Cerebral Vasospasm: Complications and Avoidance




Abstract


Treatment of vasospasm associated with aneurysmal subarachnoid hemorrhage can be complex and fraught with potential complications. The long-time course requires continual diligence to avoid these complications. At present, no clear, consistent, and codified treatment of vasospasm is recommended in the literature, and as a result, research is robust and ever-advancing.




Keywords

aneurysmal subarachnoid hemorrhage, cerebral vasospasm, complications, medical treatment, microsurgery, neuroendovascular

 




Highlights




  • •

    Multimodal management of cerebral vasospasm should include both medical and neuroendovascular options as part of the treatment paradigm.


  • •

    Correct application of intraarterial calcium channel antagonists should be the initial neuroendovascular treatment applied.


  • •

    Appropriate sizing of an intracranial-arterial balloon for angioplasty is crucial. Oversizing a balloon must be avoided to prevent potentially devastating sequelae.





Introduction


Subarachnoid hemorrhage as a result of aneurysm rupture (aSAH) is a worldwide phenomenon. The annual incidence is 9 per 100,000 persons (>30,000 cases) in the United States and is as high as 23.5 per 100,000 in Japan and 21.3 per 100,000 in Finland. The incidence tends to be slightly higher in women than in men. Cerebral vasospasm as a result of aSAH is a major source of morbidity and mortality and can occur in up to 70% of patients after aSAH. The study of cerebral aneurysms as a simultaneously devastating and awe-inspiring intracranial disease process and key contributor in subarachnoid hemorrhage (SAH) has continued to progress since Symonds’ description of hemorrhage within the subarachnoid space in 1923. Initial treatments were surgically focused with wrapping by Dott in 1931, clip ligation by Dandy in 1938, and proliferation of the use of the operative microscope in the 1960s. With the introduction of coil embolization by Guglielmi et al. in 1990, neuroendovascular therapy forever changed the treatment of cerebral aneurysms and subsequently the treatment of aSAH.


Cerebral vasospasm continues to be the leading treatable cause of mortality and morbidity in patients with aSAH. Vasospasm has also been linked to nonaneurysmal sources such as skull-base tumor resection, meningitis, amygdalohippocampectomy, sexual intercourse, and even high consumption of black licorice. However, aSAH initiates the most robust vasospastic response in the cerebral vasculature, which is what we will focus on in this chapter.


Cerebral vasospasm as a sequelae of aSAH was initially described in the literature by Ecker and Riemenschneider in 1951. Allcock and Drake described vasospasm further in 1965. Major advances in the perioperative management of vasospasm were spearheaded with the introduction of induced hypertension, hypervolemia, and hemodilution (“HHH” or “triple-H” therapy) in the 1960s. Ongoing research evolves regarding the mitigation of the vasospastic effects of aSAH. An immense quantity of data has been studied and reported in the literature regarding cerebral vasospasm as a result of aSAH; however, no clear and definitive treatment paradigm has emerged.




Pathophysiology


Vasospasm after aSAH is typically seen 3 to 14 days after aneurysm rupture. The biochemical and pathologic bases of cerebral vasospasm have been extensively studied and reviewed. Several hypotheses attempt to explain the pathogenesis and pathophysiology of vasospasm. Pasqualin and Findlay et al. revealed an increase in the production of protein kinase C (PKC) with an additional increase in the production of vasoconstricting prostaglandins and an inhibition of the production of prostacyclin (a vasodilator) as a partial contributor to the underlying pathophysiology.


Takenaka et al. used rodent vascular smooth muscle cells as a model in conjunction with cerebrospinal fluid (CSF) from patients with aSAH. They surmised that the subsequent increase in PKC led to excessive mobilization and intracellular activity of free calcium. They further theorized that increased PKC led to extracellular and intracellular influx into vascular smooth muscle, causing phosphorylation of contractile proteins and subsequent contraction of the vessels.


