Critical review of the evidence for each question
4. Preventing cerebral ischaemia How to prevent delayed cerebral ischaemia
The main results are summarized in Table 14.2.
Calcium antagonists
Arterial narrowing (‘vasospasm’) is one of the factors involved in the complex pathogenesis of delayed cerebral ischaemia. Calcium antagonists have been used because they inhibit the contractile properties of smooth muscle cells, particularly those in cerebral arteries, and also because they may, to some extent, protect neurones against the dele-terious effect of calcium influx after ischaemic damage.
A Cochrane Review of calcium antagonists in SAH included 12 trials, totalling 2844 patients with SAH (1396 in the treat-ment group and 1448 in the control group) [65]. The drugs analysed were: nimodipine (eight trials, 1574 patients), nicardipine (two trials, 954 patients), AT877 (one trial, 276 patients) and magnesium (one trial, 40 patients). Overall, calcium antagonists reduced the risk of poor outcome: RR 0.82 (95% CI 0.72–0.93); the absolute risk reduction was 5.1%, the corresponding number of patients needed to treat Chapter 14: Aneurysmal subarachnoid haemorrhage 131
Table 14.2 Treatment for preventing ischaemia.
Type of Intervention Outcome Number of Control Relative risk Absolute risk Comment study (follow-up time) patients group risk (95% CI) reduction
(reference) (number (range) (95% CI)
of trials)
SR Calcium Death or dependency 2507 30% 0.82 5% Calcium antagonists better
[65] antagonists (3/6 months) (8) (13–69) (0.72–0.93) (2–9) Mainly nimodipine 60 mg
versus control orally every 4 h
Heterogeneity
Secondary ischaemia 2187 40% 0.67 13% Calcium antagonists better
(11) (17–65) (0.60–0.76) (9–17)
RCT Magnesium Death or dependency 283 35% 0.77 8% Magnesium better
[73] versus placebo (3 months) (1) (0.54–1.09) (ns)
SR Volume Death or severe 114 17% 1.00 0%
[89] expansion disability (2) (11–19) (0.45–2.22) (ns)
versus control Secondary ischaemia 114 21% 1.08 2% Volume expansion worse
(2) (19–22) (0.54–2.16) (ns)
SR Intracisternal Death or disability 652 24% 9.5% Only one RCT
[95] fibrinolysis (9) (4.2–14.8)
versus control Secondary ischaemia 652 30% 14.4%
(9) (6.5–22.5)
SR: systematic review; RCT: randomized controlled trial; CI: confidence intervals; ns: not statistically significant.
to prevent a single poor outcome event was [20]. For oral nimodipine alone the RR was 0.70 (0.58–0.84). The RR of death on treatment with calcium antagonists was 0.90 (95%
CI 0.76–1.07), that of clinical signs of secondary ischaemia 0.67 (95% CI 0.60–0.76), and that of CT or MR confirmed infarction 0.80 (95% CI 0.71–0.89).
In brief, the risk reduction for ‘poor outcome’ is statistically robust, but depends mainly on trials with oral nimodipine, and especially on a single large trial, in which patients received 60 mg orally every 4 h, for 3 weeks [66]. The intermediate factors through which nimodipine exerts its beneficial effect after aneurysmal SAH remain uncertain. Interestingly, sev-eral studies with nimodipine found there was no difference between treated patients and controls with regard to the fre-quency of arterial narrowing on a repeat angiogram [66–68].
If the patient is unable to swallow, the tablets should be crushed and washed down a nasogastric tube with normal saline. Intravenous administration is advocated by the producer but there is no evidence from trials that intravenous adminis-tration of nimodipine is beneficial [65]. Moreover, intravenous administration of nicardipine does not improve outcome [65].
The lack of effectiveness of intravenous nicardipine is probably explained by the increased risk of hypotension, which also occurs after intravenous administration of nimodipine [69].
Hypotension may even be a problem even if nimodipine is given orally. If no blood loss has occurred or any other cause for hypotension is found, the dose of nimodipine can be at first halved (to 60 mg tds) and subsequently discontinued if the blood pressure does not come back to initial levels.
Magnesium sulphate
Hypomagnesaemia occurs in more than 50% of patients with SAH and is associated with the occurrence of delayed cerebral ischaemia and poor outcome [70]. Its administra-tion reduced infarct volume after experimental SAH in rats [71]. Its putative modes of action consist in inhibition of the release of excitatory amino acids and blockade of the N-methyl-D-aspartate-glutamate receptor. Magnesium is also a non-competitive antagonist of voltage-dependent calcium channels and it has a dilatatory effect on cerebral arteries.
