End Points The primary end points were the occurrence, between 4 and 10 days after SAH onset, of SV and new ischemic 682 J Neurosurg / Volume 112 / March 2010

3 Methylprednisolone in subarachnoid hemorrhage area(s) on CT scan. Symptomatic vasospasm was defined as the occurrence of DIND associated with objective vasospasm; DINDs were defined as new motor paresis or new worsening of the consciousness level and as any new clinical neurological abnormalities not explained by other possible causes occurring between 4 and 10 days after SAH onset; and objective vasospasm was defined as the occurrence of either angiographic narrowing or accelerated flow on transcranial Doppler, or both. A new ischemic area following vasospasm was defined as any new low-density zone on CT scan not explained by other causes of focal cerebral ischemia between 4 and 10 days after SAH onset. The secondary end points were improvement at 1 year follow-up of both the overall outcome measured by the FOS and GOS, and the severity of DINDs (clinically assessed as regressive or persistent). In addition, we explored some biological characteristics related to inflammatory processes. Statistical Analysis In conjunction with the results of preceding trials that showed an incidence of ~ 40% of DINDs in placebo-treated patients, 2 we expected that the treatment with methylprednisolone would reduce such incidence by nearly 50%. Power calculation based on that assumption led the trial to recruit 46 patients per group to obtain a power of 80% at a probability level of 0.05 to detect a 50% reduction in the incidence of DINDs. Comparisons of demographic data, clinical variations, and radiological and clinical assessments between groups were performed by the chi-square test, Fisher exact test, Student t-test, and Mann-Whitney U- test. The results of the laboratory tests were evaluated by a 2-way ANOVA for repeated measures. All tests used a significance level of Risk difference (RD) and benefit increase (BI) were calculated as the arithmetic difference in event rates between experimental (experimental event rate [EER]) and control (control event rate [CER]) patients: RD = EER CER. According to evidence-based medicine rules, RD is used when the experimental treatment reduces the risk for a bad event and BI is used when the experimental treatment increases the probability of a good event. Number needed to treat (NNT) is calculated as 1/RD. Results Recruitment of Patients During a period of 2.5 years, 95 patients (Methylprednisolone 49, Placebo 46) were enrolled in the trial. One patient assigned to the Methylprednisolone Group and 3 assigned to the Placebo Group had no surgical or endovascular treatment of their aneurysms because of early death: 2 of these patients suffered recurrent hemorrhages prior to treatment (rebleeding), 1 patient died early after the first hemorrhage, and 1 patient with acute renal failure, acute respiratory failure, and hypoglycemia, was regarded as not treatable. These 4 patients were regarded as not adapted to the study and were excluded from the on-treatment analysis Comparability of s The baseline clinical data and, in particular, the percentage of patients whose Hunt and Hess grades at admission J Neurosurg / Volume 112 / March 2010 were III V did not differ significantly between the groups (Table 1), although there was a slight tendency toward more severe Hunt and Hess grades in the Placebo Group. There was little difference between the 2 groups in the rates of aneurysm clipping and detachable coil occlusion. Prior to Day 4, ~ 97% of all patients underwent aneurysm occlusion. Fourteen patients (28.5%) in the Methylprednisolone Group and 12 (26%) in the Placebo Group required care in the intensive care unit. These patients were treated with mild, induced hypervolemia as a routine prophylactic measure against vasospasm, and hypertension-hypervolemia was induced as a therapy after the occurrence of DINDs. Ventricular CSF drainage was used when required. The use of antihypertensive drugs (mostly urapidil) and the medical events observed were similar in the 2 groups. Incidence of Vasospasm, DINDs, and Low-Density Areas on CT All patients were