A comprehensive analysis of the relationship between ACA velocities and ACA infarction following aneurysmal subarachnoid hemorrhage

Journal of the Neurological Sciences 376 (2017) 143–150

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A comprehensive analysis of the relationship between ACA velocities and ACA infarction following aneurysmal subarachnoid hemorrhage Michael Moussouttas a,⁎, Jocelyn Cheng b, Joseph Antonakakis c, Ameesh Patel d, Maria Iuanow a

Neurologic Intensive Care Unit, Department of Neurology, Capital Regional Medical Center, Trenton, NJ, United States Department of Neurology, Drexel University College of Medicine, Philadelphia, PA, United States School of Psychology, Rutgers University, New Brunswick, NJ, United States d School of Public Health, New York Medical College, Valhalla, NY, United States b c

a r t i c l e

i n f o

Article history: Received 11 May 2016 Received in revised form 17 February 2017 Accepted 15 March 2017 Available online 18 March 2017 Keywords: Subarachnoid hemorrhage Anterior cerebral artery Cerebral vasospasm Cerebral infarction Velocities

a b s t r a c t Purpose: To evaluate the relationship between anterior cerebral artery (ACA) velocities (and ancillary parameters) and ACA infarction following aneurysmal subarachnoid hemorrhage (aSAH), and to examine the factors that influence velocities. Methods: Retrospective investigation of 500 consecutive aSAH patients. ACA mean velocities (Vm) were evaluated by daily transcranial ultrasound during the early (days 1–4) and late (days 5–20) periods posthemorrhage. Presence and timing of acute ACA infarctions were identified by serial retrospective review of cerebral computerized tomography (CT) scans. Predictors of ACA velocities were identified and compared to predictors of vasospasm and infarction from the literature. Results: Decreased velocities on the day of infarction were observed in infarct-positive vessels when compared to infarct-negative vessels. ACA velocity increases, ipsilateral/contralateral ACA velocity ratios, and ACA velocity ranges, were inaccurate in anticipating infarction. Decreased ACA index velocities were moderately accurate in anticipating ACA infarction during the early [Vm b 60 cms/s], late [Vm b 70 cms/s] and overall [Vm b 70 cms/s] time periods. Decreased index velocities also independently predicted infarction during all time periods. ACA velocities were most consistently predicted by age, race, hemorrhage quantity on CT, and ACA/ACom (anterior communicating artery) aneurysm location. Conclusions: ACA velocity increases and ancillary parameters do not relate to the development of infarction, whereas velocity decreases are moderately accurate in anticipating infarction. Predictors of velocity increases generally coincide with those of vasospasm, whereas predictors of velocity decreases coincide more with those of infarction following aSAH. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Following aneurysmal subarachnoid hemorrhage (aSAH), cerebral vasospasm (VS) develops in approximately 70% of patients [1], and typically occurs during the subacute period between days 5–20 post-hemorrhage [2]. However, an acute form of VS arising between days 1–4 has also been described [3], which may or may not be etiologically related to subacute VS. [3,4] VS may become symptomatic in 25–33% of patients [1], and may cause infarction in ~10% [5]. Cerebral infarction following aSAH ranks as one of the most powerful determinants of outcome, variably exceeding advanced age, clinical grade and hemorrhage features

⁎ Corresponding author at: 750 Brunswick Avenue, Trenton, NJ 08638, United States. E-mail address: [email protected] (M. Moussouttas).

http://dx.doi.org/10.1016/j.jns.2017.03.024 0022-510X/© 2017 Elsevier B.V. All rights reserved.

