Cerebral vasospasm: looking beyond vasoconstriction

doi:10.1016/j.tips.2007.04.002

Trends in Pharmacological Sciences

Volume 28, Issue 6, June 2007, Pages 252-256

https://doi.org/10.1016/j.tips.2007.04.002 Get rights and content

Cerebral vasospasm is an important syndrome that afflicts 30% of patients in the aftermath of, and secondary to, subarachnoid hemorrhage. Starting approximately one week after the hemorrhage, the condition worsens the prognosis of the hemorrhage significantly. Apart from general supportive care, no treatment exists for cerebral vasospasm. During the past 50 years, it was thought that the ischemia that signifies poor outcome is more or less exclusively caused by arterial narrowing. However, this idea has recently been challenged by the failure of the drug clazosentan to improve patient outcome, despite reversing vasoconstriction. In this article, we discuss the opinion that factors other than vasoconstriction are important in the pathophysiology and prognosis of cerebral vasospasm. Such factors include global ischemia, disruption of the blood–brain barrier, activation of apoptotic and inflammatory pathways, and cortical spreading depression.

Section snippets

Cerebral vasospasm: a deadly contraction of smooth muscle

Spontaneous subarachnoid hemorrhage (SAH) arising from the rupture of an intracranial aneurysm (see Glossary) is a multiphasic disease [1]. Presentation ranges from simple sudden-onset headache to the patient requiring ventilatory assistance to ensure survival, to the patient dying before arrival at hospital. After this initial crisis, another can occur four or five days later: a syndrome labeled cerebral vasospasm (Table 1) because of its association with angiographic narrowing of cerebral

Achieving vascular dilatation but failing to improve outcome

Consistent with the classical idea of arterial narrowing being the hallmark of cerebral vasospasm, a long-awaited powerful vasodilator arrived in the form of clazosentan, an antagonist to the endogenous peptide vasoconstrictor endothelin [7]. A double-blind, randomized clinical trial of clazosentan showed a dose-dependent 65% reduction in the relative risk of angiographic vasospasm in patients treated with the highest drug dose [8]. Despite this, there was only a small reduction in the number

Classical ideas regarding the contraction of vascular smooth muscle cells in cerebral vasospasm

The essence of the clazosentan study [8] is not that it is yet another drug that fails to challenge cerebral vasospasm in the clinical setting. The true implication of this study could be that the basic pathological process of cerebral vasospasm is not understood at all or, more specifically, that the simple sequence of SAH leading to angiographic narrowing of arteries, leading to ischemia and poor outcome is not so simple after all. If this were true, a long-term beneficial effect would have

New frontiers – pre-SAH and pre-vasospasm research

There have been major developments in research into the phase preceding vasospasm, including recognition of the early events after SAH such as increased intracranial pressure [23], disruption of the blood–brain barrier (BBB), global cerebral ischemia [24], inflammation [25] and cortical spreading depression [26]. Because all of these events are directly or indirectly related to and/or evoked by the presence of arterial blood clots in the subarachnoid space, they could be equally as responsible

Concluding remarks

The emerging consensus among researchers in the field is that future efforts must concentrate on all consequences of SAH, how they relate to each other and how they lead to delayed cerebral ischemia. The treatment efforts in the past 50 years, targeting only the reversal or prevention of cerebral vasospasm, might not be enough to achieve a better outcome from delayed cerebral ischemia because pre-vasospasm factors such as intracranial pressure, BBB breakdown, brain edema, inflammation, cell

Glossary

Cortical spreading depression: a non-physiological global depolarization of the cerebral cortex that can be initiated by a given stimulus. The phenomenon propagates across the cerebral cortex at a rate of 2–5 mm min⁻¹ and is accompanied by transient marked changes in cerebral blood flow, local tissue oxygen tension and, probably, metabolic rate.
Intracranial aneurysm: localized blood-filled dilatation of one of the major cerebral arteries. The aneurysm is often dome shaped. Its walls are thin, making

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Cited by (108)

Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage – Serum D-dimer and C-reactive Protein as Early Markers
2020, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
The etiopathogenesis of vasospasm (VS) and delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is still incompletely understood. Apart from VS, a variety of mechanisms have been shown to contribute to the multi-causal chain reaction that leads to the development of DCI.1-3 In the past, inflammatory processes were shown to play a role in the rupture of aneurysms and the development of VS.4-6 Procalcitonin is a rather specific parameter for detecting infections and for differentiating between sepsis and noninfectious systemic inflammatory response syndrome other than white blood count (WBC) and C-reactive protein (CRP), which can be elevated during different kinds of inflammatory processes.7-9
Identifying patients at risk for delayed cerebral ischemia after an aneurysmal subarachnoid hemorrhage remains challenging and both delayed treatment and over-treatment are reasonable concerns.
To evaluate the role of the serum markers C-reactive protein, white blood count, and d-dimer as prognostic factors for the occurrence of delayed cerebral ischemia.
All patients admitted within 24 hours after an aneurysmal subarachnoid hemorrhage were included over a 6-year period. The World Federation of Neurosurgery and Fisher grading scales as well as the extended Glasgow Outcome Scale were documented at discharge and after a 3-to-6-month follow-up period. C-reactive protein, d-dimer, white blood count, and procalcitonin were assessed on admission, day 1, day 4, day 9, day 14, and at discharge. Radiologically confirmed delayed cerebral ischemia before discharge was the primary endpoint. Severe angiographic vasospasm and outcome were used as secondary endpoints.
Delayed cerebral ischemia occurred in 19.6% of the 138 patients included. Delayed cerebral ischemia correlated with severe vasospasm and with a worse outcome. Serum C-reactive protein levels were higher in patients with severe vasospasm during the period of vasospasm. D-dimer levels on admission correlated with Fisher grades. Delayed cerebral ischemia occurred more frequently in patients with Fisher grade IV hemorrhage, if d-dimer levels were higher on admission. The cut-off was .445 µg/ml.
Our observations support a multifactorial genesis for delayed cerebral ischemia, including vasospasm and microthrombotic and inflammatory processes. Serum d-dimer levels greater than .445 µg/ml might be a predictor for the occurrence of delayed cerebral ischemia in patients with a Fisher grade IV aneurysmal subarachnoid hemorrhage.
Carbon monoxide attenuates vasospasm and improves neurobehavioral function after subarachnoid hemorrhage
2019, Archives of Biochemistry and Biophysics
Citation Excerpt :
Delayed neurologic deterioration from vasospasm remains the greatest cause of death and disability after SAH [8,9]. Cerebral vasospasms occur in more than one-half of all patients with SAH and they are recognized as the main cause of delayed cerebral ischemia after SAH [10–12]. This condition normally advances between 4 and 14d and the most severe conditions are observed between 7 and 9d after SAH [13].
Subarachnoid hemorrhage (SAH) is a devastating form of hemorrhagic stroke and is a serious medical condition caused by bleeding usually due to a ruptured aneurysm. Oxidative stress and inflammation from hemoglobin and heme released from lysed red blood cells are some postulated causes of vasospasm during SAH, which could lead to delayed cerebral ischemia. At low amounts, carbon monoxide (CO) gas may be neuroprotective through anti-inflammation, anti-cell death, and restoration of normal blood flow. Hence, this study focuses on a noninvasive strategy to treat SAH by using CO as a therapeutic medical gas. Mice were treated with 250 ppm CO or air for 1h started at 2h after SAH. Various anatomical and functional outcomes were monitored at 1 and 7d after SAH. CO decreased neurological deficit score (47.4 ± 10.5%) and increased activity (30.0 ± 9.1%) and stereotypic counts (261.5 ± 62.1%) at 7d. There was a significant increase in lumen area/wall thickness ratio in the middle cerebral artery (173.5 ± 19.3%), which tended to increase in the anterior cerebral artery (25.5 ± 4.3%) at 7d. This is the first report to demonstrate that CO minimizes delayed SAH-induced neurobehavioral deficits, which suggests that post-treatment with CO gas or CO-donors can be further tested as a potential therapy against SAH.
Low Glasgow Coma Score in Traumatic Intracranial Hemorrhage Predicts Development of Cerebral Vasospasm
2018, World Neurosurgery
Citation Excerpt :
However, the incidence and the exact mechanism by which post-traumatic vasospasm (PTV) occurs remain unknown. Several mechanisms have proposed, including the physical stretching of vessels causing vasospasm,1-3 dysregulation of calcium, upregulation of endothelin-I,4 and an apoptotic/inflammatory pathway activated by global ischemia and/or disruption of the blood–brain barrier.5 Furthermore, much of the literature examining PTV includes a mixed patient population in which vasospasm has been identified using transcranial Doppler (TCD), computed tomography (CT) angiography, or to a much lesser, extent digital subtraction angiography (DSA).
The exact mechanism, incidence, and risk factors for cerebral vasospasm after traumatic intracranial hemorrhage (ICH) continue to be poorly characterized. The incidence of post-traumatic vasospasm (PTV) varies depending on the detection modality.
We aimed to shed light on the predictors, associations, and true incidence of cerebral vasospasm after traumatic ICH using digital subtraction angiography (DSA) as the gold standard.
We examined a prospectively maintained database of traumatic brain injury (TBI) patients to identify patients with ICH secondary to TBI enrolled between 2002 and 2015 at our trauma center. Patients with TBI-associated ICH and evidence of elevated velocities on transcranial Doppler and computed tomography angiograms, confirmed with DSA were included. The diagnostic cerebral angiograms were evaluated by 2 blinded neurointerventionalists for cerebral vasospasm. Statistical analyses were conducted to determine predictors of PTV.
Twenty patients with ICH secondary to TBI and evidence of vasospasm underwent DSAs. Seven patients (7/20; 35%) with traumatic ICH developed cerebral vasospasm and of those, 1 developed delayed cerebral ischemia (1/7; 14%). Of these 7 patients, 6 presented with subarachnoid hemorrhage (6/7; 85%). Vasospasm was substantially more common in patients with a Glasgow Coma Scale <9 (P = 0.017) than in all other groups.
PTV as demonstrated by DCA may be more common than previously reported. Patients who exhibit PTV were more likely to have a Glasgow Coma Scale <9. This subgroup of patients may benefit from more systematic screening for the development of PTV, and earlier monitoring for signs of delayed cerebral ischemia.
Early Diagnosis of Delayed Cerebral Ischemia: Possible Relevance for Inflammatory Biomarkers in Routine Clinical Practice?
2017, World Neurosurgery
Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) is one of the main causes of neurologic deterioration. However, it frequently evades timely detection. Early identification and effective reversal may improve the clinical outcome. In this prospective study, we evaluate several serum inflammatory markers after aneurysmal SAH with regard to the occurrence of DCI.
On days 1, 4, 7, 10, and 14 after SAH, leucocyte count, C-reactive protein, interleukin 6, E-selectin, matrix metallopeptidase 9, intercellular adhesion molecule 1, and leukemia inhibitory factor were assessed in patients' serum samples. Using a Cox regression model (SPSS 21.0), associations of baseline parameters, maximum and delta (maximum minus baseline) values with occurrence of DCI were evaluated.
Considering the assessed parameters, leucocyte count (high baseline and delta values) matches most closely with occurrence of DCI. Although baseline levels of C-reactive protein are also associated with occurrence of DCI, neither maximum (only on a borderline level) nor delta levels do so.
Our data analysis identified leucocyte count as the parameter most likely associated with occurrence of DCI. However, because of its lack of specificity leucocyte count, it cannot be used as a biomarker. As hypothesized earlier, the results indicate a possible involvement of the inflammatory reaction after aneurysmal SAH in the pathomechanism of DCI.
Perioperative Infection after Aneurysmal Subarachnoid Hemorrhage: Risk Factors, Causative Pathogens, and Long-Term Outcomes
2024, Neurosurgery
The impact of pre-ictal statin use on vasospasm and outcome in aneurysmal subarachnoid hemorrhage
2023, Acta Neurochirurgica

