Table 1.
Summary of medication with anti-inflammatory activity tested in SAH.
| Drug | Design | Dose | Patients | Outcome | Mechanism of action | Conclusion |
|---|---|---|---|---|---|---|
| Cyclosporin A (21) | Prospective cohort study | Loading dose of 7.5 mg/kg Maintenance: enteral administration every 12 h for two doses, to maintain levels of 50–400 ng/kg |
Nine patients with Fisher Grade 3 | GOS at 6 months | Prevent vasospasm, inhibit IL-2 production, and prevent T-cell dysfunction | CycA proved safe to use but failed to prevent the development of cerebral vasospasm or delayed ischemic deficits in patients considered at high risk |
| Cyclosporin A (22) | Randomized clinical trial | Cyclosporine A orally 6–9 mg/kg/day to maintain level of cyclosporine in the blood at 100–400 ng/ml | 25 patients (9 received treatment) | Neurological state | Prevent vasospasm, inhibit IL-2 production, and prevent T-cell dysfunction | Patients treated with early clipping (up to 72 h after SAH) plus cyclosporine A had significantly better “neurological outcome” than controls |
| Methylprednisolone (23) | Case-control study | Methylprednisolone started within 3 days following the tapering regimen:
|
42 patients (21 received treatment) | Corticosteroids have multiple anti-inflammatory actions, mostly on chronic inflammation | ||
| Methylprednisolone (24) | Double-blind, placebo-controlled, randomized trial | Methylprednisolone 16 mg/kg IV every day for 3 days (started within 6 h after angiographic diagnosis of aneurysm rupture), or placebo | 95 patients |
Symptomatic vasospasma mRS in living patients GOS at 1 year after SAH, in all patients |
Corticosteroids have multiple anti-inflammatory actions, mostly on chronic inflammation | The treatment did not reduce the incidence of symptomatic vasospasm but improved functional outcome |
| Hydrocortisone (25) | Double-blind, placebo-controlled, randomized trial | Hydrocortisone 3 g IV BID, repeated 6 times | 140 patients, 71 patients who received hydrocortisone | Mental, speech, and motor function | Hydrocortisone reduces vascular sensitivity to various vasoconstrictive stimuli. It inhibits phospholipase to reduce production of prostaglandins. It stabilizes the cell membrane and prevents cerebral edema | Patients who received hydrocortisone showed improvement in mental, speech, and motor function |
| Dexamethasone (26) | A propensity score analysis | Dexamethasone 4 mg q6h, then tapering down by 1 mg per dose every 24 h until discontinuation | 309 patients, 101 (33%) received treatment | Unfavorable outcome (mRS > 3) | Dexamethasone was associated with a significant reduction in mRS >3, but its use had no association with DCI or infection | |
| Simvastatin (1, 27) | Meta-analysis | Simvastatin 40 or 80 mg/day up to 21 days | Six randomized clinical trials, including 1,053 patients | Delayed ischemic deficit and delayed cerebral infarction | Neuroprotection independent of cholesterol reduction and exclusively associated with upregulation of endothelial nitric oxide synthase | No effect on delayed ischemic deficit, delayed cerebral infarction, mRS ≤2, vasospasm, ICU stay, hospital stay, and mortality |
| Acetylsalicylic acid (aspirin), ADP P2Y12 receptor antagonists (thienopyridines), and thromboxane synthase inhibitors (28) | Meta-analysis | Multiple regimensb | Seven randomized clinical trials, including 1,385 patients | Poor outcome (death, or dependence on help for activities of daily living) | Aspirin exerts its antiplatelet activity by the irreversible inhibition of COX-1 enzyme, thereby blocking the formation of thromboxane A2 in the platelets Because aspirin block the COX-1 enzyme, which decreases prostaglandin synthesis, leading to an anti-inflammatory effect Thienopyridines are ADP P2Y12 receptor antagonists (e.g., ticlopidine) that inhibit the intracellular pathways leading to platelet activation |
No effect on case fatality, aneurysmal rebleeding, poor outcome, secondary brain ischemia, and intracranial hemorrhagic complications. Ticlopidine was the sole antiplatelet agents associated with a significant reduction in the occurrences of a poor outcome (RR 0.37, 95% CI 95% CI 0.14–0.98), however, this result was based on one small RCT |
| Non-steroidal anti-inflammatory (29) | A propensity score-matched study | Multiple regimens not describedc | 178 patients were matched [89 received non-steroidal anti-inflammatory drug (NSAIDs), 89 did not] | Clinical outcomes included 6-week mortality, 12-week modified Rankin scale (mRS) score, DCI, and delayed ischemic neurological deficit (DIND) | NSAIDs inhibit COX, which decreases prostaglandin synthesis; ibuprofen inhibits expression of endothelial adhesion molecules and reduces subarachnoid inflammation | No significant difference in functional outcome, in the development of DINDs, angiographic vasospasm, or need for rescue therapy |
