Management of Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: An Update

Abstract

Cerebral vasospasm is one of the major complications of aneurysmal subarachnoid hemorrhage (aSAH). The term vasospasm generally refers to angiographical findings, and clinically is defined by delayed neurological deterioration and delayed cerebral ischemia. Symptomatic vasospasm occurs in 20 to 40% of aSAH patients and is one of the least understood components of management. Diagnosis can be made clinically by using bedside modalities and radiography. Management begins with the use of preventive modalities, augmentation of cerebral perfusion, attempts at reversal, and the use of brain protection. Early use of endovascular therapy with mechanical or pharmacological angioplasty remains a reasonable approach. Of proven benefit are the use of cerebral vasodilators such as nimodipine and milrinone and the use of induced hypertension for cerebral perfusion augmentation. Agents for the spasmogenic blockade, inhibition of smooth muscle contraction, and brain protection remain largely experimental. This narrative review aims to update readers on the mechanism, diagnosis, prevention, and management of vasospasm in aSAH.

Keywords

cerebral vasospasm - aneurysmal subarachnoid hemorrhage - delayed cerebral ischemia

Introduction

Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular event that requires prompt and meticulous management to reduce the risk of severe neurological deficits and mortality. While SAH can result from traumatic injury, spontaneous cases are most commonly due to the rupture of an intracranial aneurysm, which accounts for approximately 85% of spontaneous SAH occurrences.[1] The immediate effects of SAH are determined mainly by the volume and duration of hemorrhage, which dictate the severity of primary brain injury. This initial injury is often heralded by a sudden, severe headache, commonly called a “thunderclap headache,” a hallmark symptom of aneurysmal SAH (aSAH).

Following the initial hemorrhagic event, the presence of blood within the subarachnoid space poses a significant risk for secondary brain injury. This secondary injury is mediated by several complications, including rebleeding, hydrocephalus, cerebral vasospasm, and delayed cerebral ischemia (DCI).[2] [3] The primary objective in managing aSAH is to mitigate these secondary complications, which are the principal determinants of patient outcomes. Among these, cerebral vasospasm is particularly insidious due to its delayed onset and potential to cause severe, irreversible neurological damage.[4]

Cerebral Vasospasm: Definition and Mechanisms

Cerebral vasospasm is the prolonged and pathological narrowing of cerebral arteries, most commonly occurring after SAH. This condition is associated with significant morbidity and mortality, particularly due to its role in delayed neurological deterioration (DND) and DCI. Vasospasm typically manifests between days 4 to 14 following aSAH, with the highest incidence around day 7.[5] Despite extensive research, the exact pathophysiological mechanisms behind cerebral vasospasm remain incompletely understood, making its prevention and treatment challenging.

• Vasospasm: the prolonged constriction of cerebral arteries, leading to reduced blood flow and increased risk of ischemic events.[6]

• DND: neurological decline occurring after the initial hemorrhage, not directly attributable to rebleeding, often linked to cerebral vasospasm.

• DCI: persistent neurological deterioration lasting more than 1 hour, typically due to ischemia following aSAH, after excluding other causes.[7]

The clinical significance of cerebral vasospasm is evident in its prevalence, affecting approximately 20 to 40% of SAH patients.[8] It is a major contributor to early mortality among those who survive the initial hemorrhage, responsible for nearly half of these deaths. Historical research, such as the International Cooperative Study on the Timing of Aneurysm Surgery, has demonstrated the harmful effects of performing surgery during periods of peak vasospasm, highlighting the critical importance of carefully timing interventions to improve patient outcomes.[9]

Pathophysiology of Cerebral Vasospasm

The development of cerebral vasospasm following SAH is a multifactorial process that involves complex interactions between the vascular endothelium, smooth muscle cells, and various biochemical mediators. The initial trigger is the release of oxyhemoglobin from lysed red blood cells into the subarachnoid space. Oxyhemoglobin is a potent vasoconstrictor that induces several pathological changes within the arterial walls.[10] These changes include the activation of endothelin (ET)-1, a potent vasoconstrictor peptide, inhibition of nitric oxide (NO) synthesis, and the generation of reactive oxygen species (ROS).[11] [12] [13]

