IN this issue of Anesthesiology, Weiss et al.1
report their observations regarding prognostic validity of measuring blood S100B concentrations in patients with aneurysmal subarachnoid hemorrhage (SAH). Their key finding is that this neurochemical marker of acute brain injury, tracked noninvasively during the first few days after ictus, can provide useful information in prognosticating quality of neurologic outcome at 6 months after hemorrhage.
Aneurysmal subarachnoid hemorrhage remains a lethal or disabling disease. Approximately 10–15% of patients experience sudden death.2
The probability of full neurologic recovery among those receiving medical attention is low.3
This morbidity is attributable to several factors, including direct damage to the brain from hemorrhage, surgical clipping and coiling complications, and vasospasm.
Because the disease presents multiple complex mechanisms of injury, it is of no surprise that little progress has been made in alleviating SAH morbidity. Treatment of unruptured intracranial aneurysms is largely restricted to those discovered incidentally or those causing a mass effect on adjacent structures such as the optic nerves. Therefore, the potential for preventive therapy is limited. There has been some advance in the management of ruptured aneurysms. Certainly, neuroimaging modalities have vastly improved, particularly computerized tomographic angiography, which provides exquisite three-dimensional preoperative images defining location, structure, parent blood vessels, and regional brain anatomy and can be important in identifying vasospastic vessels amenable to angioplasty. Another advance has been endovascular aneurysm coiling. The sizes, shapes, and locations of aneurysms amenable to this therapy continue to increase. A recent prospective randomized investigation found that risk of death or dependence at 1 yr after hemorrhage was reduced by 7.4% in patients treated with coiling compared with craniotomy and clipping.4
However, coiling may carry a greater incidence of rebleeding4
and does not seem to decrease the incidence of cerebral vasospasm.5
In most respects, treatment of vasospasm has changed little during the past 25 yr. Standard management now includes monitoring for spasm with serial transcranial Doppler ultrasonography, prevention and treatment of spasm with L-type calcium channel blockers, and treatment of spasm-induced neurologic deficits with hemodilutional hypervolemic hypertensive therapy or angioplasty, all of which were introduced in the early 1980s.6–9
Vasospasm is a complex process. It exceeds simple physiologic arterial contraction in response to hemorrhage. Although not fully elucidated, it is becoming clearer that vasospasm represents a vasculopathy characterized by increased concentrations of endothelin (a potent and long-acting vasoconstrictor), depleted nitric oxide (attributable to increased consumption by reaction with superoxide and depressed nitric oxide synthesis due to inhibited endothelial nitric oxide synthase), disequilibrium of pro- and antiproliferative growth factors, inflammation, and endothelial injury. Definition of this multifactorial response to hemorrhage has presented numerous novel targets for pharmacologic intervention, and therefore, there is reason to believe that therapeutic breakthroughs will occur. However, such advances require complex and expensive human trials, which must occur in a stepwise progression to cause changes in practice.
One problem with such trials is lack of validated surrogate markers that define therapeutic efficacy. The key dependent variable in any such intervention is long-term neurologic outcome. However, for screening purposes, it is important to first identify responses to intervention that indicate a pathomechanism has been modified.
S100B is calcium-binding protein in astrocytes, oligodendrocytes, and Schwann cells and therefore is present in large quantities in the human central nervous system. S100B can be measured in blood, cerebrospinal fluid, urine, or microdialysates. During the past 5 yr, it has been reported that extracellular S100B is increased in patients with cerebral pathology including traumatic brain injury, stroke, chemical or infectious encephalopathy, cardiac surgery, subarachnoid hemorrhage, major depression, multiple sclerosis, and other disorders. In most of these scenarios, a neurochemical marker is not necessary to diagnosis brain injury, which can readily be determined by neurologic or neurocognitive evaluation. What S100B offers is a potential repeatable estimate of the severity and progression of injury. This can have value in terms of prognostication and perhaps more important as a sentinel marker of changes in neurologic condition. If something as simple as a S100B blood test could detect neurologic change (for better or worse), and that change in S100B has been shown to be predictive of outcome, substantially greater opportunity would be present to track efficacy, titrate doses, and screen novel vasospasm therapies.
The work of Weiss et al.1
provides information as to whether measurement of S100B constitutes a step forward in meeting this goal. Seventy-four patients with angiographically proven aneurysmal SAH were treated in a neurointensive care unit with a standardized care protocol. The World Federation of Neurological Surgeons score, patient age, aneurysm location and size, and the magnitude of hemorrhage (Fisher score) were recorded on admission. Blood S100B concentrations were measured on a daily basis for 8 days. Patients underwent either aneurysm clipping (28%) or coiling (72%). Vasospasm was defined according to clinical criteria and confirmed by transcranial Doppler and angiography. At both neurointensive care unit discharge and at 6 months after hemorrhage, neurologic outcome was measured using the Glasgow Outcome Scale score.
Patients with worse initial World Federation of Neurological Surgeons or Fisher scores or middle cerebral artery aneurysms had greater admission blood S100B concentrations than those patients with less initial neurologic morbidity, smaller hemorrhage size, or aneurysms at other locations. This is consistent with other studies that have associated the magnitude of brain injury with S100B concentration. S100B concentration was also greater in patients subjected to clipping versus
coiling. Although this would seem to be consistent with the decreased morbidity previously reported for coiling,4
absence of randomization to treatment condition or control for surgical manipulation in the current study precludes drawing any conclusions regarding superiority of either technique. S100B did not detect onset of cerebral vasospasm for the entire population, within which initial S100B concentrations varied widely. However, in patients with low initial S100B concentrations, a significant increase in S100B was observed at spasm onset. This likely indicates that the background signal from already damaged brain reduces sensitivity of the assay to detect change and demonstrates potential limits in using repeated analysis of a neurochemical marker to screen for vasospasm.
A quantitative association between S100B values and 6-month outcome was established, i.e., blood values greater than 0.4 μg/ml significantly predicted a poor outcome. Outcome was associated with both initial and mean daily S100B values. The World Federation of Neurological Surgeons score and patient age similarly predicted outcome. Although this indicates an independent prognostic value for S100B, evidence was not provided that prognostic accuracy is increased by measurement of S100B over readily obtained neurologic scores or demographics.
Weiss et al.1
identified an inexpensive neurochemical marker of post-SAH injury that is predictive of long-term outcome. To some extent, we already have this prognostic capacity in the initial standardized neurologic examination, although factors such as examination complexity and intraobserver and interobserver variability limit its utility.10
The step forward in this investigation was definition of a quantitative and objective assessment that has potential to be used as a simple short-term surrogate to accelerate screening of therapeutic efforts aimed at reducing SAH-associated long-term morbidity. The next step is to definitively determine whether reduction of S100B concentrations caused by an intervention in the acute phase can be associated with improved long-term outcome, as has been suggested in pilot studies investigating S100B during treatment with simvastatin.11
Then, a surrogate neurochemical marker with clinical value will be in hand.
David S. Warner, M.D.*
Daniel T. Laskowitz, M.D.†
*Departments of Anesthesiology, Neurobiology, and Surgery, †Departments of Medicine (Neurology), Neurobiology, and Anesthesiology, Duke University Medical Center, Durham, North Carolina. firstname.lastname@example.org
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© 2006 American Society of Anesthesiologists, Inc.