[5–10]. Anterior cerebral artery (ACA) infarcts are associated with deficits in sensory-motor function, language, spatial perception, executive function, motivation, emotion, praxis and memory, and may therefore represent a major contributor to morbidity and disability [11,12]. Transcranial ultrasound (TCUS) is a noninvasive, portable and reproducible technique for measuring and trending intracranial arterial flow velocities that serve as markers for the development and progression of cerebral VS. [13] However, intracranial velocities may be influenced by multiple clinical and physiologic factors beyond simply cerebral VS. [14] Similarly, cerebral hypoperfusion may occur independent of VS [15,16], and cerebral infarction may result from numerous non-vasospastic processes [5,17]. Therefore, any putative association that may exist between arterial velocities and cerebral ischemia may not be solely dependent on or mediated by VS. Prior investigations have assessed the accuracy and predictive value of ACA velocities for identifying ACA VS

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[18,19], but no previous investigation has specifically analyzed the association between ACA velocities and ACA infarction. The primary aim of our investigation was to determine whether any relationship exists between ACA velocities (and various velocity parameters) and the development of ACA infarction during the acute and subacute time periods following aSAH. A second goal of our investigation is to define the variables that determine ACA velocity changes, and to compare these variables to those that are known to predict angiographic VS and infarction. We theorize that comparing these determinants may explain the concordance or discordance that may exist between the occurrence of ACA velocity elevations and ACA territory infarctions. 2. Materials and methods 2.1. Project approval & disclosure The investigation was approved by the Institutional Research Review Board which did not require informed consent due to the retrospective nature of the project and the minimal risk involved to patients/participants. The project did not receive any specific grant from any funding agencies in the public, commercial or non-profit sectors. 2.2. Patient selection The investigation is a retrospective analysis from a large prospectively collected TCUS database of 500 consecutive aSAH patients admitted to the neurological intensive care unit. Patients with nonaneurysmal SAH due to trauma, primary intracerebral hemorrhage, or arteriovenous malformation were excluded, as were patients without cerebral imaging. 2.3. Data collection & variable categorization Data collection included demographic characteristics (age, gender, race), medical history (hypertension, tobacco use), clinical presentation (clinical grade), radiologic information (CT scans), anatomic features (aneurysm location), and treatment modality (endovascular vs surgical). Clinical condition was graded using the Hunt-Hess (H/H) scale, and CT scans were graded using the modified Fisher scale (mFs) [20]. For the categories of H/H grade and mFs score, data was dichotomized into grades 1–3 versus grades 4/5, and scores 0–2 versus scores 3/4, respectively. 2.4. Identification of ACA infarction All patients had admission CT scans upon presentation which served as the basis for comparison, and final CT scans were obtained when the patient was stable and no new ischemia was suspected. Postoperative/ postinterventional CT scans were not routinely obtained unless clinically indicated. ACA infarction was defined as any new ACA infarct present on cerebral CT imaging that developed at any time during the current hospitalization. To determine the presence or absence of infarction, the last CT scan done during hospitalization was evaluated for recent ACA territorial infarct. To determine timing of infarction, all prior CT scans were reviewed serially in retrospective fashion. The first CT to reveal infarction, and the last CT without infarction, were used as index images to determine exact/approximate day of infarction. If necessary, infarct lesion density was interrogated so as to most accurately determine infarction age. CT scans were interpreted independently by a dedicated neuroradiologist and by a certified cerebrovascular specialist who jointly adjudicated uncertainties regarding presence/timing of infarction. ACA infarctions occurring between post-hemorrhage day 1 and day 4 were considered early infarctions, while those occurring between day 5 and day 20 were considered late infarctions.

2.5. Transcranial ACA insonation During hospitalization, all patients were routinely evaluated by TCUS twice daily for the detection of cerebral VS, typically for a minimum of 14 days and occasionally for a maximum of 21 days. The sonographic protocol routinely entails insonation of all anterior circulation vessels bilaterally, including the intracranial internal carotid arteries, middle cerebral arteries and ACAs. Insonation of the posterior circulation vessels was only performed if considered necessary. Via a temporal cranial window, the ACA vessels are typically identified by the distance from the ultrasound probe (60-70 mm) and by the direction of flow (antidromic) [21]. TCUS procedures were performed using the Nicolet Pioneer TC8080 System [Viasys - Conshohocken, PA, USA] using a 2 MHz probe. Similar to infarct classification, insonation periods were defined as early (days 1–4) or late (days 5–20).