ET-1 plays a central role in the pathogenesis of vasospasm by binding to ET receptors on vascular smooth muscle cells, leading to sustained vasoconstriction. Concurrently, the inhibition of NO, a key vasodilator, exacerbates this constriction by impairing the endothelium's ability to mediate the relaxation of the smooth muscle cells. The resultant imbalance between vasoconstrictive and vasodilatory forces leads to prolonged arterial narrowing and reduced cerebral blood flow (CBF), which increases the risk of ischemia.[14] [15] [16]

Moreover, the inflammatory response elicited by SAH further compounds the risk of vasospasm.[17] Systemic inflammatory response syndrome (SIRS) is commonly observed in SAH patients and is characterized by elevated levels of pro-inflammatory cytokines in the cerebrospinal fluid (CSF). These cytokines contribute to the structural and functional changes in the arterial walls, promoting vasospasm. Additionally, leukocyte infiltration into the vessel walls and the production of ROS further amplify the inflammatory cascade, leading to sustained vasoconstriction and increased risk of DCI.

Delayed Cerebral Ischemia beyond Vasospasm

Traditionally, the development of DCI following SAH was primarily attributed to large-vessel vasospasm, wherein the constriction of cerebral arteries leads to reduced CBF and subsequent ischemia. However, recent evidence has expanded our understanding of DCI as a multifactorial and complex phenomenon. While vasospasm remains a significant contributor, it is now recognized that other mechanisms, including microvascular dysfunction, cortical spreading depolarizations (CSDs), the formation of microthrombi, and impaired cerebral autoregulation, play crucial roles in the pathogenesis of DCI.[18]

Microvascular Dysfunction

Post-SAH, microvascular changes, such as microvasospasms and the disruption of the blood–brain barrier, have been implicated in DCI.[19] These microvascular abnormalities can occur independently of angiographically detectable large-vessel vasospasm, leading to diffuse cerebral ischemia. The exact mechanisms include endothelial cell dysfunction, pericyte contraction, and inflammatory responses that exacerbate microcirculatory disturbances.

Cortical Spreading Depolarizations

Another critical mechanism is the occurrence of CSDs—waves of intense neuronal and glial depolarization that propagate through the cortex. These waves lead to a temporary loss of ionic gradients, disrupting neuronal function and potentially exacerbating ischemic injury.[20] [21] CSDs have been associated with microcirculatory changes and are thought to contribute to the delayed onset of DCI in SAH patients.[22]

Microthrombi Formation

The formation of microthrombi within the cerebral microvasculature has been observed in both experimental models and clinical cases of SAH.[23] [24] These thrombi obstruct blood flow at the microvascular level, leading to localized ischemia that may not be detectable by conventional imaging techniques. The role of microthrombi highlights the importance of considering anticoagulation or antiplatelet therapies in the management of DCI, although such strategies must be carefully balanced against the risk of rebleeding.

Dysfunctional Cerebral Autoregulation

Impairment of the brain's autoregulatory mechanisms—whereby CBF is maintained constant despite fluctuations in systemic blood pressure—further complicates the management of DCI.[25] Post-SAH, autoregulation can become severely compromised, making the brain more vulnerable to both hypotension and hypertension, each of which can precipitate ischemic events.

This broader understanding of DCI underscores the need for a multifaceted approach to its diagnosis and management, integrating strategies that target not only large-vessel vasospasm but also microvascular health, neuronal function, and systemic physiological stability.

Risk Factors for Cerebral Vasospasm

Several risk factors have been identified that predispose patients to the development of cerebral vasospasm following SAH. These include the severity and location of the initial hemorrhage, with larger volumes of subarachnoid blood correlating with a higher risk of vasospasm.[26] [27] Additionally, the presence of SIRS and elevated CSF cytokine levels are strong predictors of vasospasm, as they reflect the degree of inflammation and endothelial dysfunction. Other factors, such as the patient's age (younger age group), gender, smoking status, and history of hypertension or diabetes, have also been implicated in increasing the likelihood of vasospasm.[28]

Diagnosis of Cerebral Vasospasm

Accurate and timely diagnosis of cerebral vasospasm is critical for initiating appropriate therapeutic interventions. Diagnosis is typically based on a combination of clinical assessment and radiographic imaging ([Tables 1] and [2]). The gold standard for radiographic diagnosis is cerebral angiography, which allows direct visualization of arterial narrowing. However, cerebral angiography is an invasive procedure that carries risks such as bleeding, embolism, and radiation exposure, making it impractical for routine surveillance.

Table 1 Grading of vasospasm[29]

Grade 0: No reduction in vessel spasm

Grade 1: Decrease in vessel diameter less than 50% of initial diameter

Grade 2: Decrease in diameter >50% compared to initial DSA

Abbreviations: DSA, digital subtraction angiography.

