Curr Treat Options Neurol (2014) 16:278 DOI 10.1007/s11940-013-0278-x
CRITICAL CARE NEUROLOGY (KN SHETH, SECTION EDITOR)
Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage and Traumatic Brain Injury Saef Izzy, MD1 Susanne Muehlschlegel, MD, MPH1,2,3* Address *,1Department of Neurology (Neurocritical Care), University of Massachusetts Medical School, 55 Lake Ave North, S-5, Worcester, MA 01655, USA Email: [email protected] 2 Department of Surgery, University of Massachusetts Medical School, 55 Lake Ave North, S-5, Worcester, MA 01655, USA 3 Department of Anesthesiology/Critical Care, University of Massachusetts Medical School, 55 Lake Ave North, S-5, Worcester, MA 01655, USA Published online: 18 December 2013 * Springer Science+Business Media New York 2013
This article is part of the Topical Collection on Critical Care Neurology Keywords Cerebral vasospasm I Angiographic vasospasm I Delayed cerebral ischemia I Traumatic brain injury I Subarachnoid hemorrhage I Traumatic subarachnoid hemorrhage I Blast injury I Treatment I Aneurysmal subarachnoid hemorrhage
Opinion statement Cerebral vasospasm (cVSP) consists of the vasoconstriction of large and small intracranial vessels which can lead to cerebral hypoperfusion, and in extreme cases, delayed ischemic deficits with stroke. While most commonly observed after aneurysmal subarachnoid hemorrhage (aSAH), cVSP can also occur after traumatic brain injury (TBI) as we have described in detail in this review. For the past decades, the research attention has focused on cVSP because of its association with delayed cerebral ischemia, which is the largest contributor of morbidity and mortality after aSAH. New discoveries in the cVSP pathophysiology involving multifactorial complex cascades and pathways pose new targets for therapeutic interventions in the prevention and treatment of cVSP. The goal of this review is to demonstrate the commonalities and differences in epidemiology and pathophysiology of both aSAH and TBI-associated cVSP, and highlight the more recently discovered pathways of cVSP. Finally, the latest cVSP surveillance methods and treatment options are illustrated.
Introduction Cerebral vasospasm (cVSP) consists of the vasoconstriction of large and small intracranial vessels. It can lead to cerebral hypoperfusion, culminating in delayed ischemic
deficits with stroke. CVSP has most commonly been associated with aneurysmal subarachnoid hemorrhage (aSAH), but can also occur in traumatic brain injury (TBI).
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Epidemiology of cVSP For decades, the attention has focused on cVSP because of its association with delayed cerebral ischemia (DCI), which is the largest contributor of morbidity and mortality after aSAH [1••, 2, 3]. Fifteen percent of intracranial hemorrhages and 5 % of all strokes are due to aSAH from acute rupture of an intracranial aneurysm, affecting 145/100,000 persons annually [1••]. Following aSAH, 30–70 % of patients will develop cVSP between day 4 and day 14 after aneurysm rupture. Approximately half of these patients will develop DCI [1••]. Compared to aSAH-related cVSP, data on TBI-associated cVSP is sparse. The mechanistic etiologies of TBI-associated cVSP can be divided into cVSP following traumatic SAH (tSAH) [4] and blast-related cVSP after nearby high-explosive detonation. TSAH has been reported to occur in 39 %–65 % of all TBI cases [5–7], with 10 %–30 % having TBI-associated radiographic cVSP in the presence of SAH on head computed tomography (hCT) [7–9]. Its presence has been independently associated with poor functional outcome [6, 10, 11] albeit SAH may just be a marker of more severe TBI and not causing cVSP. To date, the largest study in tSAH (n=299) describing transcranial Doppler (TCD) defined cVSP reported the incidence of TBI-related cVSP to be lower than after aSAH [7]. It is not clear, however, whether this is due to a truly lower incidence, or whether it is less commonly detected because it is not suspected, and therefore, not routinely monitored. Blast-related cVSP is often associated with the presence of SAH, but SAH is not required for the development of cVSP [10, 12, 13], suggesting a different underlying mechanism. Both in vivo and in vitro studies have suggested that mechanical alteration of the cerebral blood vessels through direct impact or stretch from the blast may trigger the development of cVPS [10, 14]. In contrast to aSAH-related cVSP, where the onset of cVSP is between 3– 5 days after aSAH, lasting up to 14–21 days [1••], the onset of tSAH-related cVSP has been reported as early as within 1–2 days after injury [5, 8], with a peak at 5–7 days [10, 13]. The duration of tSAH-associated cVSP is generally shorter than that of aSAH with complete resolution usually in less than 14 days [10, 13]. Blast-related cVSP, however, has been reported to have an early onset within two days, with average cVSP duration of 14 days, lasting up to 30 days [13].
Risk factors ASAH-associated symptomatic cVSP and DCI share the same risk factors: admission hypertension, poor clinical grade, thick cisternal clot and intraventricular hemorrhage (modified Fisher score 4) [15–17]. In contrast, angiographic cVSP has been associated with younger age, tobacco use, poor clinical grade, and intracerebral hemorrhage [15, 18]. TBI-related cVSP has been associated with severe SAH on initial hCT and low Glasgow Coma Scale (GCS) on admission; however, this relationship is less concrete compared to aSAH [7, 9, 13].
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Clinically relevant definitions of cVSP and DCI Multiple definitions of cVSP exist, making the standardization of treatments and research end points difficult. Recently, investigators from the SAH Outcomes Project (Columbia University, New York, NY) reported the clinically most important definitions of cVSP [15], which are summarized in Table 1. DCI is clinically important as it has been independently associated with mortality and poor 3-month outcome [15, 19]. DCI commonly develops during the second week after SAH, peaking around day 9 [2]. Clinical worsening, a key determinant of DCI, can be acute focal weakness or loss of consciousness, but may be as subtle as worsening headaches [20••], and always has to be differentiated from rebleeding or other causes of deterioration such as seizures or sepsis-associated encephalopathy [1••]. Therefore, the diagnosis of DCI is limited in comatose and poorly responsive highgrade aSAH patients. Extensive research has been conducted on the relationship between angiographic cVSP and DCI and whether angiographic evidence of cVSP is required for a diagnosis of DCI. In one study, only 84 % of a DCI cohort had radiographic cVSP [15]. Furthermore, only 24–35 % of SAH patients imaged with hCT, and only 81 % imaged with magnetic resonance imaging (MRI) displayed an area of cerebral infarction correlating with the vessel territory of the vessel in angiographic cVSP [21, 22]. This raises the possibility of other underlying mechanisms, as described below. In TBI, the ability to detect clinically significant deficits is challenging due to the commonly decreased level of consciousness in the patients, and heterogeneity of the disease mechanisms.