2.6. Standard treatment protocols Upon admission to the neurological intensive care unit, all aSAH patients typically receive maintenance normal saline at a rate of 6080 ml/h, and receive no enteral nutrition in preparation for angiography and aneurysm treatment. Mean arterial pressures (MAP) are maintained below 90 mmHg, agitated patients are given sedation (diprivan or versed or fentanyl), and patients with impaired consciousness are intubated and ventilated. No patients receive antifibrinolytic agents. Ventriculostomies are inserted for hydrocephalus, prophylactic antiepileptic medication is given, and patients routinely start nimodipine 60 mg po q4. Following aneurysm treatment, sedating medications are tapered, MAPs are maintained between 90 and 100 mmHg, patients are weaned from ventilator support, intravenous fluids are continued to maintain euvolemia, and enteral nutrition is initiated. Neurological worsening at any time is uniformly evaluated by an emergent portable head CT. If sonographic VS is suspected, MAP parameters are raised to 100110 mmHg, and for symptomatic VS MAP parameters are increased to 110-120 mmHg. VS refractory to hypertensive therapy may be treated by the endovascular injection of nicardipine, and possibly by angioplasty at the discretion of the treating interventionalist. Intracranial pressures (ICP) are maintained below 20 mmHg and cerebral perfusion pressures (CPP) above 60 mmHg.

2.7. Data abstraction & interpretation strategy Data entry and assessments were done on a per vessel basis, such that all data was abstracted and analyzed for each ACA vessel (not for each patient). Insonation days were defined according to time elapsed from the time of hemorrhage onset. Only mean velocity (Vm) values were considered, which are the conventional TCUS velocity measure. For every vessel insonated, the representative Vm for any given day was the greatest individual Vm value recorded from the two daily insonations performed, and was used towards identification of maximum (max) Vm for any given time period. In addition, for infarct-positive vessels the max Vm on the day of infarction (iVm) was used in place of the max Vm for separate parallel analyses. The max Vm and iVm values of infarct-positive vessels were compared to the max Vm values of infarct-negative vessels for every time period, as well as during the entire investigative period. Ratios of ipsilateral ACA (iACA) Vm or iVm to contralateral ACA (cACA) Vm or iVm were calculated and assessed in similar fashion. Peri-infarct velocity elevations, defined as the maximum velocity increase from the day prior to infarction to the day after infarction, and per-period velocity ranges, defined as the greatest velocity minus the lowest velocity during each time period, were also calculated and evaluated as ancillary parameters.

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2.8. Statistical analyses

in 36 (61%) vessels, unilateral in 13 patients (36%), and bilateral in 23 patients (64%).

In univariate analyses, the Student's (two-tailed) t-test was used for comparison of continuous variables from two separate sample groups, whereas the paired t-test was used for comparison of continuous variables from a single sample group. Pearson's coefficient was used for correlation calculations between continuous variables. ROC curves were constructed to determine the accuracy of ACA max Vm (as a continuous variable) in determining the occurrence of ACA infarction. ROC curve graphic and tabular data were interrogated to identify candidate velocities that may serve as indexes for accurately dichotomizing infarct-positive from infarct-negative vessels. AUC analyses and sensitivity/ specificity (S/S) calculations were performed for identified index velocities, as well as for several commonly employed index velocities. Multivariate linear regression analyses were performed to identify independent predictors of ACA velocity elevations by entering all candidate variables simultaneously, excluding those that failed to demonstrate association in univariate analyses. Additionally, multivariate logistic regression analyses were performed so as to identify independent predictors of index velocities identified by visual inspection of ROC curve and AUC analyses. Candidate index velocities were also entered into logistic regression analyses along with additional clinical covariates to determine predictive value for the outcome of ipsilateral ACA infarction. Vessels missing data were excluded from analyses. All univariate and multivariate analyses were performed for the early, late and overall time periods. For all analyses, a p-value b 0.05 was considered statistically meaningful. All statistical computations were performed using the SPSS v12 program, and the PSPP 0.10.4-g50f7b7 program. 3. Investigative results 3.1. Subject characteristics Demographic, clinical, radiologic, anatomic, and therapeutic characteristics for the entire investigative population are provided in Table 1. Overall, mean age was 55 years, 66% of patients were female, and 67% were Caucasian (the remainder - 20% African, 4% Hispanic and 9% Asian). A total of 803 vessels were assessed at some time during the early period, 812 vessels were assessed at some time during the late time period, and 901 vessels were assessed at some time overall. In all, 59 vessels experienced infarction in 36 patients. Since CT scans were available for only 478 cases, infarctions were seen in 6.17% of vessels and in 7.53% of patients. Infarcts were early in 23 vessels (39%), late Table 1 Characteristics of investigative population. N = 500 Demographics Age (mean)[years] Female (%) Caucasian (%)