Table 2 Advantages and disadvantages of diagnostic modalities for cerebral vasospasm

Modality	Advantages	Disadvantages
Clinical assessment	Quick, repeatable, can assess response to therapy, noninvasive	Subjective, interobserver variability, not a gold standard, nonspecific
Transcranial Doppler	Easy to perform, noninvasive, bedside availability	Requires significant expertise, interobserver variability
4-Vessel angiography	Diagnostic and therapeutic, repeatable, gold standard	Invasive, risk of bleeding and embolism, radiation exposure, logistical challenges
CTA/MRI	Noninvasive, assesses both perfusion and anatomical structures, useful in the presence of surgical clips/coils	Limited by artifacts from surgical hardware, requires contrast
EEG	High sensitivity and specificity, prognostic value	Limited availability; requires specialized expertise
SPECT/PET	Correlates well with vasospasm, provides functional imaging	Resource-intensive, radiation exposure

Abbreviations: CTA, computed tomography angiography; EEG, electroencephalography; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single photon emission computed tomography.

Cerebral vasospasm typically manifests 1 week after aneurysm rupture, though vigilance is required for up to 2 weeks post-SAH. Symptoms often emerge gradually, beginning with increased headache, behavioral changes like agitation or somnolence, and progressing to focal neurological deficits. Key signs include diminished attention, verbal output changes, or pronator drift in awake patients.[30] Symptomatic vasospasm may present with hemiparesis or monoparesis, particularly in the middle cerebral artery (MCA) territory, or leg weakness and confusion in anterior cerebral artery (ACA) involvement. In vertebrobasilar vasospasm, early signs include reduced consciousness and generalized weakness. In comatose patients, ancillary monitoring is crucial for early detection.

Transcranial Doppler (TCD) ultrasonography offers real-time monitoring of CBF velocities, particularly in the MCA, where it continues to demonstrate high sensitivity and specificity.[31] TCD's capacity to provide dynamic assessments of cerebral hemodynamics makes it invaluable for detecting the onset and progression of vasospasm, particularly in the critical window of 2 to 14 days post-ictus, when the risk of DCI is highest. Studies have consistently validated TCD's effectiveness in this context, showing that an MFV (mean flow velocity) exceeding 120 cm/s is predictive of vasospasm, with severe cases indicated by velocities over 200 cm/s.[32] The Lindegaard ratio, which compares the MFV in the MCA to the extracranial internal carotid artery (ICA), is especially useful for differentiating true vasospasm from hyperemia, with a ratio above 6 typically indicative of severe vasospasm.[33] This diagnostic tool not only helps in identifying vasospasm early but also allows for the evaluation of therapeutic responses, such as the effectiveness of intra-arterial (IA) nimodipine administration.

However, the utility of TCD is not without its challenges. While it excels in monitoring the MCA, its accuracy diminishes when assessing vasospasm in the posterior circulation and smaller vessels, such as the ACA and posterior cerebral artery. Anatomical variations, collateral flow, and difficulty insonating certain arteries contribute to these limitations. For example, TCD's sensitivity in detecting vasospasm in the basilar artery (BA) is around 77%, with a specificity of 79%, and an MFV above 85 cm/s suggests vasospasm. To enhance accuracy in these cases, a modified Lindegaard ratio, which involves the comparison of the MFV in the BA to the extracranial vertebral artery, is often employed, further improving the detection rates of vasospasm in these challenging areas.[34] Despite these limitations, TCD remains a cornerstone in the monitoring and management of SAH patients, providing critical information that guides clinical decision-making and helps prevent the potentially devastating consequences of DCI.

Computed tomography angiography (CTA) and magnetic resonance angiography are increasingly used in clinical practice for the detection of cerebral vasospasm.[35] These modalities offer the advantage of noninvasiveness while providing detailed images of the cerebral vasculature. Recent studies have shown that CTA correlates well with digital subtraction angiography and may reduce the need for unnecessary angiograms. Sensitivity and specificity rates for CTA in detecting vasospasm are reported to be 80 and 93%, respectively, making it a valuable tool in the diagnostic arsenal.[36]

Electroencephalography (EEG) is an increasingly valuable tool in the identification of cerebral vasospasm following SAH.[37] While EEG is traditionally used for monitoring brain activity, its role in detecting vasospasm is based on the ability to identify changes in cerebral function that occur due to reduced blood flow. In patients with vasospasm, EEG may reveal a variety of abnormalities, such as focal slowing, attenuation of background rhythms, or the appearance of delta waves, which correspond to areas of ischemia or compromised cerebral perfusion.[38] These EEG changes often precede clinical symptoms of DCI, making EEG a potentially sensitive early marker for vasospasm. Continuous EEG monitoring can help detect subtle changes over time, providing a noninvasive method to guide timely intervention. However, the interpretation of EEG findings requires expertise, and the specificity of EEG for vasospasm is lower compared to other imaging modalities.