classified according to the occurrence between 4 and 10 days after SAH of DIND, objective vasospasm, and low-density areas on CT scans. The number of patients in whom these events occurred was verified by the review committee prior to key code breaking. In 3 patients in the Methylprednisolone Group and 5 in the Placebo Group, the occurrence of signs of cerebral ischemia that could be attributed to SAH was found to be impossible to assess due to ischemic events occurring during either surgical clipping (bad clip positioning) or endovascular occlusion (thrombosis requiring emergency thrombolysis) (Table 1; see footnotes to Tables 1 and 2 for details). These 8 patients as well as the 4 who died soon after SAH were all excluded from the on-treatment analysis. There was no statistically significant intergroup difference in the incidence of either SV or new hypodensities on CT in either the intention to treat or the on-treatment analysis (Table 2). Outcome Scores The FOS scores assessing ability to engage in activities of daily life in patients alive 1 year after SAH were significantly improved in the Methylprednisolone Group as compared with the Placebo Group (p = 0.025, Table 3). The percentage of patients with good functional outcome (FOS 1 2) was 65.7% in the Placebo Group; this figure was increased to 85% in the Methylprednisolone Group, providing a significant 19.3% RD (95% CI %, NNT: 6, [95% CI ]), owing to a marked decrease in the occurrence of FOS 4 5 scores in the Methylprednisolone Group. Overall outcome measurement according to the GOS score was also used because of its status as a classical standard, allowing comparison with other studies. Comparison of GOS scores revealed a near-significant difference between the 2 groups (p = 0.08, Table 3), but this methodology includes patients who died early. Between 3 and 6 months of follow-up, neurological deficits/symptoms in the subgroup of patients with SV were assessed and classified as permanent or regressive deficits. The incidence of regressive neurological deficits increased to 84.6% in the Methylprednisolone Group compared with 75% in the Placebo Group (Table 3; RD 9.6%, 95% CI 21.7 to 41.0%). These findings strongly suggest that methylprednisolone had some neuroprotective properties. 683

4 P. Gomis et al. TABLE 1: Baseline clinical data* Parameter Subgroup Analysis of Outcome Methylprednisolone Placebo p Value no. of patients female sex 30 (61.2) 30 (65.2) 0.6 age in yrs (mean ± SD) 50.8 ± ± bo dy weight in kg (mean 66.2 ± ± ± SD) de lay at admission in 1.5 ± ± days (mean ± SD) systolic BP (mm Hg) ± ± treated hypertension 16 (32.6) 13 (28.2) 0.7 treated diabetes 3 (6.1) 1 (2.1) 0.5 location of 1st aneurysm ACoA 17 (34.6) 17 (36.9) 0.7 MCA 15 (30.6) 15 (32.6) ICA 12 (24.4) 12 (26.0) other 5 (10) 2 (4.2) pr esence of additional 5 (10.2) 5 (10.8) 0.9 aneurysm(s) H & H grade I 10 (20.4) 7 (15.2) 0.7 II 22 (44.9) 18 (39.1) III 11 (22.4) 12 (26.0) IV 4 (8.1) 5 (10.8) V 2 (4.0) 4 (8.7) I & II 32 (65.3) 25 (54.3) 0.3 III V 17 (34.7) 21 (45.7) WFNS grade I 22 (44.9) 21 (45.6) 0.1 II 13 (26.5) 7 (15.2) III 1 (2.0) 6 (13.0) IV 11 (22.4) 7 (15.2) V 2 (4.0) 5 (10.8) I & II 35 (71.4) 28 (60.9) 0.3 III V 14 (28.6) 18 (39.1) GCS score (44.8) 23 (50.0) (44.8) 15 (32.6) 8 5 (10.2) 8 (17.4) Fisher grade 1 4 (8.1) 5 (10.8) (24.4) 15 (32.6) 3 18 (36.7) 13 (28.2) 4 15 (30.6) 13 (28.2) (continued) TABLE 1: Baseline clinical data* (continued) Parameter Methylprednisolone Placebo p Value recurrent bleeding 4 (8.3) 6 (13.0) 0.4 treatment clipping 24 (48.9) 19 (41.3) 0.9 coiling 23 (46.9) 23 (50.0) coiling & clipping 1 (2.0) 1 (2.1) no treatment** 1 (2.0) 3 (6.5) ischemic events 3 (6.1) 5 (10.8) 0.4 * Values represent numbers of patients (%) unless otherwise indicated. Abbreviations: ACoA = anterior communicating artery; H & H = Hunt and Hess; ICA = internal carotid artery; MCA = middle cerebral artery. Chi-square test. Student t-test. Mann-Whitney U-test. Two patients underwent secondary surgical clipping because of failure of endovascular coil embolization. ** Four patients had no treatment because of early death (2 rebleeding, 1 early death after first hemorrhage, 1 not treatable because