Aneurysmal subarachnoid hemorrhage (SAH) is a form of stroke in which secondary neurological deterioration is an important cause of mortality and morbidity. These secondary changes, so called delayed cerebral ischemia (DCI), are caused by lysis of erythrocytes which can react to form iron, an toxic substance to the brain. Iron chelators remove the excess of iron and are standard care in iron-overloaded patients. Deferoxamine (DFO) an chelator has not been evaluated in SAH patients. This study evaluates the safety of deferoxamine in SAH patients
Aneurysmal subarachnoid hemorrhage (SAH) is a devastating form of stroke affecting relatively young patients. It has an incidence of about 7 per 100,000. Associated economic costs are high. Treatment of the aneurysm to prevent rebleeding is the primary goal. Nevertheless, 3 to 12 days after the initial bleeding secondary ischemic changes occur in 30% of the patients. This delayed cerebral ischemia (DCI) remains the most important cause of mortality and morbidity in patients surviving aneurysm treatment.
Aneurysmal SAH exposes the brain to erythrocytes. Several days after the hemorrhage lysis of erythrocytes takes place and the brain is exposed to high concentrations of hemoglobin. Elevated hemoglobin concentrations are present not only at the basal surface of the brain, but also distributed around the brain and into deeper layers of the cortex. Heme is degraded by heme-oxygenase into carbon monoxide, biliverdin and iron. Free iron can react with H2O and O2- to form hydroxyl radicals (OH*). The generation of hydroxyl radicals in this cascade, known as the Haber-Weiss or Fenton reaction, leads to extraction of hydrogen from unsaturated lipids in the cell membrane and initiates lipid peroxidation. Additionally it can exacerbate excitotoxicity by increased intracellular iron accumulation.
Iron chelators remove the excess of iron and are standard care in iron-overloaded patients. The use of iron chelators for SAH has been subject of animal studies with promising results on reduced vasospasm, oxidative stress, neuronal cell death and mortality. No clinical study for the use of deferoxamine in aneurysmal subarachnoid hemorrhage has been performed. A safety study for the use of Deferoxamine in patients in intracerebral hemorrhage (which is distinct from subarachnoid hemorrhage) has been performed. There were no associated serious adverse events or mortality, Deferoxamine is a chelator is used for more than 40 years in patients with iron overload diseases. This study investigates the safety and tolerability of deferoxamine versus placebo in patients with SAH for 3 consecutive days.
- Placebo Drug
Intervention Desc: placebo (NaCl 0.9%) in equal dose to treatment ARM 1: Kind: Experimental Label: placebo Description: NaCl 0.9% in similar dosis to treatment arm
- Deferoxamine Drug
Other Names: desferal Intervention Desc: Patients will be given deferoxamine 32 mg/kg/day (max iv rate 15 mg/kg/hr), patients with ferritin levels between 2,000 and 3,000 ng/ml will receive 32 mg/kg/day and patients with serum ferritin levels below 2,000 ng/ml wil receive 25 mg/kg/day.during 3 days ARM 1: Kind: Experimental Label: Treatment Description: Patients will be given deferoxamine 1000 mg iv as initial dose (max iv rate 15 mg/kg/hr), subsequently 500 mg every 4 hours for 7 days.
- Allocation: Randomized
- Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
- Purpose: Treatment
- Endpoint: Safety/Efficacy Study
- Intervention: Parallel Assignment
|Type||Measure||Time Frame||Safety Issue|
|Primary||safety (drug related adverse events; i.e. renal and hepatic dysfunction)||6 months||Yes|