Role of Invasive Neuromonitoring

The management of DCI in patients with SAH has been significantly enhanced by the advent of invasive neuromonitoring (INM) techniques, which allow for continuous and real-time assessment of cerebral physiology. INM includes modalities such as brain tissue oxygenation monitoring (ptiO2) and cerebral microdialysis, which provide valuable data on cerebral oxygenation and metabolic status, respectively.

• ptiO2 monitoring offers direct insights into the oxygenation levels of brain tissue, which is critical in detecting early signs of cerebral ischemia.[39] Studies have shown that higher levels of ptiO2 correlate with improved outcomes in aSAH patients.[40] INM-guided interventions, such as the adjustment of blood pressure to optimize cerebral perfusion, have been associated with reduced rates of DCI-related infarctions and better long-term neurological outcomes.[41]

• Cerebral microdialysis allows for the measurement of metabolites in the extracellular fluid of the brain, including glucose, lactate, pyruvate, and glutamate. The lactate-to-pyruvate ratio (LPR) is particularly useful as an indicator of cellular energy failure and ischemia. An elevated LPR (usually >30) suggests anaerobic metabolism, a hallmark of ischemic conditions, and can prompt timely therapeutic interventions.[42] In patients with SAH, cerebral microdialysis has been instrumental in guiding treatment decisions, particularly in those who are neurologically unassessable due to sedation or secondary deterioration.[42]

Clinical Impact of INM

Introducing INM into clinical practice can significantly reduce the incidence of silent infarctions and overall DCI-related infarctions. Additionally, INM has reduced the need for repetitive imaging studies, which minimizes radiation exposure and decreases the risk associated with transporting critically ill patients. The ability to continuously monitor cerebral oxygenation and metabolism allows for more precise and individualized treatment, leading to better neurological recovery.[43]

Noninvasive Monitoring and Diagnostic Advances

While INM has clear benefits, noninvasive techniques also play a critical role in the early detection and management of DCI. Among these, perfusion computed tomography (CTP) has emerged as a valuable tool for assessing cerebral perfusion deficits that may not be apparent in standard CT or MR imaging.

• CTP: CTP imaging allows for the visualization of CBF, cerebral blood volume, and mean transit time—parameters that are crucial for identifying regions of hypoperfusion.[44] In the context of SAH, CTP can detect early ischemic changes that precede clinical deterioration, enabling earlier intervention. This modality is beneficial in patients who do not exhibit significant large-vessel vasospasm but are still at risk for DCI due to microvascular disturbances or impaired autoregulation.[45]

The integration of CTP into routine diagnostic protocols for SAH has been associated with improved outcomes, as it facilitates the timely initiation of therapies to restore adequate cerebral perfusion. CTP also helps in stratifying patients based on their risk of DCI, guiding decisions regarding the intensity of monitoring and the need for interventions such as induced hypertension or endovascular therapies.[46]

Biomarkers

Biomarkers have emerged as crucial tools for the early detection and management of DCI. Recent advances in genomics have identified specific single nucleotide polymorphisms that may predict individual susceptibility to DCI, such as those related to the epoxyeicosatrienoic acid metabolic pathway, catechol-O-methyltransferase, angiotensin-converting enzyme, and high mobility group box 1 (HMGB1) proteins. These genetic markers provide insight into the molecular mechanisms that increase the risk of ischemic events post-SAH, potentially allowing for more personalized therapeutic approaches.

