Facilitation of recovery after ischaemic stroke : Early dexamphetamine and physiotherapy treatment

Abstract: Purpose: The overall aims of the thesis were to investigate the safety, efficacy, and pharmacokinetics of dexamphetamine (d-amph) after cerebral infarct, and the effects of different amounts of physiotherapy in combination with d-amph on recovery, early after cerebral infarct in patients with severe stroke. Patients and methods: The thesis is based on three studies on patients in the department of Neurology, Karolinska Hospital, Sweden, and on one meta-analysis based on data collected from previously published studies. I) Forty-five patients, aged 18-85 years and included <72 hours after cerebral infarct, were randomised to d-amph (2.5 mg, 5 mg, or 10 mg) or placebo twice daily for five consecutive days. Safety of the drug was the primary outcome and efficacy measured as neurological function, motor function, and activities of daily living (ADL) were secondary outcomes. Patients were followed for three months. II) Thirty patients, aged 55-85 years, included <96 hours after cerebral infarct, with an impaired level of consciousness and severe motor dysfunction were randomised to 'standard' or 'intensive' physiotherapy in combination with d-amph for five consecutive days. Motor function was the primary outcome and neurological function, ADL, and residence of living were secondary outcomes. Patients were followed for twelve months. III) Pharmacokinetics of d-amph were analysed in 26 patients from study 1. IV) In the meta-analysis seven studies including a total of 172 patients with stroke (including 45 patients from study I) were analysed regarding safety and efficacy of amphetamine treatment versus placebo using the Cochrane Collaboration methodology. Results: Systolic and diastolic blood pressure as well as heart rate increased significantly (p<0.01) with damph treatment compared to placebo but not the number of adverse events, or body temperature. During treatment damph improved neurological and functional outcome (p<0.05), but the differences were not maintained at follow-up. Patients with severe stroke did improve significantly over time (p<0.05) but neither short- nor long-term outcome seemed to depend on whether the patient had received 'standard' or 'intensive' physiotherapy during the first week after stroke onset. Increasing s-creatinine correlated with increasing dosenormalised area under the plasma concentration time curve, for d-amph (p=0.013) as well as with increasing terminal half life time (p=0.009). The terminal half-life time and the time to maximal plasma concentration (T.) did not differ between dose levels, while maximal plasma concentration (Cmax) was significantly higher in the 10 mg d-amph group compared to the 2.5 mg group (p<0.001). In the meta-analysis there was a trend for more deaths at the end of follow-up among patients allocated to amphetamine (p=0.05). There was evidence of a better relative improvement in motor function (p=0.003) and in language function (p=0.03) with amphetamine treatment. Conclusions: Overall d-amph was safe and well tolerated by patients early after cerebral infarct, but blood pressure and heart rate increased with treatment. Patients with severe stroke at baseline do not seem to benefit from 'intensive' physiotherapy at an early stage. In the present patient population the dosing regimen of d-amph should be based on body weight and special precautions should be taken for patients with elevated s-creatinine. In the meta-analysis, there were imbalances at baseline, with more serious strokes and older patients allocated to amphetamine. This imbalance may account for the trend for more deaths at the end of follow-up among patients allocated to amphetamine. The evidence of beneficial effects of d-amph on motor and language function needs to be confirmed.