Other forms of medical treatment In the past, treatment by hemodilution was popularized by the studies of Wood and Fleischer, who showed a high incidence of short-term improvement when the hematocrit was reduced to approximately 33 percent. That lowering blood viscosity improves regional blood flow in the heart had been known for some time, and a similar effect on the brain has been demonstrated by CBF studies. Earlier observations had shown a reduction in the overall neurologic deficit, but almost all larger randomized trials—which included patients in many settings who were treated at various times up to 48 h after stroke—failed to confirm any such benefit and the use of this treatment has been virtually abandoned. Therapies aimed at improving blood flow by enhancing cardiac output (aminophylline, pressor agents), by improving the microcirculation (mannitol, glycerol, dextran), or by use of a large number of vasodilating drugs (see below) have failed to show consistent benefits, but several are still under study. Normobaric and hyperbaric oxygen may reduce ischemic deficits temporarily but have no sustained effect. A trial in over 8,000 patients failed to demonstrate benefit of low dose supplemental oxygen in the acute setting (Roffe et al). Induced hypothermia limits the size of ischemic stroke, but it is technically difficult to administer and often has serious side effects. In the past, much attention was paid to head and body positioning in the acute phase of stroke but the sitting up position failed to confer an advantage over the supine position in a randomized trial (Anderson et al).
Calcium channel blockers of the types administered for cardiac disease increase CBF and to reduce lactic acidosis in stroke patients. However, several multicenter clinical trials that compared calcium channel blockers with placebo did not establish a difference in outcome in the two groups. There has also been interest, as noted earlier in this chapter, in drugs that inhibit excitatory amino acid transmitters and free-radical scavengers such as dimethyl sulfoxide (DMSO) and growth factors, but so far none of these has been successfully applied to humans.
Despite some experimental evidence that certain vasodilators, such as CO2 and papaverine, increase CBF, none has proved beneficial in carefully studied human stroke cases at the stage of TIAs, thrombosis in evolution, or established stroke. Vasodilators may actually be harmful, at least on theoretical grounds, because by lowering the systemic blood pressure or dilating vessels in normal brain tissue (the autoregulatory mechanisms are lost in vessels within the infarct); they may reduce the intracranial anastomotic flow. Moreover, the vessels in the margin of the infarct (border zone) are already maximally dilated. New discoveries regarding the role of nitric oxide in vascular control will probably give rise to new pharmacologic agents that will require evaluation. The metabolic stresses of ischemia and the production of destructive oxygen-free radicals were referred to earlier. Among the numerous “brain-sparing” agents that have been tried in an attempt to reduce the size of infarction, certain ones have had erratic results in large randomized trials. Two trials, for example, gave initially promising results and later proved ineffective (Shuaib et al). These agents were of interest because they can be administered up to several hours after the stroke (continuing for 72 h). So far, the results of neuroprotective agents in stroke have been discouraging.
Primary and Secondary Prevention of Ischemic Stroke
In addition to reduction in the well-known risk factors for vascular disease, certain measures have been shown to reduce the risk of a subsequent stroke and to prevent a first stroke. Many of these approaches have required large randomized trials, sometimes in selected populations, in order to demonstrate significant differences compared to no treatment or to various comparators. For this reason, it is often uncertain how to apply these findings to the individual patient but they have found their way into guidelines.
Anticoagulants for the Primary Prevention of Strokes (See Table 33-3)