Proteomic studies have also highlighted several protein biomarkers, such as phosphorylated neurofilament heavy chain, neuropeptide Y, copeptin, and glial fibrillary acidic protein, which have shown associations with DCI. For instance, copeptin, a marker of the hypothalamic–pituitary–adrenal axis, has been strongly correlated with vasospasm-related stress responses and poor outcomes, according to recent studies. Inflammatory biomarkers, including C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, are frequently elevated in patients with SAH who develop DCI, reflecting the significant role of systemic and local inflammation in the pathophysiology of these conditions.[47]

Despite the identification of these biomarkers, their translation into routine clinical practice is still limited. The variability in study designs, patient demographics, and outcome measures has contributed to the difficulty in establishing standardized biomarker panels for clinical use. Most of the current data come from retrospective studies, which are subject to bias and lack the rigor of prospective, randomized trials. Until these biomarkers are validated and standardized, their application in clinical practice will remain primarily research-based, serving as a promising yet underutilized resource in neurocritical care.

Strategies for the Prevention and Management of Cerebral Vasospasm

Directions and Emerging Therapies

As our understanding of DCI evolves, so does the potential for novel therapeutic approaches that target the underlying mechanisms of this complex condition.

• Targeting microvascular dysfunction and inflammation: therapies that preserve microvascular integrity and reduce inflammation are promising avenues for preventing and treating DCI. These may include agents that stabilize endothelial function, inhibit the formation of microthrombi, or modulate the inflammatory response in the brain. Additionally, the use of neuroprotective agents that can mitigate the effects of CSDs and other neuronal stressors is an area of active investigation.

• Personalized medicine approaches: the future of DCI management may also see a shift toward personalized medicine, where treatment protocols are tailored based on individual patient risk profiles. This could involve using genetic and biomarker studies to identify patients at high risk for DCI, allowing for early and targeted interventions.

Prevention of Vasospasm

Given the high morbidity and mortality associated with cerebral vasospasm, preventive strategies are of paramount importance in the management of SAH patients. Several approaches have been investigated to reduce the incidence and severity of vasospasm, with varying degrees of success.

Inhibition of Inflammation

The inflammatory response following SAH is a critical factor in the development of vasospasm. Studies have shown that leukocyte infiltration into the arterial walls and the subsequent production of pro-inflammatory cytokines play a central role in promoting vasoconstriction. Elevated levels of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in the CSF have been correlated with the development of vasospasm.[48]

Various anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs, corticosteroids, and immunosuppressive agents such as FK-506 and cyclosporine A, have been evaluated for their potential to reduce vasospasm. However, while these therapies have shown some promise in preclinical studies, their efficacy in clinical practice remains unproven, and their use is not currently recommended as a standard of care.

Blockade of Spasmogens

Pharmacological blockade of spasmogenic substances, such as ET-1, has emerged as a promising strategy for preventing vasospasm. ET-1 is a potent vasoconstrictor whose levels are elevated in the plasma and CSF of patients with SAH.[49] The ET-1 antagonist clazosentan has been studied extensively in clinical trials and has shown a dose-dependent reduction in the incidence of severe vasospasm and new infarcts on computed tomography imaging.[50] Despite these findings, the impact of clazosentan on overall clinical outcomes remains unclear, and further research is needed to determine its role in the routine management of SAH.

Statins, widely used for their lipid-lowering effects, have also been investigated for their potential to reduce vasospasm. Statins may exert protective effects by upregulating endothelial nitric oxide synthase and reducing the production of inflammatory cytokines. Clinical studies have shown that statin therapy is associated with a reduced risk of vasospasm and improved outcomes in SAH patients. However, the optimal dosing and timing of statin therapy in this context are still under investigation.

Cisternal Thrombolysis and CSF Drainage

The removal of blood from the subarachnoid space is another approach that has been explored to prevent vasospasm. Cisternal irrigation with saline during aneurysm surgery is routinely performed to clear subarachnoid blood, though its efficacy in reducing vasospasm has not been conclusively demonstrated.[51] Some studies have investigated the use of tissue plasminogen activator instilled into the cisterns or ventricles, either directly or via a ventricular drain, to accelerate blood clearance and reduce the risk of vasospasm.[52]

An alternative approach is lumbar CSF drainage, which several studies have shown to reduce the incidence of vasospasm and vasospasm-related infarctions.[53] By lowering CSF pressure and facilitating the removal of subarachnoid blood, lumbar drainage may help prevent the cascade of events leading to vasospasm.

Management of Established Vasospasm

Once vasospasm has developed, aggressive management is required to prevent DCI and its associated neurological sequelae. The mainstays of treatment include pharmacological therapies, endovascular interventions, and supportive care.