Table 1. Definitions of cVSP and DCI* Type of cVSP
Definition
Symptomatic cVSP
Clinical worsening in the setting of new focal neurological signs, deterioration in level of consciousness, or both, in the absence of other possible causes (seizures, hydrocephalus, and edema); does not necessarily imply documented angiographic cVSP; occurs in 20 % to 40 % of aSAH patients [15, 97]; only symptomatic cVSP, but not TCD or angiographic cVSP correlated with DCI and mortality 3 months post aSAH [15] Arterial narrowing on DSA not attributable to catheter-induced spasm or atherosclerosis [1••]; occurs in up to 70 % of aSAH patients, indicating that angiographic cVSP can occur in the absence of symptoms [1••]; not all patients with angiographic cVSP experience DCI and vice versa [21, 98] Defined as a mean blood flow velocity in any vessel 9120 cm/sec, associated with symptomatic or angiographic cVSP [99] Defined as the presence of new infarction on hCT or MRI when the cause is felt to be attributable to cVSP; is primarily a clinical diagnosis, because it does not require DSA evidence of cVSP [3, 15]
Angiographic cVSP
TCD cVSP Delayed cerebral ischemia (DCI)
*Shown are clinically relevant definitions of cVSP and DCI, which were recently adopted into aSAH clinical practice guidelines and research [15].
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Pathophysiology of cVSP The underlying pathophysiologic mechanisms of cVSP remain poorly understood, but appear to be multifactorial.
Does SAH cause cVSP? Extensive basic and clinical research studies have attempted to validate this causal relationship. Initial animal studies had suggested that blood products from the SAH may cause cVSP [3, 23]. This theory was indirectly supported in an animal model [24] and a small human study in which removing the clot resulted in cVSP prevention. This, however, awaits validation in larger studies [25]. Hematoma location, volume, duration of presence, and density have all been shown to be independently associated with angiographic cVSP [3, 26, 27], however, without proving causation.
What causes cVSP? Several mechanisms may be responsible for the development of cVSP.
Hemoglobin (Hb) and cVSP Strong evidence exists from in vivo and in vitro studies that the release of oxyHb from the lysis of subarachnoid red blood cells is present in high concentrations in the cerebral spinal fluid (CSF) during the cVSP period. OxyHb acts as a spasmogen and may be a key mechanism responsible for cVSP [2, 28]. In addition, superoxide free radicals are released during autoxidation of Hb and may directly or indirectly cause vasoconstriction [2, 28]. Despite the extensive body of research, there is no general theory that can explain the role of the Hbs in all the events that lead to cVSP. This raises the hypothesis that the presence of Hb in the subarachnoid space may influence the arterial vasodilatory response by causing multiple, multifaceted interactions with endothelium, neuron or smooth muscle cells [2].
Alternative proposed mechanisms for cVSP Nitric oxide (NO) pathway Endothelial NO (eNO) is an endogenous signaling molecule which directly acts on vascular smooth cells causing vascular relaxation [2]. An altered NO pathway due to scavenging by Hb in the cisternal space or dysfunction of eNO synthase (eNOS) has been proposed to play an essential pathophysiological role in the development of cVSP [2]. Therapeutic intervention in a rat model with 17b-estradiol benzoate (E2) activating the estrogen receptor subtype A (ERa) was reported to attenuate cVSP and preserve the eNOS expression [29]. Vasodilators with pharmacological actions involving the NO pathway, nitrite [30] and
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Page 5 of 16, 278 sildenafil [31], have recently been studied with promising early safety results. Phase II trials of both medications are ongoing.
Hypoxia Inducible Factor-1 (HIF-1) Is a transcription factor that plays a key pathophysiological role in oxygen homeostasis and adaptive responses to hypoxia and oxidative stress. HIF-1 regulates more than 40 identified genes including erythropoietin, BNIP3, vascular endothelial growth factor (VEGF) and glucose transporter-1[32]. In animal studies, HIF-1 has been shown to possibly cause vasoconstriction within 24 hours and vasorelaxation at ~7 days after SAH [33]. This led to the hypothesis that the role of HIF-1 may be harmful in the early stage and neuroprotective at a later stage after SAH [33, 34]. HIF-1’s early pro-death and late pro-survival role remains under investigation.
Endothelin pathway Elevated levels of endothelin have been found in the CSF of aSAH patients [35, 36]. Endothelin-1 is a potent vascular smooth muscle cells vasoconstrictor, and acts on two specific receptors, ET(A) and ET(B). Activation of ET(A) and ET (B2) receptors on the vascular smooth muscle cells results in vasoconstriction, whereas activation of ET(B1) receptor subtype, expressed on the vascular endothelial cells, causes vasorelaxation [37] . Preclinical and early phase clinical prophylactic treatment with clazosentan, an ET-1 antagonist, were promising in limiting cVSP, but two recent Phase III trials did not improve 90-day clinical outcomes [38•].
Thrombin A serine protease is a coagulation protein produced in blood clots; it binds to fibrin and gradually releases from the clot. Rat models of intracerebral hemorrhage and ischemic stroke illustrated a role of thrombin in pathogenesis of cerebral edema and blood brain barrier permeability [39]. Human studies showed a correlation between the increased thrombin activity in patients’ CSF and the degree of SAH and cVSP [40]. To further evaluate the relationship between thrombin and cVSP, the role of antithrombin III was studied in a rabbit model. Antithrombin III inhibited thrombin activity and attenuated cVSP [41]. These studies highlight the possible neuroprotective role of antithombin III and the need for future studies.
Inflammation Pro-inflammatory cascades involving IL-6 have been shown to be critical in the development and maintenance of cVSP after SAH [42, 43]. Leukocytes contribute the complex pathophysiology of cVSP through multiple potential pathways, primarily by causing free-radical induced endothelial dysfunction [44] and significant vascular effects by leukotrienes, ET-1 and possibly consumption of NO [45]. Anti-inflammatory medications such as simvastatin have resulted in decreased perivascular migration of granulocytes as well as cVSP attenuation in a rabbit model within 72 hours after SAH [46]. Several Phase II studies with statins have shown safety and a promising efficacy signal in preventing cVSP after aSAH [47]. The results of an ongoing Phase III trial (STASH) are eagerly awaited [48]. Further studies are needed to validate the new theories, eluci-
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Curr Treat Options Neurol (2014) 16:278 date the time course and evaluate the optimal time windows for treatment targeting the inflammatory reactions and oxidative stress after SAH.
Pathophysiology in TBI-related cVSP Several mechanisms that are alternatives from the aSAH mechanisms have been proposed to account for the pathophysiology of cVSP secondary to tSAH.
Extravascular blood products causing a decrease in vessel caliber Few studies have proposed the correlation between quantity of blood in the subarachnoid cisterns and risk of cVSP following tSAH [8, 49, 50].