Experimental evidence exists to support the local depletion of nitric oxide (NO) as a major contributor in vasospasm, which is a crucial tonic dilator of intracranial arteries, by virtue of its activation of cyclic guanosine monophosphate (cGMP). Inactivation of NO by oxyhemoglobin or superoxide radicals may have a role in initiating or contributing to the vasospastic process. Pluta used a primate model to study the role of oxyhemoglobin in the development of delayed cerebral vasospasm. The author noted that oxyhemoglobin and its oxidized bilirubin metabolic fragments exert oxidative stress by damaging NO-producing neurons in the vessel walls. As a result, there is less available NO in the vessel wall. The vessel wall is unable to dilate appropriately, and constriction is then unopposed. This may lead to the activation of calcium channels and of vasoactive proteins such as arachidonic acid to produce vasoactive lipids or, alternatively, bilirubin oxidation products that can precipitate vessel wall contraction. Animal models have been instrumental in outlining the changes related to smooth muscle contractility. aSAH can facilitate an increase in the availability, relative potency, and sensitivity of endothelin-1 (ET-1), which is a potent vasoconstrictor. ET-1 levels rise in response to shear stress, hypoxia, catecholamines, insulin, and angiotensin II. ET-1 levels are subsequently counteracted by NO through the intermediary roles of endothelin-3, prostaglandin E2, and prostacyclin.




Time Course


Some data indicate that cerebral vasospasm can occur in as many as 10% of patients within 3 days after aSAH. However, it is commonly accepted that cerebral vasospasm almost never occurs <3 days after aSAH. The peak onset of vasospasm is quoted at day 6 to 10 post aSAH with a typical at-risk range of 3 to 14 days post aSAH. There is the possibility of cerebral vasospasm up to 21 days post aSAH; however, this is uncommon. The clinical manifestations of cerebral vasospasm are generally resolved within day 12 to 14. However, radiographic vasospasm, whether clinically significant or not, resolves much more slowly (within 3–4 weeks). Radiographic vasospasm has been identified in 20% to 100% of angiograms on post aSAH day 7. However, clinically evident vasospasm is typically seen in only approximately 30% of that same cohort of patients. Vasospasm, as it pertains to the degree of aSAH, is associated with the presenting clinical grade as well as with the amount and location of blood present on the initial computed tomography (CT) scan. CT results are currently one of the more widely used and reliable predictors of future vasospasm. The clinical examination, coupled with regular monitoring by transcranial Doppler (TCD) imaging, is the most common and useful means of posthemorrhage surveillance as well as cerebral vasospasm diagnosis after aSAH.




Treatment of Vasospasm


Medical Treatment


The most commonly used therapy for medical treatment of cerebral vasospasm is triple-H, or HHH, therapy. The physiologic goals of the triple-H therapy paradigm are to augment blood flow by increasing intravascular volume while reducing viscosity. Hypertension is often the modality initially employed, according to the literature, but also at our institution. It is achieved with vasopressor augmentation, most often by administering a low dose of phenylephrine or dopamine and titrating to blood pressure (BP) parameters to achieve the desired clinical or radiographic effect. The component of hemodilution in the triple-H therapy continues to be the least-defined aspect of the treatment. Enhancing the volume status can precipitate increases in cardiac output and peripheral vascular resistance, which translates into increased cerebral perfusion. However, it may also contribute to volume overloading and the associated sequelae. A hematocrit goal of 30% to 35% is often suggested as an ideal balance to maximize oxygen-carrying capacity while limiting the negative effects of increased viscosity. Instituting triple-H therapy should be cautiously considered given the risk profile. Cardiopulmonary failure, worsening of cerebral edema, renal failure, hyponatremia, and sepsis are all known complications associated with triple-H therapy.


Despite a limited number of prospective clinical trials, triple-H therapy is widely used to varying degrees. At our institution, we more often employ hypertension as the initial medical modality instituted. As mentioned, hypervolemic therapy can have negative sequelae, whereas hypovolemia carries a known risk for delayed ischemia. Euvolemia may have similar positive effects on vasospasm with a lower risk profile when compared with hypervolemia in triple-H therapy. In a systematic review of the triple-H components, analysis suggested that induced hypertension as monotherapy may be more efficacious with respect to cerebral perfusion and blood flow than hemodilution or hypervolemia alone. The American Heart Association (AHA) recommendations for triple-H therapy currently suggest maintaining euvolemia to prevent vasospasm and suggest induced hypertension for patients in active vasospasm. However, the AHA recommendations advise against inducing hypervolemia without radiographic evidence of vasospasm.