Pharmacological Management

• Nimodipine is currently the only Food and Drug Administration-approved pharmacological agent for the treatment of cerebral vasospasm. This dihydropyridine calcium channel blocker acts primarily on arterial smooth muscle, preventing vasoconstriction by inhibiting calcium influx. Nimodipine is administered orally at a dose of 60 mg every 4 hours for 21 days, beginning as soon as possible after the onset of SAH.[54] Numerous studies have demonstrated the efficacy of nimodipine in reducing the incidence of DCI and improving neurological outcomes in SAH patients.

• Milrinone is another agent that has gained attention in the management of vasospasm. Milrinone is a phosphodiesterase III inhibitor that increases intracellular cyclic adenosine monophosphate levels, leading to vasodilation and improved CBF. Both IA and intravenous administrations of milrinone have been studied, and significant improvements in vessel diameter and neurological outcomes have been reported. The “Montreal Neurological Hospital Protocol,” which includes a bolus followed by a continuous infusion of milrinone, has been shown to be effective in treating vasospasm while minimizing hemodynamic complications.[55]

• Fasudil, a Rho kinase inhibitor, has been studied for its ability to reduce smooth muscle contraction and thereby alleviate vasospasm.[56] Unlike many other vasodilators, fasudil does not significantly lower systemic blood pressure, making it a potentially safer option for patients with hemodynamic instability.

• Magnesium sulphate has been investigated as a noncompetitive calcium antagonist that induces vasodilation by blocking voltage-dependent calcium channels.[57] In addition to its vasodilatory effects, magnesium reduces the production of vasoconstrictors such as ET-1 and ROS. However, clinical trials have produced mixed results, and the routine use of magnesium in the management of vasospasm is not currently recommended ([Table 3]).

Table 3 Pharmacotherapy for vasospasm

Drug	Mechanism	Advantage
Papaverine	cAMP inhibitor, blocks Ca++ channels	Improves CBF and CMRO2
Milrinone	cAMP PDE III inhibitor	Safe, effective, minimal hemodynamic changes
Verapamil	NDHP Ca++ channel blocker	Tolerated at higher doses, minimal ICP increase
Nimodipine	DHP Ca++ channel blocker	Neuroprotective, prevents excitotoxicity
Nicardipine	DHP Ca++ channel blocker	Selective for vascular smooth muscle cells

Abbreviations: cAMP, cyclic adenosine monophosphate; CBF, cerebral blood flow; DHP, dihydropyridine; ICP, intracranial pressure; NDHP, nondihydropyridine; PDE, phosphodiesterase.

Endovascular Therapy

Endovascular interventions are often required for patients who do not respond adequately to pharmacological therapy or for those who cannot tolerate the hemodynamic manipulations associated with interventions aimed at augmenting perfusion, such as the previously popular “triple-H” therapy (hypertension, hypervolemia, and hemodilution).[58] Endovascular techniques include balloon angioplasty and IA drug infusion, each with its own set of indications, advantages, and potential complications ([Table 4]).

Table 4 Summary of key trials pertaining to intervention in aSAH

Trial name	Year	Intervention	Key findings	Conclusion
Cooperative Aneurysm Study [9]	1990s	Early vs. Late Surgery	Early surgery during peak vasospasm led to worse outcomes compared to delayed surgery.	Delayed surgery until after peak vasospasm is associated with better outcomes.
ISAT (International Subarachnoid Aneurysm Trial) [60]	2002	Endovascular Coiling vs. Surgical Clipping	Endovascular coiling had better outcomes with fewer disabilities compared to surgical clipping.	Endovascular coiling is preferred for suitable aneurysms, especially in low-risk patients.
BRAT (Barrow Ruptured Aneurysm Trial) [61]	2012	Clipping vs. Coiling	No significant difference in outcomes between clipping and coiling for ruptured aneurysms.	Both clipping and coiling are viable options; choice depends on aneurysm characteristics.
ISAT 2 [62]	Ongoing	Endovascular Coiling vs. Surgical Clipping	Expected to refine guidelines based on advancements in techniques since the original ISAT.	Aims to further clarify the role of coiling vs. clipping in contemporary practice.

• Balloon angioplasty is typically reserved for the treatment of vasospasm in large, proximal arteries such as the ICA, MCA, and BA.[59] The procedure involves the insertion of a balloon catheter into the affected vessel, followed by controlled inflation to mechanically dilate the artery. While balloon angioplasty often provides more durable results than pharmacological treatments, it carries risks such as vessel rupture, reperfusion injury, and embolization. The procedure is technically challenging and should be performed by experienced interventionalists.