of chronic renal failure, respiratory insufficiency, and hypoglycemia). Ischemic events during surgical clipping and endovascular coil embolization. Fisher exact test. To further analyze drug efficacy at each end point, we performed a layered analysis based on the Hunt and Hess grades at admission (Table 4). The effect of methylprednisolone was always more obvious in patients with Hunt and Hess grades of III V, although statistically nonsignificant. Among patients with Hunt and Hess Grades III V, the RD of SV in the Methylprednisolone Group was 25% (p = 0.07, 95 CI 0.6 to 50.6%), and the BIs of a good FOS result (defined as an FOS score of 1 or 2) and a good GOS result (defined as a GOS score of 1 or 2) were, respectively, 6.6% (95% CI 32.8 to 46.1%) and 15.9% (95% CI 15.5 to 47.52%) in patients treated with methylprednisolone. Laboratory Data, Adverse Reactions, and Mortality Rate The laboratory data showed a significant difference in mean values from Day 0 to Day 9 between the 2 groups for C reactive protein and fibrinogenemia (p = 0.02 and p = 0.04, respectively). There were significant increases in the C reactive protein level and fibrinogenemia in the Placebo Group but not in the Methylprednisolone Group from Day 0 to Day 9 (within-subjects analysis: p = and p < 0.001, respectively). These differences are in accordance with the known antiinflammatory properties of methylprednisolone (Fig. 1). Prevalence of diabetes mellitus, use of insulin, and rates of infection were similar in the 2 groups. Although the use of antihypertensive drugs was higher in the Methylprednisolone Group, the increase was not statistically significant; this tendency suggests a longer duration of arterial hypertension in the patients treated with methylprednisolone. The overall mortality rates in the Placebo and the Methylprednisolone Groups were 17 and 18%, respectively (Table 3). No causal relationship between treatment and causes of death was suspected. 684 J Neurosurg / Volume 112 / March 2010

5 Methylprednisolone in subarachnoid hemorrhage TABLE 2: Incidence of symptomatic vasospasm and hypodensities on CT 4 10 days after aneurysm rupture* Methylprednisolone Analysis & Variable Placebo p Value intention-to-treat analysis no. of patients sy mptomatic vasospasm 13 (26.5) 12 (26.0) 0.9 hypodensities on CT 14 (28.5) 12 (26.0) 0.7 on-treatment analysis no. of patients sy mptomatic vasospasm 13 (28.8) 12 (31.5) 0.7 hypodensities on CT 11 (24.4) 7 (18.4) 0.8 su bgroup analysis of ontreatment analysis H & H Grades I & II sy mptomatic vaso- 12 (41.3) 7 (31.8) 0.4 spasm hypodensities on CT 6 (20.7) 4 (18.2) 0.8 H & H Grades III V sy mptomatic vaso- 1 (6.2) 5 (31.2) 0.07 spasm hypodensities on CT 5 (31.3) 3 (18.8) 0.4 Discussion Methylprednisolone in very high doses acts as a free radical scavenger and is used in the treatment of spinal cord injury. 4 The advantage of methylprednisolone over hydrocortisone or prednisolone is its negligible mineralocorticoid effect. Despite some favorable experimental results, 19 only one clinical study of high-dose methylprednisolone in the treatment of SAH in humans has been reported. 6 The patients showed a significantly better clinical result as well as a reduction of the incidence of vasospasm. This study was not randomized, and only patients at high risk for vasospasm were included, so that it is difficult to draw any conclusions about clinical implications. By analogy with steroid therapy in brain tumors, and in light of the results so obtained and some positive results from experimental studies, patients with SAH have been given dexamethasone or methylprednisolone routinely because of the suspected, though not formally demonstrated, favorable effects of these drugs. 