The role of calcium channel antagonists in the medical treatment of vasospasm associated with aSAH has been well studied. However, most of the randomized controlled trials have been focused on treatment with nicardipine and nimodipine. A metaanalysis of 16 studies including more than 3300 patients concluded that calcium channel antagonists reduced the risk of poor outcomes. The results were largely attributed to the administration of oral nimodipine, which is cemented as a nearly universal practice in the treatment of aSAH. It is crucial to note that although nimodipine is widely used in the setting of aSAH and reduces the risk of poor outcome, it does not reverse angiographic vasospasm. The effect of nimodipine is believed to be associated with a decrease in vessel resistance in the smaller arterial beds with associated pial collateral augmentation of flow. There is also a reported effect of neuroprotection due to the reduction of calcium-mediated excitotoxicity. Other calcium channel antagonists, such as nicardipine and fasudil, have been intently studied. Although they produce a variable effect on vasospasm, there is minimal effect on the overall clinical outcome.


The success of calcium channel antagonists led to research with magnesium for cerebral vasospasm prophylaxis in the setting of aSAH. Magnesium, like calcium, is also a divalent cation with tropism for voltage-dependent calcium channels. Magnesium may have some additional neuroprotective effects secondary to its inhibition of glutamate. Much of the initial data with magnesium, albeit based on small sample sizes, showed trends toward improvements in Glasgow Outcome Scale (GOS) scores and TCD velocities. Further studies showed nonstatistically significant trends toward improved outcomes. However, the results did show significant side effects, including hypocalcemia and hypotension. Larger trials with magnesium did not provide clear evidence of effectiveness, and the side-effect profile remained constant. In a metaanalysis that investigated seven trials and more than 2000 patients, no reduction of poor outcomes was established, prompting the authors to recommend against the use of intravenous (IV) magnesium for treatment or prophylaxis of cerebral vasospasm. Numerous trials have been conducted to search for the ideal medical treatment for cerebral vasospasm. Multiple studies investigating statins, endothelin receptor antagonists, NO, free radical scavengers, thromboxane inhibitors, antiinflammatory treatments, thrombolytics, and the search for other neuroprotective agents have not yielded any definitive medical treatment.


Interventional Treatment


Microsurgery


Microsurgery is used for the acute treatment of appropriate aneurysms. Currently, there is no well-established open microsurgical treatment of vasospasm. Data support that microsurgical treatment for acutely ruptured aneurysms can yield good outcomes and that intraoperative measures can help reduce the incidence of vasospasm. Fenestration of the lamina terminalis in the microsurgical treatment of anterior communicating artery aneurysms has been reported to reduce the need for shunting from ~14% to 4.2% as well as reduce the frequency of vasospasm from 54.7% to 29.6% and ultimately improve outcome in ~34% to ~70% of patients. Additional operative maneuvers that have been noted to further reduce the occurrence of vasospasm include clot removal, intracisternal injection of thrombolytics, and local application of vasodilators.


Neuroendovascular


Currently, there is no standard treatment paradigm for the endovascular treatment of cerebral vasospasm. Survey investigations have yielded a varying degree of identification and treatment of cerebral vasospasm. Hollingworth et al. analyzed survey data from 344 physicians (177 US, 167 non-US) from 32 countries. Approximately half of the physicians had 10+ years of experience as well as a mix of low- and high-volume clinical practices. TCD ultrasound was the most commonly used screening modality by both US (70%) and non-US (53%) physicians. Verapamil was the most common intraarterial (IA) first-line therapy in the United States, whereas nimodipine was the most common therapy used by non-US physicians. Balloon angioplasty was widely performed by 91% of US physicians and 83% of non-US physicians.