Stretch injury from blast Mechanical alteration of the cerebral blood vessels, through either direct impact or stretch, has been implicated in blast-related cVSP in the absence of SAH [13, 14]. In vitro studies have supported this theory and revealed that blast injury can trigger cVSP by distinct mechanics resulting in vascular smooth muscle hypercontractility [51].
Alternative causes for DCI The tSAH has been noted to have distinctly different patterns of DCI on hCT, rarely correlating with vascular territories [10, 52]. In tSAH, cVSP may not play a large role in the clinical deterioration of TBI patients, possibly because the majority of the injuries may be explained by contusions and direct impact [10, 13]. At the same time, the pattern of SAH in tSAH appears to differ from that in aSAH, occurring more in the tentorial region with a more diffuse type of hemorrhage [10]. This suggests different mechanisms of DCI in TBI. They are either caused by small-vessel cVSP or a phenomenon called “spreading depression depolarizations” [53•, 54]. This rapid and nearly complete depolarization of a sizable population of brain cells with massive redistribution of ions between intracellular and extracellular compartments propagates slowly as a wave in brain tissue and results in ischemia. In animal and small human studies after TBI and aSAH, such “spreading ischemia” has been independently associated with DCI and worse clinical outcomes [55, 56••].
CVSP surveillance Transcranial Doppler (TCD) Is a noninvasive, inexpensive, rapid, and portable diagnostic tool. It provides immediate clinical information about cerebral blood flow velocities, and thereby indirectly about vessel diameter. It has become the most widely used technique in the neurocritical care unit for evaluating cVSP [57]. In a meta-analysis, TCD reliably predicted proximal middle cerebral artery (MCA) cVSP in 97 % of SAH patients. Despite its high specificity (99 %) it has limited sensitivity (67 %). However, the
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Page 7 of 16, 278 combination of the Spasm Index (TCD velocity/hemispheric cerebral blood flow [CBF]) [58] and the Lindegaard ratio (mean middle cerebral artery flow velocity/mean extracranial internal carotid artery flow velocity) [59] increased the sensitivity of TCD to detect clinical cVSP to 85 % [18]. Disadvantages of TCD include its operator dependence with limited ability to obtain consistent measurements in distal skull base arteries and decreased utility in the evaluation of the anterior and posterior cerebral territories [60].
Cerebral arteriogram (DSA) Remains the gold standard for the diagnosis of cVSP due to its high resolution and real-time imaging. In addition, it offers the benefit of endovascular treatment.
CT angiography (CTA) has become the first-line modality in the identification of cVSP due to its availability. The image quality can be limited by motion artifact and the technique of dye administration. CTA in general tends to overestimate the size of larger blood vessels, which creates an over-accentuation of cVSP [60].
CT perfusion (CTP) scanning has increasing diagnostic utility [61]. A recent prospective study on CTP has validated the sensitivity of CBF (93 %) and mean transit time (MTT) (88 %) in diagnosing DCI [62]. CTP could be a valuable tool in evaluating distal vasculature and functional perfusion compared to DSA and CTA, which are less accurate in evaluating smaller distal vessels . In a recent study, CTP specificity to detect cVSP was 990 %, when it was done within 3 days after SAH, with noticeable prolongation of MTT and decrease in CBF on the baseline test [62]. These findings possibly suggest the utility of CTP as a future technique for an early prediction of DCI but further validation is warranted.
Perfusion-weighted MRI This imaging modality may reveal small regions of early ischemic insults, indicating territories suffering from severe cVSP [63]. Its limitations include the usual limitations for MRI, including the need for transport, and prolonged imaging time, thereby excluding many critically ill and high-risk patients.
Other imaging modalities At this point, there are several other techniques, including single-photon emission computed tomography (SPECT), positron emission tomography (PET) and xenon-enhanced CT (Xe-CT), which are available for evaluation of brain tissue perfusion distal to the large intracranial vessels, but are not widely available.
Continuous brain tissue monitoring Continuous EEG (cEEG) monitoring Is currently a widely used monitoring modality for several reasons. Its high sensitivity was shown in one prospective study in which decreases
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Curr Treat Options Neurol (2014) 16:278 in alpha wave activity had 100 % sensitivity detecting cVSP almost 3 days earlier than TCD or DSA [64]. It has an additional benefit for diagnosing subclinical seizures in patients with an unreliable exam. Lastly, cEEG can differentiate cVSP from seizure activity. Although it does so with variable reliability, quantitative analysis of cEEG suggested achieving such differentiation earlier than other non-continuous monitoring and imaging modalities such as MRI or CT [65]. Limitations of cEEG include the vast amount of data requiring real-time analysis, and the labor associated with the analysis and process of applying electrodes.
Brain tissue oxygen (PbtO2) monitoring Requires the implantation of a probe in a region at risk for cVSP and provides local brain tissue oxygenation data about changes in the surrounding microenvironment at repeated time intervals. Small studies showed a strong association between PbtO2 and cVSP [66]. A different study of 67 aSAH patients suggested that PbtO2 pressure reactivity is a reliable indicator of impaired autoregulation and cVSP [67]. These new findings questioned the reliability of this invasive monitoring technique in cVSP monitoring, given that it only provides information about local brain tissue oxygenation, and may miss other brain areas at risk for DCI [68].
Cerebral microdialysis Is capable of measuring local levels of various interstitial cerebral metabolic markers including glutamate, lactate, pyruvate, and glucose, and can signify changes in values in areas undergoing DCI [69]. Microdialysis has been shown to be 89 % specific for ischemia, before a patient becomes symptomatic, by detecting changes in glucose, lactate and glutamate [70]. In another SAH study, higher levels of microdialysis measured cerebral markers taurine, lactate and nitrite that were found to be associated with poor neurologic outcome [71]. The limitations of this technique, similar to PbtO2 monitoring, are that in addition to being invasive, information can only be gathered about a small region in the brain. Therefore, it has limited sensitivity in a condition that can have regional or global effects.
Continuous CBF measurement using thermal diffusion Via a brain tissue thermal diffusion probe can detect DCI and cVSP early [72]. Similar to PbtO2 monitoring and microdialysis, a thermal diffusion probe may be inserted into the brain via a burr hole into the white matter of a region deemed to be at risk for ischemia. In small study of 14 patients with high grade SAH, thermal diffusion was more reliable than TCD in detecting symptomatic cVSP. A regional CBF of 15 mg/100 g/min was identified using a single probe as reliable for a cutoff that had 90 % sensitivity and 75 % specificity for cVSP [72].