Two controlled trials have studied the efficacy of magne-sium sulphate in preventing delayed cerebral ischaemia and poor outcome. The smallest one, including 40 patients and necessarily inconclusive [72], was provisionally included in the most recent Cochrane Review of calcium antagonists.
A larger trial included 283 patients but was still intended as a preliminary (‘phase II’) study, with delayed cerebral ischaemia and not overall outcome as primary measure of efficacy [73]. Magnesium treatment consisting of a continu-ous intravencontinu-ous dose of 64 mmol/L per day reduced the risk of delayed cerebral ischaemia (defined as the occurrence of a new hypodense lesion on CT, compatible with clinical fea-tures of delayed cerebral ischaemia, analysed according to the ‘on-treatment principle’) by 34% (hazard ratio 0.66, 95%
CI 0.38–1.14). After 3 months, the risk reduction for poor outcome (analysed according to the ‘intention-to-treat’
principle) was 23% (risk ratio 0.77, 95% CI 0.54–1.09). At that time, 18 patients in the treatment group and 6 in the placebo group had an excellent outcome (risk ratio 3.4, 95%
CI 1.3–8.9). A phase III trial is now ongoing.
Aspirin and other antithrombotic agents
Several studies have found that blood platelets are activated from day three after SAH. This was mostly inferred from increased levels of thromboxane B2, the stable metabolite of thromboxane A2, which promotes platelet aggregation and vasoconstriction [74,75].
Two small trials with aspirin have been performed in patients with SAH, and three with antiplatelet agents other than aspirin. In a systematic overview of these five trials, the rate of delayed cerebral ischaemia (reported in only three of the five studies) was decreased (RR 0.65, 95% CI 0.47–0.89), but poor outcome was not significantly different between patients treated with antiplatelet agents and controls [76]. A still unpublished trial aiming to include 200 patients did not confirm a beneficial effect of aspirin (van den Bergh, for the MASH study group). The trial was prematurely stopped after the second interim analysis, because by then the chances of a positive effect were negligible. Aspirin did indeed not reduce the risk of delayed cerebral ischaemia (HR 1.83, 95% CI 0.85–3.9). The RR reduction for poor outcome was 21% (RR 0.79, 95% CI 0.38–1.6). It is unknown whether other platelet aggregation inhibitors are more beneficial.
A low-molecular-weight heparinoid, enoxaparin (40 mg subcutaneously once a day after aneurysm occlusion), was tested in a trial of 170 patients [37]; the treatment did not improve outcome and was associated with haemorrhages in 4 of 85 patients in the experimental group.
Statins
HMG-CoA reductase inhibitors or statins are primarily used because these drugs lower LDL-cholesterol levels, but they also have anti-inflammatory, immunomodulatory, antithrombotic and vascular effects. It has often been claimed that these
‘pleiotropic effects’ contribute to cardiovascular risk reduc-tion beyond that expected from LDL-cholesterol reducreduc-tion alone, but this is not confirmed by a meta-regression analy-sis of clinical trials [77].
In patients with SAH, two controlled trials have been per-formed so far. One included only 39 patients and found that 80 mg simvastatin given within 48 h after the ictus reduced
‘vasospasm’ (undefined) [78], the other enrolled 80 patients and found that 40 mg pravastatin given within 72 h reduced angiographic vasospasm and impairment of autoregulatory responses as well as vasospasm-related ischaemic compli-cations [79]. On the other hand, an observational study found that previous use of statins increased the risk of angio-graphic vasospasm though not that of associated ischaemic 132 Part 3: Neurological diseases
complications [80]. In conclusion, the evidence for a benefi-cial effect of statins after SAH is still rather meagre.
Free radical scavengers
Tirilazad mesylate, a 21-aminosteroid free radical scavenger, has so far failed to show consistent improvement of out-come in four randomized controlled trials, with a total of more than 3500 patients [81–84]. The only beneficial effect on overall outcome was seen in a single subgroup of a single trial, that is, those treated with 6 mg/kg/day (two other groups received 0.2 mg/kg/day or 2 mg/kg/day) [81]. Delayed cere-bral ischaemia was reduced in only one of the four trials, although there was no effect on overall outcome [83]. A for-mal overview of the complete clinical evidence is not yet available, but the case for the drug seems weak, for any dose and either sex.