Intensive endovascular treatment of vasospasm may result in favorable outcomes. Mortimer et al. prospectively analyzed patients of similar aSAH grade (World Federation of Neurosurgical Societies Grade 1–2) presenting within 72 hours of SAH. They identified those with no vasospasm and those with severe vasospasm (>50% luminal narrowing on cerebral angiogram). These authors noted no statistical difference in outcome for low-grade patients with no vasospasm versus low-grade patients with severe vasospasm who were treated with induced hypertension, IA verapamil, and transluminal balloon angioplasty. They concluded that maximal combined medical and endovascular treatment of severe vasospasm can produce favorable outcomes similar to those for aSAH patients who do not have vasospasm (90-day modified Rankin Scale [mRS] scores of 0–2, 88.2%; GOS scores of 4–5, 94%).


The use of IA verapamil as an adjunct to progressive and symptomatic medically managed vasospasm or as an addition to intraluminal balloon angioplasty is a constant at our institution. The addition of verapamil is a safe and effective means of endovascular management of vasospasm. In their retrospective review of 34 procedures of IA verapamil infusion as an adjunct to balloon angioplasty, Feng et al. noted the relative safety and efficacy of the infusion. They used IA verapamil in three settings: (1) before balloon angioplasty for prophylaxis against catheter-initiated vasospasm, (2) for treating mild vasospasm that did not warrant balloon angioplasty, and (3) for treating moderate to more severe vasospasm that could not be safely treated with balloon angioplasty. No clinically significant systemic changes (e.g., BP, heart rate) were observed after 10 minutes of verapamil administration. However, others did note systematic changes after IA verapamil infusion. Prospective in vivo data from Flexman et al. show that each 5 mg of IA verapamil is associated with a 3.5 mm Hg reduction in systemic mean arterial pressure and minimal cardiac chronotropic effects. Stuart et al. noted that patients receiving high doses of IA verapamil (total dose ≥15 mg) had transient postprocedural increases in intracranial pressure (ICP) and brain glucose and reductions in cerebral perfusion pressure for up to 12 hours after administration. The infusion rate should be cautiously monitored because rapid administration of IA verapamil can induce seizures. We typically use 10 to 30 mg per vessel and infuse slowly over 3 to 4 min per 10 mg and have had minimal negative sequelae.


Nicardipine, a dihydropyridine calcium channel antagonist, has also been studied as an IA agent for the treatment of vasospasm. It has advantages similar to those of verapamil in its relative tissue selectivity, which allows for minimal cardiac effects. A great deal of the research that evaluated calcium channel antagonists as potential antispasmodic agents was generated by cardiothoracic research with coronary artery bypass grafts. The initial results from He and Yang in their work with human radial arteries pointed to dihydropyridine calcium channel antagonists (nicardipine, nifedipine) as potentially more advantageous than verapamil or diltiazem in the treatment of vasospasm. Additional rationale came from the intraoperative subarachnoid or intracisternal use of calcium channel antagonists in aSAH patients treated with microsurgery and an experimental SAH model in the rabbit. Then, in a prospective, double-blinded trial of 125 patients conducted in 1983, Allen et al. showed that nimodipine improved outcomes of patients with aSAH. Lavine et al. noted a more robust response to IA nicardipine than verapamil in ET-1–induced vasospasm in rabbits. Badjatia et al. reported their results with IA nicardipine in 44 treated vessels in 18 patients. They angiographically confirmed that nicardipine produced an immediate improvement in vessel caliber with no sustained cardiovascular sequelae. However, these authors noted transient and some prolonged instances of elevated ICP post procedure as well as sustained improvements in TCD velocities as long as 4 days postinfusion. Currently, Level 1 evidence does not exist to confirm which IA antispasmodic agent is more efficacious.


At our institution, we favor IA verapamil (10–30 mg per vessel, infused over 3–4 min per 10 mg) with or without balloon angioplasty in treating patients with aSAH-induced vasospasm that is refractory to medical management (see medical management section). Some centers favor balloon angioplasty only, as opposed to IA antispasmodics.