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55 ± 14 66 67

Medical history Hypertension (%) Tobacco use (%) [n = 499] Clinical / Radiologic H/H Grade 4/5 (%) mRs Score 3/4 (%) [n = 478]

27 26

Aneurysm features ACA/ACom (%) [n = 480] Endovascular (%) [n = 353]

26 78

62 57

Data partially incomplete/unavailable for tobacco use [n = 1], CT score [n = 22] and aneurysm location [n = 20]. 29% [n = 147] of patients did not undergo any endovascular or surgical treatment, and 1.5% [n = 5] patients underwent combined endovascular/surgical treatment or parent vessel sacrifice. ACA/ACom = anterior cerebral artery/anterior communicating artery complex.

3.2. Vm/iVm & velocity parameter comparisons In comparing ACA velocities between infarct-positive and infarctnegative vessels (Table 2), no differences were observed in Vm during the early (70 cms/s vs 81 cms/s, p = 0.109), late (101 cms/s vs 102 cms/s, p = 0.910) and overall investigational time periods (101 cms/s vs 101 cms/s, p = 0.941). Conversely, substantially lower iVm were observed on the day of infarction in infarct-positive vessels than the Vm for infarct-negative vessels during the early (54 cms/s vs 81 cms/s, p b 0.001), later (78 cms/s vs 102 cms/s, p b 0.001) and overall time periods (69 cms/s vs 101 cms/s, p b 0.001). When comparing Vm and iVm among infarct-positive vessels during each investigational time period, iVm were statistically lower during the early (p = 0.002), later (p b 0.001) and overall (p b 0.001) time periods. For the early infarct analyses, excluding hyperacute infarctions that may theoretically have been related to procedural complications from aneurysm treatment revealed comparable results for the Vm versus Vm comparison (69 cms/s vs 81 cms/s, p = 0.093) as well as for the iVm versus Vm comparison (51 cms/s vs 81 cms/s, p b 0.001). In comparing iACA/cACA ratios for Vm between infarct-positive and infarct negative vessels, no differences were observed during the early (1.09 vs 1.05, p = 0.600), later (1.06 vs 1.04, p = 0.839) or overall (1.03 vs 1.04, p = 0.876) time periods. Similarly, comparisons of Vm and iVm also revealed no differences between the groups during the early (1.05 vs 1.05, p = 0.989), later (1.04 vs 1.04, p = 0.988) or overall (1.03 vs 1.05, p = 0.706) periods. No intragroup differences were observed when comparing Vm and iVm among the infarct-positive vessels during the early (p = 0.617), later (p = 0.765) or overall (p = 0.326) investigative time periods. Velocity ranges (excursions) were similar between infarct-positive and infarct-negative vessels during the early (31 cms/s vs 35 cms/s, p = 0.443), late (41 cms/s vs 35 cms/s, p = 0.420) and overall (67 cms/s vs 64 cms/s, p = 0.502) time periods. However, velocity ranges for infarct-positive vessels during the peri-infarct period were lesser than for non-infarct vessels during the early (19 cms/s vs 35 cms/s, p = 0.001), late (24 cms/s vs 35 cms/s, p = 0.012) and overall (37 cms/s vs 64 cms/s, p b 0.001) time periods. Among infarct positive vessels, velocity ranges were less when considering iVm against Vm during the early (p = 0.021), later (p = 0.009) and overall (p b 0.001) time periods. 3.3. ROC & AUC analyses ROC curves (Fig. 1) revealed generally poor accuracy for max Vm in anticipating infarctions during the early [AUC 0.38 (95%CI 0.36–0.50) p = 0.083], later [0.51 (0.42–0.60) p = 0.826] and overall [0.51 (0.44–0.59) p = 0.752] investigative periods. Substituting iVm for max Vm resulted in a diminished accuracy for elevated ACA velocities to anticipate the development of ACA infarction during the early [0.20 (0.10–0.30) p b 0.001], later [0.32 (0.24–0.40) p = 0.001] and overall [0.25 (0.19–0.31) p b 0.001] investigative time periods. However, visual inspection of the curves suggested the possibility of lower index velocities below which ACA infarction may be accurately anticipated. ROC tabular coordinate points were reviewed in conjunction with the graphic representation to identify candidate velocities that may most accurately dichotomize infarctpositive from infarct-negative vessels during the various time periods. Vm below 60 cms/s during the early period [0.78 (0.69– 0.88) p b 0.001], Vm below 70 cms/s during the late period [0.64 (0.55–0.73) p = 0.010], and Vm below 70 cms/s during the overall time period [0.71 (0.64–0.78) p b 0.001], demonstrated the greatest accuracy in anticipating occurrence of infarction. Standard velocities for defining VS during the later time period demonstrated poor accuracy in anticipating ACA infarction – 100 cms/s [0.55 (0.46–0.63)

