Hyperventilation reduces ICP by reducing CBF. Carbon dioxide is a potent cerebral vasodilator, and thus vasoconstriction is induced by rapidly decreasing the pCO2 (thereby concomitantly increasing the CSF pH), subsequently reducing the entry of blood into the cerebral circulation and lowering the ICP. The effect is almost immediate, reducing ICP typically within minutes. However, it is short lived, and may theoretically result in worsening of the cerebral infarction volume secondary to vasoconstriction affecting the ischemic penumbrum. Furthermore, there is also a risk of rebound vasodilation and worsening ICP when the pCO2 returns to normal, and thus the use of hyperventilation should be seen as a bridge at best, used toward a more definitive treatment in an acutely herniating patient. There have been no recent clinical trials, but evidence from the 1970s did not reveal an effect on outcome. Furthermore, there is growing evidence that hyperventilation is not always used according to guidelines, and may lead to worse outcomes.51 Hyperventilation is not a technique that lends itself to adequate clinical study, as most clinicians, recognizing its acute effectiveness, would not consider it ethical to randomize decompensating patients to hyperventilation versus no hyperventilation.
Osmotherapy employs agents such as mannitol, glycerol, and hypertonic saline to create an osmotic gradient between the brain (optimally, the edematous infarcted tissue) and the bloodstream, such that water is drawn out from the brain, thereby reducing edema. Each of these agents has been shown to be effective, and may be used alone or in combination with a diuretic, such as furosemide. Their action, however, depends upon an intact blood-brain barrier (BBB), and concerns have been raised for possible paradoxical worsening when one is absent. In this hypothesis, mannitol extravasates from the vessel into the interstitial tissue and water follows a new osmotic gradient.52 Furthermore, even with an intact BBB, mannitol may concentrate in the CSF, also paradoxically increasing the ICP hours after administration.53
Mannitol is an extracellular, non metabolizable sugar, acting to create a gradient between the intravascular, intracellular, and interstitial spaces. It is also felt to have rheological effects, increasing blood flow in the cerebral microcirculation by decreasing red blood cell deformity, and thus decreasing serum viscosity.54 It should be administered in a weight-based fashion, 1-1.5 g/kg intravenously, with repeated doses every 6 hours as needed for refractory ICP.55 However, its use may be limited by the potential for nephrotoxicity, especially when there is inadequate clearance between doses. A generally employed technique is the measurement of the serum osmolarity (osms), holding the administration of the next dose of mannitol if the serum osms exceed 320. However, this may be an insensitive measure of the clearance of mannitol, and many now advocate the measurement of the osmolar gap. Multiple formulations have been evaluated for measuring the osmolar gap, and
appears to have a high correlation with serum mannitol levels.56 However, it has yet to be determined what the appropriate osmolar gap should be for the ischemic stroke patient, and thus the repeated administration of mannitol may depend upon what the treating clinician feels is the appropriate gap for that patient, or when they feel that the osmolar gap gives the best approximation for the volume status in the individual patient. In a nonrandomized head-to-head trial of mannitol with hypertonic saline, mannitol appeared to be significantly more effective in improving CPP.57 To date, mannitol has not been subjected to a prospective, randomized trial in space-occupying cerebal infarction, either versus placebo or versus any other osmotic agent.
Glycerol is also a nonmetabolizable sugar and is touted to have potential neuroprotective qualities as well. It is not felt to be as potent an osmotic agent as man-nitol. Prior animal studies suggested an effect for rheology and edema minimization.58 Human studies in acute stroke have suggested a benefit for glycerol in short-term but not long-term outcomes, and a Cochrane review did not support its routine use in controlling cerebral edema.59 One significant concern raised in a cerebral microdialysis study of 7 large MCA infarct patients with 16 ICP elevations was the short-lived ICP lowering effect of glycerol (only 70 minutes), as well as the rapid accumulation of glycerol in the brain tissue itself, which may ultimately worsen edema with cumulative doses.60
Hypertonic saline is actively excluded from an intact BBB and also acts to draw water into the intravascular space by the creation of a sodium gradient. Various concentrations have been evaluated, with continuous sodium chloride infusions ranging from 3% to 9%, and bolus infusions up to 23.4% administered over 20 minutes in a 30 mL solution.61 When a continuous infusion is used, the serum sodium is typically titrated to the 155-160 range. Sodium levels above this range raise the concern for seizures and other toxic side effects. Hypertonic saline may hold an advantage over mannitol, as it has been found in animal models to decrease edema in both the affected and unaffected hemispheres.62 It also has a higher reflection coefficient, a marker of the relative selectivity of the BBB to a particular substance.63 Hypertonic saline has also been shown to be effective in cases of cerebral edema that are refractory to mannitol therapy.64 Systemic effects include transient volume expansion, hemodilution, natriuresis, and improved pulmonary gas exchange. However, repeated use may lead to electrolyte abnormalities, congestive heart failure (CHF), bleeding, and phlebitis. To date, there have been no randomized trials of the use of hypertonic saline in hemispheric cerebral infarction, either versus placebo or versus other osmotic agents. One study by Bhardwaj et al.65 suggested that infarct volumes were increased by hypertonic saline in an animal model of transient focal cerebral ischemia, but this has not been observed in any human studies to date.
Barbiturates, including pentobarbital, have been evaluated in clinical studies of a variety of cerebral insults with ICP elevation, including traumatic brain injury, cerebral aneurysm rupture, and ischemic stroke. They are effective in reducing ICP by lowering the cerebral metabolic rate,66 and may have neuroprotective qualities by being free radical scavengers.67 Their use, however, is complicated by the side effects of hypotension and sedation, as well as an increased infection risk with prolonged use. The ability to follow the neurological exam is lost, and this is a vital tool in monitoring a patient's clinical status following a stroke. Hypotension may compound ischemia by reducing the CPP, thereby collapsing any collateral vessels that may have been feeding ischemic but not yet infarcted tissue, or by causing global ischemia in a patient with high ICP who is dependent upon a higher MAP to maintain their CPP. Thus, although there have been no randomized studies of barbiturates in cerebral infarction, their use is generally not recommended.
Tris-hydroxymethyl-aminomethane (THAM) has been evaluated in ischemic stroke to reduce mass effect and ICP. It acts as a buffer, neutralizing acidosis on a local level, including in the brain parenchyma. It has been studied in animal models of stroke, showing an effect in reducing the size of68 and swelling from69 cerebral infarction. To date, however, THAM has not been studied in a controlled fashion in humans with ischemic stroke.
Corticosteroids have been evaluated in several types of cerebral injury, including cerebral infarction. Corticosteroids reduce vasogenic edema, such as that associated with neoplasms, but not cytotoxic edema, the type associated with ischemic stroke. A large meta-analysis found no benefit to the use of corticosteroids in ischemic stroke (or intracerebral hemorrhage),70 and their use is not recommended, except to treat concomitant conditions that mandate it (e.g., COPD flare).
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