• Pharmacological angioplasty involves the IA infusion of vasodilatory agents directly into the affected vessels. Commonly used agents include papaverine, verapamil, nicardipine, and milrinone. This approach allows for more distal arterial penetration and is generally associated with a better safety profile than balloon angioplasty. However, potential drawbacks include hypotension, increased intracranial pressure (ICP), and the need for repeated treatments due to recurrent vasospasm.

• Perfusion augmentation is a crucial component of vasospasm management to improve CBF and prevent ischemia. Recent literature increasingly questions the efficacy of “Triple-H” therapy—hypertension, hypervolemia, and hemodilution—in managing vasospasm after SAH. Among these, induced hypertension remains the most supported, with vasopressors like norepinephrine being effective in improving cerebral perfusion; however, careful monitoring is essential to avoid complications like cerebral edema and increased ICP.[63] The HIMALAIA trial was designed to determine the effectiveness of induced hypertension in patients with symptoms of DCI; however, the trial was stopped prematurely due to slow recruitment and futility on CBF, with no clinical benefits.[64] [65]

• Hypervolemia, once thought to improve CBF, has shown limited benefits, with recent studies indicating it may not significantly reduce DCI and can cause pulmonary edema and heart failure, suggesting a need for individualized fluid management, or goal-directed fluid therapy.[66] Hemodilution, originally intended to decrease blood viscosity, is now largely disfavored due to its potential to impair oxygen delivery and exacerbate ischemia, with current recommendations emphasizing the maintenance of adequate hemoglobin levels rather than deliberate dilution to optimize cerebral oxygenation.

Brain Protection Strategies

In addition to the direct management of vasospasm, several neuroprotective strategies have been explored to minimize the extent of brain injury and improve overall outcomes ([Table 5]).

Table 5 Summary of key trials pertaining to neuroprotective agents in aSAH

Trial name	Year	Intervention tested	Key findings	Conclusion
Nimodipine vs. Placebo [72]	1989	High-dose Nimodipine	High-dose nimodipine did not show a statistically significant improvement in outcomes compared to standard doses.	Higher doses of nimodipine do not provide additional benefit and may increase side effects.
Tirilazad [73]	1997	Tirilazad mesylate (antioxidant)	Tirilazad did not reduce mortality or improve outcomes despite reducing vasospasm incidence.	Antioxidant therapy with tirilazad is not effective in improving outcomes post-SAH.
CONSCIOUS-1 [50]	2008	Clazosentan (Endothelin-1 antagonist)	Clazosentan significantly reduced the incidence of angiographic vasospasm, but did not improve clinical outcomes (mortality, DCI).	While effective in reducing vasospasm, clazosentan did not translate to better outcomes.
IMASH [74]	2010	Magnesium sulphate (MgSO4)	Magnesium sulphate did not reduce the incidence of DCI or improve clinical outcomes in SAH patients.	Prophylactic magnesium sulphate is ineffective in preventing DCI or improving outcomes.
CONSCIOUS-2 [75]	2011	Clazosentan	Clazosentan reduced vasospasm but did not improve clinical outcomes, including mortality and severe disability.	Clazosentan ineffective in improving overall clinical outcomes despite vasospasm reduction.
CONSCIOUS-3 [76]	2011	Clazosentan	No significant difference in the primary endpoint (death, vasospasm-related complications) between treatment and placebo groups.	Clazosentan did not improve primary clinical outcomes in SAH patients.
MASH-2 [57]	2012	Magnesium sulphate (MgSO4)	No significant reduction in poor outcomes (death, dependence) or incidence of DCI in patients receiving magnesium.	Magnesium therapy failed to show benefit in clinical outcomes for SAH patients.
STASH [77]	2014	Simvastatin	Statin therapy did not reduce the incidence of DCI or improve neurological outcomes in SAH patients.	Statins are not effective in preventing DCI or improving outcomes in SAH.
NEWTON [78]	2017	Intrathecal nimodipine microparticles	Despite theoretical benefits, the trial showed no significant improvement in clinical outcomes.	Intrathecal nimodipine did not provide clinical benefit in preventing DCI or vasospasm.
EARLYDRAIN [53]	2020	Early lumbar CSF drainage	Early lumbar CSF drainage significantly reduced the incidence of DCI and improved functional outcomes.	Early drainage shows promise in reducing DCI and improving outcomes in SAH patients.
LUMAS [79]	2012	Lumbar drainage	Lumbar drainage reduced the incidence of vasospasm but did not improve overall outcomes compared to standard care.	The efficacy of lumbar drainage in preventing vasospasm remains inconclusive.
MILRISPASM [80]	2021	Milrinone infusion	Milrinone may reduce the incidence of vasospasm, but its effect on long-term outcomes is not fully understood.	Milrinone shows potential for vasospasm reduction, but further data are needed.