Intraarterial balloon angioplasty remains the most definitive treatment of medically refractory cerebral vasospasm. The initial investigations from Zubkov et al. included more than 100 vessels and helped establish the efficacy of balloon angioplasty. The initial success rate with balloon angioplasty ranged from 30% to 90%. Later, Hoh and Ogilvy noted a 62% success rate with balloon angioplasty in a case series review. The best results associated with balloon angioplasty are seen in more proximal segments, particularly distal internal cerebral artery (ICA), M1 segment of the middle cerebral artery (MCA), and A1 segment of the anterior cerebral artery (ACA). Balloon angioplasty is avoided in more distal segments where the arterial wall is thinner.


Although quite effective, balloon angioplasty for cerebral vasospasm may be associated with certain procedural caveats and limitations worth noting. Utilizing balloon angioplasty in a ruptured but unsecured aneurysm should be avoided given the risk of rerupture. The potential complications of balloon angioplasty have been well noted in the literature. Vessel rupture, vessel perforation, thromboembolic events, intracranial hemorrhage, arterial dissection, reperfusion injury, and hemorrhage from unsecured aneurysms have been reported. At our institution, we routinely infuse IA verapamil before balloon angioplasty to assist in navigation and to reduce the risk of procedural complications. We have used compliant, semicompliant, supercompliant, and noncompliant intracranial balloons in our practice. However, these can often vary in size. When sized appropriately, even noncompliant balloons can be safe and effective for angioplasty. In a multicenter study, Patel et al. reported on 165 angioplasty procedures using noncompliant balloons for SAH-induced vasospasm with improvement in 97% of cases without any procedure-related complications. We also use compliant balloons for angioplasty. Stent retrievers have also been used to treat vasospasm in M1, M2, A1, and A2 segments with lasting (>24 h) radiographic success and without complication. Particularly when using a noncompliant balloon, it is crucial that the balloon is sized appropriately. Use of a noncompliant balloon that is too large drastically increased the risk of vessel rupture. At our institution, with rare exceptions (see case example), it is our practice to avoid choosing a balloon larger than two-thirds the size of the native vessel. However, particularly when using a noncompliant balloon, we rarely size above a 2.25-mm diameter in the MCA.


We have also had early radiographic success in the use of stent retrievers in refractive vasospasm cases that had been maximally medically treated and treated maximally with IA calcium channel antagonists as well as balloon angioplasty. This version of adjunctive mechanical angioplasty is not widely used and may have good indications for those particularly refractory cases. There is, however, a need for additional study to appropriately elucidate the long-term clinical and radiographic outcomes.




Conclusion


Treatment of vasospasm associated with aSAH can be complex and fraught with potential complications from start to finish, as exemplified in the previous case illustration. The longtime course requires continual diligence to avoid potential complications. At present, no clear, consistent, and codified treatment of vasospasm is recommended in the literature, and as a result, research is robust and ever-advancing.



Illustrative Case


A 25-year-old man with a history of congenital glaucoma with associated bilateral vision loss presented to our facility with a sudden and progressively worsening headache. The patient denied any recent or remote history of trauma. Other than his baseline lack of vision, the patient did not exhibit any focal neurologic deficits on the initial clinical examination. There was no nausea, emesis, or nuchal rigidity. The patient’s vital signs were within normal limits.


CT and CT angiography of the head showed diffuse SAH with hydrocephalus noted and no evidence of arteriovenous malformation, arteriovenous fistula, or aneurysm. Lumbar puncture showed an opening pressure of 10 mm Hg with associated and expected xanthochromia. However, there was some apparent decrease in the caliber of the intracranial vasculature that was suggestive of vasospasm ( Fig. 10.1A–E ). Magnetic resonance imaging (MRI) of the brain and cervical spine with and without contrast material was also unremarkable. Initial digital subtraction angiography (DSA) did not reveal any evidence of arteriovenous malformation, arteriovenous fistula, or aneurysm or evidence of vasculitis ( Fig. 10.2A–F ). The patient was subsequently admitted to the neuroscience intensive care unit.


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Jun 29, 2019 | Posted by in NEUROSURGERY | Comments Off on Cerebral Vasospasm: Complications and Avoidance

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