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Table 2 Comparison of ACA velocities, ratios and ranges in infarct-positive and infarct-negative vessels during the various investigational time periods. Early

Vm vs Vm iVm vs Vm Paired t-test Rat: Vm vs Vm Rat: iVm vs Vm Paired t-test Ran: Vm vs Vm Ran: iVm vs Vm Paired t-test

Late

Overall

(+)

(−)

p-value

(+)

(−)

p-value

(+)

(−)

p-value

70 ± 27 54 ± 25 p = 0.002 1.09 ± 0.54 1.05 ± 0.53 p = 0.617 31 ± 24 19 ± 18 p = 0.021

81 ± 28 81 ± 28

0.109 b0.001

102 ± 39 102 ± 39

0.910 b0.001

0.940 b0.001

0.600 0.989

1.04 ± 0.32 1.04 ± 0.32

0.839 0.988

1.04 ± 0.31 1.05 ± 0.32

0.876 0.706

35 ± 23 35 ± 23

0.443 0.001

35 ± 44 35 ± 44

0.420 0.012

101 ± 36 69 ± 30 p b 0.001 1.03 ± 0.27 1.03 ± 0.46 p = 0.326 67 ± 32 37 ± 25 p b 0.001

101 ± 38 101 ± 38

1.05 ± 0.33 1.05 ± 0.33

101 ± 36 78 ± 30 p b 0.001 1.06 ± 0.38 1.04 ± 0.44 p = 0.765 41 ± 39 24 ± 21 p = 0.009

64 ± 38 64 ± 38

0.502 b0.001

Values represent means ±SD of max Vm or iVm in cms/s, or of the iACA/cACA ratio (Rat), or the Vm or iVm range (Ran) in cms/s, with (+) or (−) denoting the presence or absence of ACA infarction. Analyses performed using Student's (two-tailed) t-test and paired t-test. p-values b 0.1 are bolded. For infarct-positive vessels, Vm (maximum velocity) and iVm (velocity on day of infarct) were analyzed separately. Data indicates that infarct-positive vessels demonstrated lower velocities on the day of infarction compared to infarct-negative vessels during every time period and during the overall time period, whereas no intergroup differences were observed when simply comparing Vm values. Also, among infarct-positive patients, iVm were statistically lower than Vm. No intergroup or intragroup differences were observed for ratios. Infarcted vessels had lesser velocity ranges (excursions) during peri-infarct days than non-infarcted vessels during each respective time period, and had lesser velocity ranges during peri-infarct days than for the entirety of each investigational time period.

p = 0.369], 120 cms/s [0.54 (0.45–0.63) p = 0.431], 150 cms/s [0.50 (0.41–0.59) p = 0.983]. Respective S/S values were 0.55/0.55, 0.35/ 0.73, 0.13/0.87. For the early infarct analyses, excluding hyperacute infarctions that may be related to procedural complications revealed similar results for Vm [0.38 (0.25–0.50) p = 0.101], iVm [0.17 (0.09–0.25) p b 0.001] and iVm60 [0.79 (0.69–0.89) p b 0.001].