Jugular bulb oximetry In this technique, an oxygen saturation probe is inserted into the jugular vein above the facial vein; providing sampling from the intracranial circulation and offering a global view of cerebral perfusion [73]. The cerebral oxygen extraction (CEO2 or AVDO2) can
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Page 9 of 16, 278 be measured by subtracting cerebral venous oxygen saturation from the arterial oxygen saturation. A small study showed that AVDO2 increased 924 hours prior to the onset of symptomatic cVSP [74]. In the same study, symptom resolution was associated with significant improvement in AVDO2 after initiating cVSP therapy (hypertensive, hemodilutional, and hypervolemic therapy) in these patients [74].
Treatment of cVSP Calcium channel blocker Nimodipine is a dihydropyridine calcium antagonist that blocks calcium influx through L-type calcium channels and has selectivity for vascular smooth muscle. Oral nimodipine has become standard therapy in the setting of aSAH after several randomized trials have demonstrated improved outcomes and secondary ischemia [75, 76]. Importantly, it does not significantly prevent or reverse angiographic cVSP [76]. A recent comprehensive meta-analysis suggested that the improvement in neurological outcomes could be secondary to alternative mechanisms other than large-vessel narrowing, including pial collateral circulation augmentation, decreased small vessel resistance and neuroprotection role via reduction of calciummediated excitotoxicity [75].
Dantrolene The continuous elevation of intracellular Ca2+-levels required for vasoconstriction is achieved by a combination of influx from extracellular Ca2+ (inhibited by nimodipine), and released from the largest intracellular Ca2+ store, the endo/sarcoplasmatic reticulum mediated by the ryanodine receptor (RyR) [77, 78]. Dantrolene is a known RyR inhibitor and is US Food and Drug Administration approved for malignant hyperthermia and spasticity. Dantrolene has been shown to be neuroprotective in many animal models of various neurological diseases [79, 80]. More cVSP specific investigations have revealed that dantrolene inhibits cerebral vasoconstriction alone as well as in combination with nimodipine in an ex-vivo rat model [81]. Two small human studies of single IV-dantrolene doses have suggested that dantrolene may attenuate cVSP after SAH [82, 83]. In addition, dantrolene given intra-arterially during angiography has been reported to improve refractory cVSP [84]. Results from a single-center feasibility study of repeated IV-dantrolene doses in aSAH patients should result soon [85]. Combining L-type specific Ca2+-channel blockers with a RyR blocker may be an important therapeutic target in cVSP.
Hemodynamic augmentation Traditionally described as “Triple H”-therapy (hypervolemia, hypertension, hemodilution), it aims to increase cerebral perfusion. However, despite its widespread use as a mainstay therapy for cVSP, there are no randomized control trials to support this intervention [1••, 86]. Prophylactic
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Curr Treat Options Neurol (2014) 16:278 hypervolemic therapy alone after surgical repair of the ruptured aneurysm has been studied in randomized controlled trials. While no benefit was shown for cVSP, CBF, or clinical outcome, these studies revealed that hypervolemia resulted in pulmonary edema, as well as hemodilution and with it a decrease in arterial oxygen and oxygen carrying capacity [87]. Anemia has been associated with a worse outcome after aSAH [88]. These studies achieved the elimination of hemodilution from “Triple-H”-therapy, leaving HHT (hypervolemic, hypertensive therapy) as the mainstay in clinical practice, as recommended in the American Heart Association and Neurocritical Care Society SAH guidelines [1••, 20••].
Endovascular management of DCI Optimal timing and method of endovascular rescue therapy is unclear. Ideally, endovascular treatment should be considered in patients at risk for cVSP-related ischemic prior to the development of DCI. The literature on this intervention is limited to very few prospective studies. The feasibility and safety profile of angioplasty, intra-arterial vasodilator therapy and the combination of both was demonstrated in previous studies [20••]. Nevertheless, there is no clear data about the superiority of any of these interventions to one another, alone or in combination, or to medical treatment alone that have been previously validated [20••]. Prophylactic angioplasty done in patients without the presence of angiographic arterial narrowing exposed patients to risk of vessel rupture and death without clear benefit in outcome [89]. Thus, routine prophylactic cerebral angioplasty is not recommended in the NCC guidelines. More vital information about the timing, duration and optimal number of the endovascular rescue therapy is still needed and necessitate more exploration.
Statins Have been studied in several small, single-center randomized trials with variable results. Although a recent meta-analysis of four Phase II trials suggested no evidence for clinical benefit [90], results from a phase III trial (Simvastatin in Aneurysmal Subarachnoid Hemorrhage ‘STASH’) are eagerly awaited [48]. The current NCS SAH guidelines recommend continuation of statins in patients who are on them prior to aSAH [20••].
Clazosentan Is an endothelin-1 receptor antagonist and had been shown in a phase IIb trial (Clazosentan to Overcome Neurological iSChemia and Infarct Occurring after Subarachnoid hemorrhage ‘CONSCIOUS-1’) to be associated with a dose-dependent reduction in the incidence of angiographic cVSP [91]. In two subsequent phase III trials there was no improvement found in 90-day functional outcome in the clazosentan group [92••, 93•].
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Magnesium sulfate Is a non-competitive calcium channel blocker with vascular and neuroprotective effects. It has been studied in several pilot trials which suggested some of reduction in DCI associated with magnesium infusion, however, there was no benefit shown in a phase III trial (Intravenous Magnesium sulfate for Aneurysmal Subarachnoid Hemorrhage ‘IMASH’) [94]. The 2011 NCS guideline does not recommend induced hypermagnesemia [20••].
Treatment of TBI-related cVSP Management of cVSP in tSAH presents challenges distinct from the ones encountered in aSAH. Treatments usually used in aSAH related cVSP such as nimodipine and HHT could be detrimental in the setting of TBI, depending on the severity of injury and associated comorbidities. HHT may worsen cerebral edema from hypertension and increased perfusion in states of poor autoregulation [95], which is common in TBI. In addition, hypertension may increase the bleeding risk systemically in the aforementioned and in the brain. Calcium-channel blockers can negatively affect cerebral perfusion and intracranial pressures. Undesirable effects of low CBF in the setting of hypotension are particularly worrisome in TBI patients as cerebral hypoperfusion is a prominent cause of secondary brain insult [96]. Finally, a pooled analysis of four studies comparing calcium-channel blocker therapy to placebo in tSAH patients showed no difference in mortality or poor outcome [97]. Therefore, TBI-related cVSP is usually treated with endovascular therapy without the use of nimodipine or HHT.
Conclusions For the past decades, the understanding of cVSP has evolved to explore new complex biochemical cascades. We have revealed commonalities and differences in aSAH and TBI-related cVSP. The extensive research summarized here has identified promising new therapeutic targets.
Compliance with Ethics Guidelines Conflict of Interest Susanne Muehlschlegel has received grant support from the American Heart Association. Saef Izzy declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with animal subjects performed by any of the authors. With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.