Abbreviations: CSF, cerebrospinal fluid; DCI, delayed cerebral ischemia; SAH, subarachnoid hemorrhage.

• Erythropoietin (EPO) is a glycoprotein with potent neuroprotective effects, including anti-inflammatory, antiapoptotic, and antioxidant properties. Although the precise mechanisms by which EPO reduces vasospasm remain unclear, several studies have demonstrated its ability to increase brain tissue oxygen tension and reduce the severity of DCI.[67] High-dose EPO therapy has been associated with improved neurological outcomes in patients with severe vasospasm, though further research is needed to establish optimal dosing and safety profiles.

• Estrogen, particularly 17β-estradiol (E2), has shown promise as a neuroprotective agent in cerebral vasospasm. E2 exerts vasodilatory effects through multiple mechanisms, including attenuating ET-1 receptor upregulation, modulation of calcium ion channels in smooth muscle cells, and normalization of nitric oxide synthase activity. Experimental studies have shown that E2 can prevent or reverse vasoconstriction following SAH, suggesting a potential therapeutic role for estrogen in the management of vasospasm.[68]

• Nitric oxide (NO) is a critical regulator of CBF and a key mediator of vascular tone. Reduced NO levels following SAH contribute to the development of vasospasm by impairing endothelial function and promoting vasoconstriction. Strategies to increase cerebral NO levels, such as the use of NO donors (sodium nitrite, nitroglycerin, sodium nitroprusside) or inhaled NO, have shown neuroprotective effects in animal models.[69] [70] However, the clinical application of these strategies requires further investigation to determine their efficacy and safety in human patients.

• Tenascin-C knockout: tenascin-C is an extracellular matrix glycoprotein involved in the neuroinflammatory response following central nervous system injury. Elevated levels of tenascin-C in the CSF have been associated with worse clinical outcomes in SAH patients, and experimental studies have shown that knockout of tenascin-C can reduce vasospasm, inflammation, and neuronal apoptosis.[71] These findings suggest that targeting tenascin-C may offer a novel therapeutic approach for preventing and managing cerebral vasospasm.

Clinical Impact and Outcomes

The clinical impact of DCI and the role of advanced monitoring techniques are particularly significant in patients with good-grade SAH, who are initially expected to have a favorable prognosis. However, even in this cohort, the development of DCI can lead to severe outcomes, including cognitive deficits and reduced quality of life.

• Outcomes in good-grade SAH patients: recent studies have highlighted that despite an initially good clinical grade, a substantial proportion of SAH patients experience secondary deterioration due to DCI. This deterioration often leads to poor outcomes comparable to those seen in patients with higher grade SAH.[81] The introduction of INM in these patients has been shown to improve outcomes by facilitating the early detection and treatment of DCI, thus reducing the burden of cerebral infarctions and improving the rate of good recovery.

• Long-term neurological and cognitive sequelae: beyond immediate survival and functional outcomes, SAH patients often suffer from long-term cognitive and psychological sequelae, including mood disturbances, memory impairment, and difficulty with complex cognitive tasks. Traditional scales, such as the Glasgow Outcome Scale, do not capture these outcomes, underscoring the importance of comprehensive neuropsychological assessment in this population.[82] The reduction in ischemic burden achieved through advanced monitoring and targeted interventions may help mitigate these long-term effects, leading to a better overall quality of life for SAH survivors.

These insights underscore the importance of aggressive monitoring and early intervention in all SAH patients, regardless of their initial clinical grade, to prevent the devastating effects of DCI and improve both short- and long-term outcomes.

Conclusion

While significant challenges remain in managing cerebral vasospasm and DCI, ongoing research and technological advances offer hope for more effective and personalized approaches to treatment. By continuing to expand our understanding of the underlying pathophysiology and integrating novel therapeutic strategies into clinical practice, we can improve outcomes for patients suffering from this devastating complication of SAH.

Conflict of Interest

None declared.

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Publication History

Article published online:
05 March 2025