| Clazosentan (19) | Meta-analysis | Multiple regimensd | Four randomized clinical trials, including a total of 2,181 patients | Glasgow Outcome Scale—extended and mortality | Synthetic endothelin A receptor antagonist, with reduction of angiographic vasospasm | Clazosentan had a significant impact in the reduction of DINDs and delayed cerebral infarction. However, functional outcomes or mortality were unaffected Side effects, such as hypotension, anemia, and pulmonary complications may have reduced the beneficial effects of the drug |
| Cilostazol (30) | Randomized, single-blind study | 109 patients undergoing clipping of ruptured aneurysms | Selective phosphodiesterase III inhibitor, which inhibits platelets through an increase in intraplatelet cAMP levels. It has an antithrombotic, vasodilatory, anti-smooth muscle proliferation, and cardiac inotropic and chronotropic effects. Cilostazol also exhibits anti-inflammatory properties including inhibiting microglial activation | A multicenter randomized clinical trial of cilostazol has shown a decrease in angiographic vasospasm but no improvement in outcomes 6 months after SAH. Cilostazol significantly reduced angiographic vasospasm, DCI and cerebral infarction but had no effect on outcome | ||
| Interleukin-1 receptor antagonist (IL-1Ra) (31) | A small Phase II, double-blind, randomized controlled study | IL-1Ra (500 mg bolus, then a 10 mg/kg/h infusion for 24 h) | 13 patients, 6 patients received IL-1Ra | Primary outcome: changein CSF IL-6 between 6 and 24 h | IL-1Ra limits brain injury in experimental stroke and reduces plasma inflammatory mediators associated with poor outcome | IL-1Ra appears safe in SAH patients. The concentration of IL-6 was lowered to the degree expected, in both CSF and plasma for patients treated with IL-1Ra. This did not reach statistical significance |
| Dual antiplatelet therapy (aspirin + clopidogrel) (32) | Single center retrospective study | Not described | 161 patients (85 patients received) | Frequency of symptomatic clinical vasospasm and DCI and of hemorrhagic complications | Aspirin has an anti-inflammatory and antiplatelet effect thorough the blockade of COX-1 enzyme Clopidogrel is an antiplatelet agent (ADP P2Y12 receptor antagonists) |
The use of DAPT was associated with a lower risk of clinical vasospasm and DCI in patients treated for SAH, without an increased risk of hemorrhagic complications |
| Albumin (33) | Open-label, dose-escalation, Phase I pilot study | Tier 1 = 0.625 g/kg Tier 2 = 1.25 g/kg Tier 3 = 1.875 g/kg Tier 4 = 2.5 g/kg The treatment was used for 7 days |
47 patients received treatment 20 in Tier 1, 20 in Tier 2, and 7 in Tier 3 |
This was a dose-escalation study; therefore, the maximum tolerated dose of albumin was established. Tolerability was based on the rate of severe-to-life-threatening heart failure and anaphylactic reaction. Also, functional outcome at 3 months was assessed | Antioxidant and scavenger properties Modulate apoptosis Enhance microcirculatory blood flow Increase organ blood flow Decrease leukocyte rolling and adherence, and reduce the inflammatory response |
Doses up to 1.25 g/kg/day × 7 days were well tolerated. Functional outcome trended toward better responses in those subjects enrolled in Tier 2 compared with Tier 1 (OR, 3.0513; CI, 0.6586–14.1367) |
aSymptomatic vasospasm (DINDs associated with angiographic arterial narrowing or accelerated flow on TCD, or both).
bSuppositories of 100 mg ASA for 21 days after surgery; ASA 300 mg twice daily orally or rectal retention enema, starting 72 h after admission, before surgery; ticlopidine 100 mg 3 times a day orally for 2 weeks after the hemorrhage; dipyridamole 100 mg/day orally or 10 mg/day intravenously starting immediately after admission; first group 80 mg OKY-046 per day, second group 400 mg OKY-046 per day, by continuous infusion until 10–14 days, starting immediately after surgery; cataclot 1 μg/kg/min via continuous infusion, starting after surgery continued for 8–14 days; Suppositories with 100 mg ASA once daily, starting after surgery for 14 days.
cSalicylates (aspirin), propionic acid derivatives (ibuprofen, naproxen), acetic acid derivatives (indomethacin, ketorolac, diclofenac), enolic acid derivatives (meloxicam), and selective cyclooxygenase-2 inhibitors (-coxib’s).
dGOS, Glasgow outcome score; mRS, modified Rankin scale; DCI, delayed cerebral ischemia; COX, cyclooxygenase; SAH, subarachnoid hemorrhage; CSF, cerebral spinal fluid.