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CRITICAL CARE NEUROLOGY (KN SHETH, SECTION EDITOR)
Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage and Traumatic Brain Injury Saef Izzy, MD1 Susanne Muehlschlegel, MD, MPH1,2,3* Address *,1Department of Neurology (Neurocritical Care), University of Massachusetts Medical School, 55 Lake Ave North, S-5, Worcester, MA 01655, USA Email: [email protected] 2 Department of Surgery, University of Massachusetts Medical School, 55 Lake Ave North, S-5, Worcester, MA 01655, USA 3 Department of Anesthesiology/Critical Care, University of Massachusetts Medical School, 55 Lake Ave North, S-5, Worcester, MA 01655, USA Published online: 18 December 2013 * Springer Science+Business Media New York 2013
This article is part of the Topical Collection on Critical Care Neurology Keywords Cerebral vasospasm I Angiographic vasospasm I Delayed cerebral ischemia I Traumatic brain injury I Subarachnoid hemorrhage I Traumatic subarachnoid hemorrhage I Blast injury I Treatment I Aneurysmal subarachnoid hemorrhage
Opinion statement Cerebral vasospasm (cVSP) consists of the vasoconstriction of large and small intracranial vessels which can lead to cerebral hypoperfusion, and in extreme cases, delayed ischemic deficits with stroke. While most commonly observed after aneurysmal subarachnoid hemorrhage (aSAH), cVSP can also occur after traumatic brain injury (TBI) as we have described in detail in this review. For the past decades, the research attention has focused on cVSP because of its association with delayed cerebral ischemia, which is the largest contributor of morbidity and mortality after aSAH. New discoveries in the cVSP pathophysiology involving multifactorial complex cascades and pathways pose new targets for therapeutic interventions in the prevention and treatment of cVSP. The goal of this review is to demonstrate the commonalities and differences in epidemiology and pathophysiology of both aSAH and TBI-associated cVSP, and highlight the more recently discovered pathways of cVSP. Finally, the latest cVSP surveillance methods and treatment options are illustrated.
Introduction Cerebral vasospasm (cVSP) consists of the vasoconstriction of large and small intracranial vessels. It can lead to cerebral hypoperfusion, culminating in delayed ischemic
deficits with stroke. CVSP has most commonly been associated with aneurysmal subarachnoid hemorrhage (aSAH), but can also occur in traumatic brain injury (TBI).
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Epidemiology of cVSP For decades, the attention has focused on cVSP because of its association with delayed cerebral ischemia (DCI), which is the largest contributor of morbidity and mortality after aSAH [1••, 2, 3]. Fifteen percent of intracranial hemorrhages and 5 % of all strokes are due to aSAH from acute rupture of an intracranial aneurysm, affecting 145/100,000 persons annually [1••]. Following aSAH, 30–70 % of patients will develop cVSP between day 4 and day 14 after aneurysm rupture. Approximately half of these patients will develop DCI [1••]. Compared to aSAH-related cVSP, data on TBI-associated cVSP is sparse. The mechanistic etiologies of TBI-associated cVSP can be divided into cVSP following traumatic SAH (tSAH) [4] and blast-related cVSP after nearby high-explosive detonation. TSAH has been reported to occur in 39 %–65 % of all TBI cases [5–7], with 10 %–30 % having TBI-associated radiographic cVSP in the presence of SAH on head computed tomography (hCT) [7–9]. Its presence has been independently associated with poor functional outcome [6, 10, 11] albeit SAH may just be a marker of more severe TBI and not causing cVSP. To date, the largest study in tSAH (n=299) describing transcranial Doppler (TCD) defined cVSP reported the incidence of TBI-related cVSP to be lower than after aSAH [7]. It is not clear, however, whether this is due to a truly lower incidence, or whether it is less commonly detected because it is not suspected, and therefore, not routinely monitored. Blast-related cVSP is often associated with the presence of SAH, but SAH is not required for the development of cVSP [10, 12, 13], suggesting a different underlying mechanism. Both in vivo and in vitro studies have suggested that mechanical alteration of the cerebral blood vessels through direct impact or stretch from the blast may trigger the development of cVPS [10, 14]. In contrast to aSAH-related cVSP, where the onset of cVSP is between 3– 5 days after aSAH, lasting up to 14–21 days [1••], the onset of tSAH-related cVSP has been reported as early as within 1–2 days after injury [5, 8], with a peak at 5–7 days [10, 13]. The duration of tSAH-associated cVSP is generally shorter than that of aSAH with complete resolution usually in less than 14 days [10, 13]. Blast-related cVSP, however, has been reported to have an early onset within two days, with average cVSP duration of 14 days, lasting up to 30 days [13].
Risk factors ASAH-associated symptomatic cVSP and DCI share the same risk factors: admission hypertension, poor clinical grade, thick cisternal clot and intraventricular hemorrhage (modified Fisher score 4) [15–17]. In contrast, angiographic cVSP has been associated with younger age, tobacco use, poor clinical grade, and intracerebral hemorrhage [15, 18]. TBI-related cVSP has been associated with severe SAH on initial hCT and low Glasgow Coma Scale (GCS) on admission; however, this relationship is less concrete compared to aSAH [7, 9, 13].
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Clinically relevant definitions of cVSP and DCI Multiple definitions of cVSP exist, making the standardization of treatments and research end points difficult. Recently, investigators from the SAH Outcomes Project (Columbia University, New York, NY) reported the clinically most important definitions of cVSP [15], which are summarized in Table 1. DCI is clinically important as it has been independently associated with mortality and poor 3-month outcome [15, 19]. DCI commonly develops during the second week after SAH, peaking around day 9 [2]. Clinical worsening, a key determinant of DCI, can be acute focal weakness or loss of consciousness, but may be as subtle as worsening headaches [20••], and always has to be differentiated from rebleeding or other causes of deterioration such as seizures or sepsis-associated encephalopathy [1••]. Therefore, the diagnosis of DCI is limited in comatose and poorly responsive highgrade aSAH patients. Extensive research has been conducted on the relationship between angiographic cVSP and DCI and whether angiographic evidence of cVSP is required for a diagnosis of DCI. In one study, only 84 % of a DCI cohort had radiographic cVSP [15]. Furthermore, only 24–35 % of SAH patients imaged with hCT, and only 81 % imaged with magnetic resonance imaging (MRI) displayed an area of cerebral infarction correlating with the vessel territory of the vessel in angiographic cVSP [21, 22]. This raises the possibility of other underlying mechanisms, as described below. In TBI, the ability to detect clinically significant deficits is challenging due to the commonly decreased level of consciousness in the patients, and heterogeneity of the disease mechanisms.