24 Our study is the first randomized, placebo-controlled and double-blind clinical study carried out in an attempt to clarify 1) the efficacy and safety of methylprednisolone in preventing SV, and 2) its capacity to improve the overall outcome of SAH in human patients. J Neurosurg / Volume 112 / March 2010 TABLE 3: Outcomes Variable * Symptomatic vasospasm was defined by neurological worsening (DIND) associated with angiographic vasospasm or accelerated flow on transcranial Doppler ultrasonography. Chi-square test. Twelve patients were excluded from the on-treatment (and subgroup) analysis: 4 nontreated patients and 8 patients who experienced ischemic events during surgical clip placement or endovascular coil embolization. Methylprednisolone Placebo p Value FOS at 12 mos* no. of patients (0, 1 ) no symptoms; minor 17 (42.5) 18 (47.3) 0.02 symptoms, no restrictions of lifestyle (2) some restrictions, no help 17 (42.5) 7 (18.4) needed (3) help needed, not completely 6 (15.0) 6 (15.7) independent (4) dependent, no constant 0 (0.0) 5 (13.1) attention required (5) completely dependent 0 (0.0) 2 (5.2) GOS at 12 mos no. of patients (1) good recovery 34 (69.3) 25 (54.3) 0.08 (2) moderately disabled 6 (12.2) 6 (13.0) (3) severely disabled 0 (0.0) 5 (10.8) (4) vegetative 0 (0.0) 2 (4.3) (5) dead 9 (18.3) 8 (17.3) DIND at 3 mos no. of patients permanent 2 (15.3) 3 (25.0) 0.5 regressive 11 (84.6) 9 (75.0) * The FOS (Functional Outcome Scale) is a simplified version of the mrs, in which mrs levels 0 and 1 are combined. Chi-square test. Effects of Methylprednisolone on SV, DINDs, and Low-Density Areas on CT This study failed to show a beneficial effect of methylprednisolone on the incidences of either SVs or low-density areas on CT scans at 4 10 days following SAH. The incidence of SV in the 2 groups was 26%, which compares well with that reported in a recent series, 17 suggesting that our patients had the same risk factors for SV as those reported on previously. The incidence of low-density areas on CT scans was almost the same in the 2 groups (28 vs 26%). These results do not necessarily imply that methylprednisolone did not exert any brain-protective action. The 3-month follow-up results of SV-patient subgroups suggest a beneficial effect of methylprednisolone on the regression and improvement of the neurological deficits that emerged at the time of vasospasm and, although it was not significant, we observed a 9.6% BI of neurological improvement in patients treated with methylprednisolone (Table 3). An unexpected result was an almost significantly reduced incidence of SV for methylprednisolone treatment in the Hunt and Hess Grade III V subgroup (p = 0.07), but not in the Grades I and II subgroup (Table 2). This discrepancy is a regular finding in published studies on the prevention of vasospasm. 2 The reason for this 685

6 P. Gomis et al. TABLE 4: Number of patients with good outcome at 12 months stratified by initial severity of SAH* Outcome Scale Methylprednisolone Placebo p Value FOS 1 & 2 H & H Grades I & II 28 (93.3) 17 (73.9) 0.05 H & H Grades III V 6 (60.0) 8 (53.3) 0.7 GOS 1 & 2 H & H Grades I & II 30 (93.7) 22 (88.0) 0.4 H & H Grades III V 10 (58.8) 9 (42.8) 0.3 * Twelve-month outcome scores were obtained using both the FOS and GOS: FOS scores were available for 40 patients in the Methylprednisolone Group and 38 in the Placebo Group, whereas GOS scores were available for 49 patients in the Methylprednisolone Group and 46 in the Placebo Group. Data reported in this table represent the numbers of patients with the specified admission Hunt and Hess scores who had good outcomes based on the FOS and GOS scores at 12 months after onset of SAH, with numbers in parentheses representing the percentage of the number of patients in that Hunt and Hess grade category who had FOS or GOS scores of 1 or 2. Chi-square test. is unclear, but a plausible explanation would be as follows: The insult to the brain and the arteries inflicted by SAH is generally greater in patients with Hunt and Hess Grades III V. This is probably also true with regard to inflammatory reactions and oxidant stress. Thus, it seems likely that the inflammatory reactions that are activated immediately after SAH are substantially more severe in higher grade SAH. This would explain why the beneficial action of methylprednisolone was conspicuous only in the patients with Hunt and Hess Grades III V. Nonetheless, this does not mean that patients with Grades I and II did not sustain any inflammatory reaction/oxidative brain damage at all. In these patients, SV occurred with similar frequency in the Methylprednisolone