Velocity ratios did not anticipate ACA infarction during the early period when using max velocity from that period [0.48 (0.3–0.63) p = 0.758] or day of infarction velocity [0.52 (0.37–0.68) p = 0.732], during the late time period when using max velocity from late period [0.57 (0.46–0.68) p = 0.226] or day of infarction velocity [0.53(0.41–0.65) p = 0.636], or during the overall investigative time period when

Fig. 1. ROC curves for the accuracy of ACA velocities in determining ACA infarction ROC curves representing early infarction (A), later infarction (B &C) and overall infarction (D). Vm denotes curve for which the mean maximum velocities were used for infarct-positive and for infarct-negative vessels, all as continuous variables. iVm denotes curves in which velocity on day of infarction was used for infarct-positive vessels and Vm was used for infarct-negative vessels, all as continuous variables. iVm(N) refers to curves for which all velocity values were dichotomized as ≥N (statistical value 0) or bN (statistical value 1), and ROC analyses of velocities performed by entering the nominal variable. In the second curve for later infarctions, Vel1/Vel2/Vel3 refers to velocities of 100/120/150 cms/s entered as dichotomous nominal variables. Notable AUC findings include (A) moderate accuracy for Vm b 60 cms/s in anticipating infarction during the early time period [AUC 0.78 (95%CI 0.69–0.88) p b 0.001], (B) modest accuracy for Vm b 70 cms/s in anticipating infarction during the later time period [0.64 (0.55–0.73) p = 0.010], (C) poor accuracy for velocities conventionally used to define VS in anticipating infarction [AUC 0.50–0.55, p = ns for all], and (D) moderate accuracy for Vm b 70 cms/s in anticipating infarction during the overall investigational time period [0.71 (0.64–0.78) p b 0.001].

M. Moussouttas et al. / Journal of the Neurological Sciences 376 (2017) 143–150

using max velocity [0.50 (0.42–0.58) p = 0.949] or infarct day velocity [0.52 (0.43–0.62) p = 0.629]. Velocity ranges failed to anticipate ACA infarction during the early period when using max range from that period [0.44 (0.31–0.57) p = 0.387], but inversely anticipated infarction using ranges from the peri-infarct period [0.028 (0.018–0.038) p = 0.001]. Conversely, velocity ranges failed to anticipate infarction during the later time period when using the max range [0.55 (0.47–0.64) p = 0.301] or when using peri-infarct ranges [0.50 (0.44–0.56) p = 0.982]. Ranges did not anticipate infarction during the overall period using max range [0.54 (0.48– 0.61) p = 0.328], but inversely anticipated infarction using the peri-infarct range [0.27 (0.21–0.33) p b 0.001].

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surgery predicted elevated velocities during the later [6.95 (0.71– 13.2)] period. Excluding hyperacute infarctions provided similar predictive values for all of the variables tested, with the exception that tobacco use also became an independent predictor of velocity elevations during the late [7.01 (0.13–13.9)] and overall [0.647 (0.17–13.3)] investigative time periods. Table 4 also provides the most consistent independent predictors of the low index velocities previously obtained from ROC curve analyses, using logistic regression modeling. Additionally, worse mFs [OR 0.49 (95% CI 0.27–0.90)] and tobacco use [0.43 (0.27–0.70)] inversely predicted low ACA velocities during the late time period, and hypertension positively predicted low velocities [2.43 (1.40–4.21)] during the early time period.