Table 1. Definitions of cVSP and DCI* Type of cVSP
Definition
Symptomatic cVSP
Clinical worsening in the setting of new focal neurological signs, deterioration in level of consciousness, or both, in the absence of other possible causes (seizures, hydrocephalus, and edema); does not necessarily imply documented angiographic cVSP; occurs in 20 % to 40 % of aSAH patients [15, 97]; only symptomatic cVSP, but not TCD or angiographic cVSP correlated with DCI and mortality 3 months post aSAH [15] Arterial narrowing on DSA not attributable to catheter-induced spasm or atherosclerosis [1••]; occurs in up to 70 % of aSAH patients, indicating that angiographic cVSP can occur in the absence of symptoms [1••]; not all patients with angiographic cVSP experience DCI and vice versa [21, 98] Defined as a mean blood flow velocity in any vessel 9120 cm/sec, associated with symptomatic or angiographic cVSP [99] Defined as the presence of new infarction on hCT or MRI when the cause is felt to be attributable to cVSP; is primarily a clinical diagnosis, because it does not require DSA evidence of cVSP [3, 15]
Angiographic cVSP
TCD cVSP Delayed cerebral ischemia (DCI)
*Shown are clinically relevant definitions of cVSP and DCI, which were recently adopted into aSAH clinical practice guidelines and research [15].
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Pathophysiology of cVSP The underlying pathophysiologic mechanisms of cVSP remain poorly understood, but appear to be multifactorial.
Does SAH cause cVSP? Extensive basic and clinical research studies have attempted to validate this causal relationship. Initial animal studies had suggested that blood products from the SAH may cause cVSP [3, 23]. This theory was indirectly supported in an animal model [24] and a small human study in which removing the clot resulted in cVSP prevention. This, however, awaits validation in larger studies [25]. Hematoma location, volume, duration of presence, and density have all been shown to be independently associated with angiographic cVSP [3, 26, 27], however, without proving causation.
What causes cVSP? Several mechanisms may be responsible for the development of cVSP.
Hemoglobin (Hb) and cVSP Strong evidence exists from in vivo and in vitro studies that the release of oxyHb from the lysis of subarachnoid red blood cells is present in high concentrations in the cerebral spinal fluid (CSF) during the cVSP period. OxyHb acts as a spasmogen and may be a key mechanism responsible for cVSP [2, 28]. In addition, superoxide free radicals are released during autoxidation of Hb and may directly or indirectly cause vasoconstriction [2, 28]. Despite the extensive body of research, there is no general theory that can explain the role of the Hbs in all the events that lead to cVSP. This raises the hypothesis that the presence of Hb in the subarachnoid space may influence the arterial vasodilatory response by causing multiple, multifaceted interactions with endothelium, neuron or smooth muscle cells [2].
Alternative proposed mechanisms for cVSP Nitric oxide (NO) pathway Endothelial NO (eNO) is an endogenous signaling molecule which directly acts on vascular smooth cells causing vascular relaxation [2]. An altered NO pathway due to scavenging by Hb in the cisternal space or dysfunction of eNO synthase (eNOS) has been proposed to play an essential pathophysiological role in the development of cVSP [2]. Therapeutic intervention in a rat model with 17b-estradiol benzoate (E2) activating the estrogen receptor subtype A (ERa) was reported to attenuate cVSP and preserve the eNOS expression [29]. Vasodilators with pharmacological actions involving the NO pathway, nitrite [30] and
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Page 5 of 16, 278 sildenafil [31], have recently been studied with promising early safety results. Phase II trials of both medications are ongoing.
Hypoxia Inducible Factor-1 (HIF-1) Is a transcription factor that plays a key pathophysiological role in oxygen homeostasis and adaptive responses to hypoxia and oxidative stress. HIF-1 regulates more than 40 identified genes including erythropoietin, BNIP3, vascular endothelial growth factor (VEGF) and glucose transporter-1[32]. In animal studies, HIF-1 has been shown to possibly cause vasoconstriction within 24 hours and vasorelaxation at ~7 days after SAH [33]. This led to the hypothesis that the role of HIF-1 may be harmful in the early stage and neuroprotective at a later stage after SAH [33, 34]. HIF-1’s early pro-death and late pro-survival role remains under investigation.
Endothelin pathway Elevated levels of endothelin have been found in the CSF of aSAH patients [35, 36]. Endothelin-1 is a potent vascular smooth muscle cells vasoconstrictor, and acts on two specific receptors, ET(A) and ET(B). Activation of ET(A) and ET (B2) receptors on the vascular smooth muscle cells results in vasoconstriction, whereas activation of ET(B1) receptor subtype, expressed on the vascular endothelial cells, causes vasorelaxation [37] . Preclinical and early phase clinical prophylactic treatment with clazosentan, an ET-1 antagonist, were promising in limiting cVSP, but two recent Phase III trials did not improve 90-day clinical outcomes [38•].
Thrombin A serine protease is a coagulation protein produced in blood clots; it binds to fibrin and gradually releases from the clot. Rat models of intracerebral hemorrhage and ischemic stroke illustrated a role of thrombin in pathogenesis of cerebral edema and blood brain barrier permeability [39]. Human studies showed a correlation between the increased thrombin activity in patients’ CSF and the degree of SAH and cVSP [40]. To further evaluate the relationship between thrombin and cVSP, the role of antithrombin III was studied in a rabbit model. Antithrombin III inhibited thrombin activity and attenuated cVSP [41]. These studies highlight the possible neuroprotective role of antithombin III and the need for future studies.
Inflammation Pro-inflammatory cascades involving IL-6 have been shown to be critical in the development and maintenance of cVSP after SAH [42, 43]. Leukocytes contribute the complex pathophysiology of cVSP through multiple potential pathways, primarily by causing free-radical induced endothelial dysfunction [44] and significant vascular effects by leukotrienes, ET-1 and possibly consumption of NO [45]. Anti-inflammatory medications such as simvastatin have resulted in decreased perivascular migration of granulocytes as well as cVSP attenuation in a rabbit model within 72 hours after SAH [46]. Several Phase II studies with statins have shown safety and a promising efficacy signal in preventing cVSP after aSAH [47]. The results of an ongoing Phase III trial (STASH) are eagerly awaited [48]. Further studies are needed to validate the new theories, eluci-
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Curr Treat Options Neurol (2014) 16:278 date the time course and evaluate the optimal time windows for treatment targeting the inflammatory reactions and oxidative stress after SAH.
Pathophysiology in TBI-related cVSP Several mechanisms that are alternatives from the aSAH mechanisms have been proposed to account for the pathophysiology of cVSP secondary to tSAH.
Extravascular blood products causing a decrease in vessel caliber Few studies have proposed the correlation between quantity of blood in the subarachnoid cisterns and risk of cVSP following tSAH [8, 49, 50].