Group and the Placebo Group, although SV was much more attenuated and was associated with a significantly better outcome (p = 0.05) in the Methylprednisolone Group, as disclosed by the subgroup analysis of outcome (Table 4). Fig. 1. Graphs comparing temperature, C reactive protein, fibrinogenemia, and white blood cell count between Methylprednisolone and Placebo Groups from the day of admission for SAH (Day 0) to Day 9 after admission (mean ± SD). Dots indicate Methylprednisolone Group values. Stars indicate Placebo Group values. Probability values are given for between-groups statistical significance (repeated measures ANOVA). Effect of Methylprednisolone on Functional Outcome The overall outcome assessed by the FOS, a simplified version of the mrs, in patients still alive at 1 year after SAH, was significantly improved in the Methylprednisolone Group (p = 0.025), and a substantial RD of 19.3% was observed. The GOS scores also revealed a near-significant improvement. Population-based studies reporting on functional outcome showed that 10 20% of all SAH patients become disabled with loss of independence. 9,10 In the present study, the outcome measures were assessed at 1 year, but not at the classical 3-month follow-up time. The lesson from population-based studies reporting on functional outcome is that the improvement in the first year and a half shows that long-term follow-up is essential in evaluation of the effectiveness of new treatment strategies with respect to functional outcome after SAH. Recovery to an independent state does not necessarily mean that outcome is good. In a study on quality of life after SAH, only 19% of patients who were independent 4 months after the hemorrhage had no significant reduction in quality of life. 10 Reevaluation of this cohort at 18 months showed that outcome had improved considerably in terms of handicap and quality of life, but that still only 31% had no reduction in the quality of life. All in all, only small minorities of all patients with SAH have a truly good outcome. In the present study the differences in outcome between the 2 groups were mainly in the patients with an FOS score of 2 (some restriction in lifestyle); the percentage of patients with an FOS score of 2 was greatly increased in the Methylprednisolone Group, thus reducing the number of patients with an FOS score of 4 or 5. In fact, there were no patients in the Methylpredni- 686 J Neurosurg / Volume 112 / March 2010

7 Methylprednisolone in subarachnoid hemorrhage solone Group who had an FOS score of 4 or 5. All patients had been reviewed by surgeons in charge because it was known that the ability of a questionnaire to reliably differentiate moderate from moderately severe functional disability is uncertain. In the present study, activities of daily life, professional activities, and professional redirections were assessed by interview of the patients or their close relatives. The double-blinded procedure was maintained through 1 year, and only the last clinical assessment, using the FOS and GOS scores at 1 year, was used in the statistical analysis. Although the reduction in the incidence of bad outcome may be thought to represent some antivasospastic action of methylprednisolone, our results did not confirm this hypothesis angiographically. As previously stated, both antivasospastic and brain-protective actions are surmised to contribute to the amelioration of DINDs, but discrimination between the antivasospastic and brainprotective actions of methylprednisolone was not an object of the present trial. The mortality rate at 1 year after SAH was similar in the 2 groups in our study. If death scores were excluded, the distribution of patients with respect to GOS scores was similar to that with respect to FOS scores in the Placebo Group. The overall outcome of patients in the Placebo Group in the present trial compares well to published results. 