A single trial with another hydroxyl radical scavenger, N-propylenedinicotinamide (nicaraven) in 162 patients, showed a decreased rate of delayed cerebral ischaemia but not of poor outcome at 3 months after SAH [85]. Curiously enough, the reverse was found a trial of 286 patients with ebselen, a seleno-organic compound with antioxidant activ-ity through a glutathione peroxidase-like action: improved outcome at 3 months after SAH, but without any reduction in the frequency of delayed ischaemia [86].
Other drugs
Nizofenone, an anionic channel blocker believed to inhibit glutamate release, was studied in a randomized trial of 100 patients, of whom only 90 were included in the analysis [87];
the occurrence of angiographic vasospasm was not influ-enced by the drug, poor outcome only in a complicated sub-group analysis.
The endothelin A/B receptor antagonist TAK-044 was tested in a multicentre phase II trial (influence on the occur-rence of delayed ischaemic deficits) in 420 patients; there was a non-significant risk reduction of 0.8 (95% CI 0.61–
1.06) [88].
Increasing plasma volume
The usefulness of circulatory volume expansion to prevent delayed ischaemia after SAH was assessed in a recent Cochrane Review [89]. Three trials were identified. One truly random-ized trial and one quasi-randomrandom-ized trial with comparable baseline characteristics for both groups were included in the analyses. Preventive volume expansion therapy did not improve outcome (RR 1.0, 95% CI 0.5–2.2), nor the occur-rence of secondary ischaemia (RR 1.1, 95% CI 0.5–2.2), but tended to increase the rate of complications (RR 1.8, 95% CI 0.9–3.7). In another quasi-randomized trial, outcome assess-ment was done only at the day of operation (7–10 days after SAH). In the period before operation, treatment resulted in a reduction of secondary ischaemia (RR 0.33, 95% CI
0.11–0.99) and case fatality (RR 0.20, 95% CI 0.07–1.2). In conclusion, the effects of preventive volume expansion therapy have been studied properly in only two trials of patients with aneurysmal SAH, with very small numbers, and there is no sound evidence for the use of volume expan-sion therapy in patients with aneurysmal SAH.
Because of its mineralocorticoid activity (reabsorption of sodium in the distal tubules of the kidney) fludrocortisone might, in theory, prevent a negative sodium balance, hypo-volaemia and ischaemic complications [90]. A randomized study in which 91 patients with SAH were entered soon after admission showed that fludrocortisone acetate indeed significantly reduced natriuresis in the first 6 days after the haemorrhage. Reductions in the occurrence of plasma vol-ume depletion and of ischaemic complications were not stat-istically significant [91]. These results were confirmed by a smaller trial in 30 patients [92]. Finally, also hydrocortisone was shown in a small trial (28 patients) with an explanatory design to prevent hyponatraemia and a drop in central venous pressure [93]. The evidence from these studies is insufficiently conclusive to warrant routine administration of fludrocortisone to all patients with SAH.
Cisternal drainage and intracisternal fibrinolysis On the assumption that vasospasm increases the risk of delayed cerebral ischaemia and that extravasated blood induces vasospasm, removal of the subarachnoid blood by drainage or fibrinolysis has been studied in several trials. In a comparison of two cohorts the patients treated with lum-bar drainage of CSF had less often cerebral infarction and more often returned home than patients with no lumbar drainage [94]. A more aggressive method in removing sub-arachnoid blood is intracisternal fibrinolysis. A meta-analysis on this treatment strategy included 9 trials of which only one was randomized [95]. Pooled results demonstrated ben-eficial effects of treatment, with absolute risk reductions of 14.4% (95% CI 6.5–22.5%, P 0.001) for delayed cerebral ischaemia, and 9.5% (95% CI 4.2–14.8%, P 0.01) for poor clinical outcome. There was no difference between the type of thrombolytic agent used (tissue plasminogen activa-tor versus urokinase) or the method of administration (intra-operative versus post(intra-operative). However, the results of the analysis are limited by the predominance of non-random-ized studies. A open, randomnon-random-ized, controlled trial not yet included in the meta-analysis studied the effect of fibrinoly-sis in 110 patients treated with endovascular coiling [96].
Urokinase was administered into the cisterna magna through a microcatheter inserted via a lumbar puncture. The primary outcome measure was clinical vasospasm, defined as clinical deterioration combined with evidence of vasospasm on angiography. Treatment resulted in a statistical significant reduction of this primary outcome measurement. Case fatal-ity was not reduced, but patients in the treated group had more often a good clinical outcome. Larger studies with Chapter 14: Aneurysmal subarachnoid haemorrhage 133
overall outcome as primary measurement of outcome are needed before this treatment can be implemented in clinical practice.
5. Management of rebleeding