Stretch injury from blast Mechanical alteration of the cerebral blood vessels, through either direct impact or stretch, has been implicated in blast-related cVSP in the absence of SAH [13, 14]. In vitro studies have supported this theory and revealed that blast injury can trigger cVSP by distinct mechanics resulting in vascular smooth muscle hypercontractility [51].
Alternative causes for DCI The tSAH has been noted to have distinctly different patterns of DCI on hCT, rarely correlating with vascular territories [10, 52]. In tSAH, cVSP may not play a large role in the clinical deterioration of TBI patients, possibly because the majority of the injuries may be explained by contusions and direct impact [10, 13]. At the same time, the pattern of SAH in tSAH appears to differ from that in aSAH, occurring more in the tentorial region with a more diffuse type of hemorrhage [10]. This suggests different mechanisms of DCI in TBI. They are either caused by small-vessel cVSP or a phenomenon called “spreading depression depolarizations” [53•, 54]. This rapid and nearly complete depolarization of a sizable population of brain cells with massive redistribution of ions between intracellular and extracellular compartments propagates slowly as a wave in brain tissue and results in ischemia. In animal and small human studies after TBI and aSAH, such “spreading ischemia” has been independently associated with DCI and worse clinical outcomes [55, 56••].
CVSP surveillance Transcranial Doppler (TCD) Is a noninvasive, inexpensive, rapid, and portable diagnostic tool. It provides immediate clinical information about cerebral blood flow velocities, and thereby indirectly about vessel diameter. It has become the most widely used technique in the neurocritical care unit for evaluating cVSP [57]. In a meta-analysis, TCD reliably predicted proximal middle cerebral artery (MCA) cVSP in 97 % of SAH patients. Despite its high specificity (99 %) it has limited sensitivity (67 %). However, the
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Page 7 of 16, 278 combination of the Spasm Index (TCD velocity/hemispheric cerebral blood flow [CBF]) [58] and the Lindegaard ratio (mean middle cerebral artery flow velocity/mean extracranial internal carotid artery flow velocity) [59] increased the sensitivity of TCD to detect clinical cVSP to 85 % [18]. Disadvantages of TCD include its operator dependence with limited ability to obtain consistent measurements in distal skull base arteries and decreased utility in the evaluation of the anterior and posterior cerebral territories [60].
Cerebral arteriogram (DSA) Remains the gold standard for the diagnosis of cVSP due to its high resolution and real-time imaging. In addition, it offers the benefit of endovascular treatment.
CT angiography (CTA) has become the first-line modality in the identification of cVSP due to its availability. The image quality can be limited by motion artifact and the technique of dye administration. CTA in general tends to overestimate the size of larger blood vessels, which creates an over-accentuation of cVSP [60].
CT perfusion (CTP) scanning has increasing diagnostic utility [61]. A recent prospective study on CTP has validated the sensitivity of CBF (93 %) and mean transit time (MTT) (88 %) in diagnosing DCI [62]. CTP could be a valuable tool in evaluating distal vasculature and functional perfusion compared to DSA and CTA, which are less accurate in evaluating smaller distal vessels . In a recent study, CTP specificity to detect cVSP was 990 %, when it was done within 3 days after SAH, with noticeable prolongation of MTT and decrease in CBF on the baseline test [62]. These findings possibly suggest the utility of CTP as a future technique for an early prediction of DCI but further validation is warranted.
Perfusion-weighted MRI This imaging modality may reveal small regions of early ischemic insults, indicating territories suffering from severe cVSP [63]. Its limitations include the usual limitations for MRI, including the need for transport, and prolonged imaging time, thereby excluding many critically ill and high-risk patients.
Other imaging modalities At this point, there are several other techniques, including single-photon emission computed tomography (SPECT), positron emission tomography (PET) and xenon-enhanced CT (Xe-CT), which are available for evaluation of brain tissue perfusion distal to the large intracranial vessels, but are not widely available.
Continuous brain tissue monitoring Continuous EEG (cEEG) monitoring Is currently a widely used monitoring modality for several reasons. Its high sensitivity was shown in one prospective study in which decreases
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Curr Treat Options Neurol (2014) 16:278 in alpha wave activity had 100 % sensitivity detecting cVSP almost 3 days earlier than TCD or DSA [64]. It has an additional benefit for diagnosing subclinical seizures in patients with an unreliable exam. Lastly, cEEG can differentiate cVSP from seizure activity. Although it does so with variable reliability, quantitative analysis of cEEG suggested achieving such differentiation earlier than other non-continuous monitoring and imaging modalities such as MRI or CT [65]. Limitations of cEEG include the vast amount of data requiring real-time analysis, and the labor associated with the analysis and process of applying electrodes.
Brain tissue oxygen (PbtO2) monitoring Requires the implantation of a probe in a region at risk for cVSP and provides local brain tissue oxygenation data about changes in the surrounding microenvironment at repeated time intervals. Small studies showed a strong association between PbtO2 and cVSP [66]. A different study of 67 aSAH patients suggested that PbtO2 pressure reactivity is a reliable indicator of impaired autoregulation and cVSP [67]. These new findings questioned the reliability of this invasive monitoring technique in cVSP monitoring, given that it only provides information about local brain tissue oxygenation, and may miss other brain areas at risk for DCI [68].
Cerebral microdialysis Is capable of measuring local levels of various interstitial cerebral metabolic markers including glutamate, lactate, pyruvate, and glucose, and can signify changes in values in areas undergoing DCI [69]. Microdialysis has been shown to be 89 % specific for ischemia, before a patient becomes symptomatic, by detecting changes in glucose, lactate and glutamate [70]. In another SAH study, higher levels of microdialysis measured cerebral markers taurine, lactate and nitrite that were found to be associated with poor neurologic outcome [71]. The limitations of this technique, similar to PbtO2 monitoring, are that in addition to being invasive, information can only be gathered about a small region in the brain. Therefore, it has limited sensitivity in a condition that can have regional or global effects.
Continuous CBF measurement using thermal diffusion Via a brain tissue thermal diffusion probe can detect DCI and cVSP early [72]. Similar to PbtO2 monitoring and microdialysis, a thermal diffusion probe may be inserted into the brain via a burr hole into the white matter of a region deemed to be at risk for ischemia. In small study of 14 patients with high grade SAH, thermal diffusion was more reliable than TCD in detecting symptomatic cVSP. A regional CBF of 15 mg/100 g/min was identified using a single probe as reliable for a cutoff that had 90 % sensitivity and 75 % specificity for cVSP [72].