13 However, it should be pointed out that the percentage of patients with Hunt and Hess scores of III V was much smaller in the cited study than in the present trial. The similarity in the overall outcome, despite the considerable difference in the percentage of patients with severe SAH, can probably be attributed to recent progress in the medical and surgical treatment of patients with SAH. Thus, it is of considerable interest that the improvement in the overall outcome induced by methylprednisolone attained a statistically significant level (or near-significant level with respect to the GOS-based analysis) in the present trial. The result of stratified (subgroup) analysis demonstrates that overall outcome greatly depends on SAH grade at admission. Although the difference between the 2 groups did not attain a statistically significant level because of small sample size, the beneficial effect of methylprednisolone was still manifest, as explained below. In the subgroup of patients with Hunt and Hess grades of I and II, methylprednisolone treatment significantly increased the percentage of good outcomes measured by FOS (93.3 vs 73.9% in the placebo group, p = 0.05) with a 19.4% RD (95% CI %) at 1 year (Table 4). Such a result suggests that, although it did not reduce the incidence of SV (41.3% in the Methylprednisolone Group vs 31.8% in the Placebo Group, Table 2), methylprednisolone attenuated the severity of SV in patients with Hunt and Hess grades of I and II, which may also be stated as an improvement of the patients tolerance to SV. This is apparently indicative of a marked brain-protective action of methylprednisolone against ischemic brain damage resulting from SV. In the Hunt and Hess Grade III V subgroup, at 1 year after SAH the percentages of patients with good FOS and good GOS scores were also greater in the Methylprednisolone Group than in the Placebo Group; in addition there was a near-significant difference in the incidence of SV (6.2% in the Methylprednisolone Group vs 31.2% in the Placebo J Neurosurg / Volume 112 / March 2010 Group). The above results suggest that methylprednisolone also exerted a beneficial effect in patients with Hunt and Hess grades of III V. Although the results of the above stratified analyses must be interpreted with caution, it may at least be stated that the occurrence of SV was generally associated with poor outcome, and that the amelioration of SV due to methylprednisolone treatment was associated with a marked improvement in outcome. Biological Effects As shown in Results, the average dose of 1 g methylprednisolone every day for 3 days produced a significant 9-day decrease in C reactive protein and fibrinogen levels in accordance with the known, long-lasting, antiinflammatory properties of methylprednisolone. We surmise that these antiinflammatory effects could explain the improvement observed in the present study. Moreover, there were no side effects suspected to be due to methylprednisolone except for the increased occurrence of hypertension needing additional treatment. Conclusions Symptomatic vasospasm, defined as DINDs associated with vasospasm, develops several days after SAH, thus allowing for prophylactic drug administration. In the present placebo-controlled trial, a 3-day period of methylprednisolone treatment did not significantly reduce the overall incidence of SV, but it led to a marked significant improvement in the FOS at 1 year after SAH. Although the improvement in the GOS score at 1 year did not quite attain significance, the above beneficial effects, together with the remarkable safety and simplicity of methylprednisolone treatment, strongly support its potential usefulness in SAH. The present trial did not permit discrimination between antivasospastic and brain-protective actions of methylprednisolone, but the data, in particular in the subgroup analysis, are compatible with the contribution of both mechanisms to its beneficial action. Further investigation of the potential benefits of antiinflammatory therapy, in terms of its feasibility in the treatment of SAH as well as its mechanism of action, appears to be fully warranted. Disclosure Financial support for this study was provided by the CHU (Centre Hospitalier Universitaire) de Reims (PHRC 15A98). References 1. Almawi WY, Melemedjian OK: Negative regulation of nuclear factor-kappa B activation and function by glucocorticoids. 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