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Trends in Pharmacological Sciences

OpinionCerebral vasospasm: looking beyond vasoconstriction

Section snippets

Cerebral vasospasm: a deadly contraction of smooth muscle

Achieving vascular dilatation but failing to improve outcome

Classical ideas regarding the contraction of vascular smooth muscle cells in cerebral vasospasm

New frontiers – pre-SAH and pre-vasospasm research

Concluding remarks

Glossary

Neurosurg. Clin. N. Am.

Pharmacol. Ther.

Pathophysiology of delayed ischaemic dysfunction after subarachnoid haemorrhage: experimental and clinical data

Acta Neurochir. Suppl. (Wien)

The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: overall management results

J. Neurosurg.

Time course of vasospasm in man

J. Neurosurg.

Therapeutic approaches to vasospasm in subarachnoid hemorrhage

Curr. Opin. Crit. Care

Aneurysmal subarachnoid hemorrhage

N. Engl. J. Med.

Clazosentan (AXV-034343), a selective endothelin A receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter Phase IIa study

J. Neurosurg.

Randomized trial of clazosentan for prevention of vasospasm after aneurysmal subarachnoid hemorrhage

Stroke

Continuous elevation of intracellular Ca2+ is essential for the development of cerebral vasospasm

Curr. Vasc. Pharmacol.

Thin and thick filament regulation of contractility in experimental cerebral vasospasm

Neurosurgery

Vasospasm in monkeys resolves because of loss of and encasement of subarachnoid blood clot

Stroke

Marked reduction of cerebral vasospasm with lumbar drainage of cerebrospinal fluid after subarachnoid hemorrhage

J. Neurosurg.

A review of hemoglobin and the pathogenesis of cerebral vasospasm

Stroke

Bilirubin oxidation products (BOXes) and their role in cerebral vasospasm after subarachnoid hemorrhage

J. Cereb. Blood Flow Metab.

Mechanisms of hemolysate-induced [Ca2+]i elevation in cerebral smooth muscle cells

Am. J. Physiol.

Role of adenosine 5′-triphosphate in vasospasm after subarachnoid hemorrhage: human investigations

Neurosurgery

Protein kinase C and cerebral vasospasm

J. Cereb. Blood Flow Metab.

Recent evidence for an involvement of rho-kinase in cerebral vascular disease

Stroke

Opinion
Cerebral vasospasm: looking beyond vasoconstriction

Continuous elevation of intracellular Ca²⁺ is essential for the development of cerebral vasospasm

Mechanisms of hemolysate-induced [Ca²⁺]i elevation in cerebral smooth muscle cells