Jugular bulb oximetry In this technique, an oxygen saturation probe is inserted into the jugular vein above the facial vein; providing sampling from the intracranial circulation and offering a global view of cerebral perfusion [73]. The cerebral oxygen extraction (CEO2 or AVDO2) can
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Page 9 of 16, 278 be measured by subtracting cerebral venous oxygen saturation from the arterial oxygen saturation. A small study showed that AVDO2 increased 924 hours prior to the onset of symptomatic cVSP [74]. In the same study, symptom resolution was associated with significant improvement in AVDO2 after initiating cVSP therapy (hypertensive, hemodilutional, and hypervolemic therapy) in these patients [74].
Treatment of cVSP Calcium channel blocker Nimodipine is a dihydropyridine calcium antagonist that blocks calcium influx through L-type calcium channels and has selectivity for vascular smooth muscle. Oral nimodipine has become standard therapy in the setting of aSAH after several randomized trials have demonstrated improved outcomes and secondary ischemia [75, 76]. Importantly, it does not significantly prevent or reverse angiographic cVSP [76]. A recent comprehensive meta-analysis suggested that the improvement in neurological outcomes could be secondary to alternative mechanisms other than large-vessel narrowing, including pial collateral circulation augmentation, decreased small vessel resistance and neuroprotection role via reduction of calciummediated excitotoxicity [75].
Dantrolene The continuous elevation of intracellular Ca2+-levels required for vasoconstriction is achieved by a combination of influx from extracellular Ca2+ (inhibited by nimodipine), and released from the largest intracellular Ca2+ store, the endo/sarcoplasmatic reticulum mediated by the ryanodine receptor (RyR) [77, 78]. Dantrolene is a known RyR inhibitor and is US Food and Drug Administration approved for malignant hyperthermia and spasticity. Dantrolene has been shown to be neuroprotective in many animal models of various neurological diseases [79, 80]. More cVSP specific investigations have revealed that dantrolene inhibits cerebral vasoconstriction alone as well as in combination with nimodipine in an ex-vivo rat model [81]. Two small human studies of single IV-dantrolene doses have suggested that dantrolene may attenuate cVSP after SAH [82, 83]. In addition, dantrolene given intra-arterially during angiography has been reported to improve refractory cVSP [84]. Results from a single-center feasibility study of repeated IV-dantrolene doses in aSAH patients should result soon [85]. Combining L-type specific Ca2+-channel blockers with a RyR blocker may be an important therapeutic target in cVSP.
Hemodynamic augmentation Traditionally described as “Triple H”-therapy (hypervolemia, hypertension, hemodilution), it aims to increase cerebral perfusion. However, despite its widespread use as a mainstay therapy for cVSP, there are no randomized control trials to support this intervention [1••, 86]. Prophylactic
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Curr Treat Options Neurol (2014) 16:278 hypervolemic therapy alone after surgical repair of the ruptured aneurysm has been studied in randomized controlled trials. While no benefit was shown for cVSP, CBF, or clinical outcome, these studies revealed that hypervolemia resulted in pulmonary edema, as well as hemodilution and with it a decrease in arterial oxygen and oxygen carrying capacity [87]. Anemia has been associated with a worse outcome after aSAH [88]. These studies achieved the elimination of hemodilution from “Triple-H”-therapy, leaving HHT (hypervolemic, hypertensive therapy) as the mainstay in clinical practice, as recommended in the American Heart Association and Neurocritical Care Society SAH guidelines [1••, 20••].
Endovascular management of DCI Optimal timing and method of endovascular rescue therapy is unclear. Ideally, endovascular treatment should be considered in patients at risk for cVSP-related ischemic prior to the development of DCI. The literature on this intervention is limited to very few prospective studies. The feasibility and safety profile of angioplasty, intra-arterial vasodilator therapy and the combination of both was demonstrated in previous studies [20••]. Nevertheless, there is no clear data about the superiority of any of these interventions to one another, alone or in combination, or to medical treatment alone that have been previously validated [20••]. Prophylactic angioplasty done in patients without the presence of angiographic arterial narrowing exposed patients to risk of vessel rupture and death without clear benefit in outcome [89]. Thus, routine prophylactic cerebral angioplasty is not recommended in the NCC guidelines. More vital information about the timing, duration and optimal number of the endovascular rescue therapy is still needed and necessitate more exploration.
Statins Have been studied in several small, single-center randomized trials with variable results. Although a recent meta-analysis of four Phase II trials suggested no evidence for clinical benefit [90], results from a phase III trial (Simvastatin in Aneurysmal Subarachnoid Hemorrhage ‘STASH’) are eagerly awaited [48]. The current NCS SAH guidelines recommend continuation of statins in patients who are on them prior to aSAH [20••].
Clazosentan Is an endothelin-1 receptor antagonist and had been shown in a phase IIb trial (Clazosentan to Overcome Neurological iSChemia and Infarct Occurring after Subarachnoid hemorrhage ‘CONSCIOUS-1’) to be associated with a dose-dependent reduction in the incidence of angiographic cVSP [91]. In two subsequent phase III trials there was no improvement found in 90-day functional outcome in the clazosentan group [92••, 93•].
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Magnesium sulfate Is a non-competitive calcium channel blocker with vascular and neuroprotective effects. It has been studied in several pilot trials which suggested some of reduction in DCI associated with magnesium infusion, however, there was no benefit shown in a phase III trial (Intravenous Magnesium sulfate for Aneurysmal Subarachnoid Hemorrhage ‘IMASH’) [94]. The 2011 NCS guideline does not recommend induced hypermagnesemia [20••].
Treatment of TBI-related cVSP Management of cVSP in tSAH presents challenges distinct from the ones encountered in aSAH. Treatments usually used in aSAH related cVSP such as nimodipine and HHT could be detrimental in the setting of TBI, depending on the severity of injury and associated comorbidities. HHT may worsen cerebral edema from hypertension and increased perfusion in states of poor autoregulation [95], which is common in TBI. In addition, hypertension may increase the bleeding risk systemically in the aforementioned and in the brain. Calcium-channel blockers can negatively affect cerebral perfusion and intracranial pressures. Undesirable effects of low CBF in the setting of hypotension are particularly worrisome in TBI patients as cerebral hypoperfusion is a prominent cause of secondary brain insult [96]. Finally, a pooled analysis of four studies comparing calcium-channel blocker therapy to placebo in tSAH patients showed no difference in mortality or poor outcome [97]. Therefore, TBI-related cVSP is usually treated with endovascular therapy without the use of nimodipine or HHT.
Conclusions For the past decades, the understanding of cVSP has evolved to explore new complex biochemical cascades. We have revealed commonalities and differences in aSAH and TBI-related cVSP. The extensive research summarized here has identified promising new therapeutic targets.
Compliance with Ethics Guidelines Conflict of Interest Susanne Muehlschlegel has received grant support from the American Heart Association. Saef Izzy declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with animal subjects performed by any of the authors. With regard to the authors’ research cited in this paper, all procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 and 2008.
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