3.4. Univariate associations for ACA velocities 3.6. Predictive value of index velocities for infarction Univariate associations between clinical variables and ACA max Vm are provided in Table 3. Age was inversely associated with ACA velocity elevations during early (ρ = − 0.11, p = 0.002), late (ρ = − 0.16, p b 0.001) and overall time periods (ρ = − 0.18, p b 0.001). Early velocity elevations were associated with Caucasian race (82 cms/s vs 78 cms/s, p = 0.035), and tended to associate with female gender (82 cms/s vs 78 cms/s, p = 0.055). Tobacco use was positively associated with velocity elevations during the early (83 cms/s vs 77 cms/s, p = 0.003), later (107 cms/s vs 95 cms/s, p ≤ 0.001) and overall (105 cms/s vs 94 cms/s, p b 0.001) time periods. Worse H/H grade was positively associated with elevated ACA velocities during the later time period (112 cms/s vs 99 cms/s, p b 0.001), whereas severe mFs score was positively associated with velocity elevations during the later (113 cms/s vs 99 cms/s, p b 0.001) and overall (109 cms/s vs 100 cms/s, p = 0.003) periods. Surgical treatment was associated with velocity elevations during the late (115 cms/s vs 107 cms/s, p = 0.046) and overall (115 cms/s vs 107 cms/s, p = 0.038) periods, and ACA/ACom aneurysm location tended towards a negative association for early velocity elevations (79 cms/s vs 83 cms/s, p = 0.079). 3.5. Multivariate predictors of ACA velocities Linear regression analyses identified independent predictors of ACA velocity elevations, the most consistent of which are presented in Table 4. In addition, male gender inversely predicted velocity elevations during the early [PE -5.51 (95% CI − 10.6 to − 0.38)] time period, and

Multivariate logistic regression analyses were performed for the outcome of ipsilateral ACA infarction using the index velocities identified on the ROC review as a nominal variable (Table 5). Low index velocities independently predicted ipsilateral ACA infarction at every time period. Statistical findings were - for Vm b 60 cms/s during the early period [4.18 (1.77–9.84)], for Vm b 70 cms/s during the late period [6.58 (2.35–18.4)] and for Vm b 70 cms/s during the overall investigative time period [7.99 (3.45–18.5)]. H/H grade independently predicted ACA infarction during the early [2.26 (1.02–5.01)], later [11.98 (4.21– 34.1)] and overall [9.86 (4.08–23.8)] periods. ACA/ACom aneurysm also predicted infarction during the early [2.79 (1.24–6.26)], later [16.6 (5.28–52.1)] and overall [14.1 (5.48–36.3)] periods. Surgical treatment independently predicted infarction during the late [2.39 (1.27– 4.51)] and overall [2.31 (1.33–4.00)] investigative time periods, and male gender inversely predicted infarct later [0.26 (0.09–0.76)] and overall [0.29 (0.12–0.75)]. 4. Discussion The primary findings of our investigation indicate that maximum mean ACA velocities do not differ between infarct-positive and infarct-negative vessels, and that velocity elevations and related velocity parameters (ratios & ranges) are not reliable for identifying vessels at risk of infarction. Conversely, our findings reveal that decreased velocities may provide moderate accuracy in anticipating the development of ACA infarction. Findings contradict the belief that infarction following

Table 3 Mean maximum ACA Vm for clinical variables during the acute/subacute and overall time periods. Early

Late

Overall

(+)

(−)

p

(+)

(−)

p

(+)

(−)

p

Demographics Age Female Caucasian

ρ = −0.11 82 ± 28 82 ± 28

78 ± 28 78 ± 28

0.002 0.055 0.035

ρ = −0.16 102 ± 38 102 ± 40

101 ± 40 101 ± 36

b0.001 0.582 0.566

ρ = −0.18 101 ± 38 102 ± 39

100 ± 40 98 ± 37

b0.001 0.537 0.209

Medical history Hypertension Tobacco use

79 ± 28 83 ± 29

83 ± 28 77 ± 26

0.108 0.003

102 ± 39 107 ± 39

102 ± 38 95 ± 37

0.936 b0.001

101 ± 39 105 ± 39

100 ± 38 94 ± 36

0.914 b0.001

Clinical/radiologic H/H Grade 4/5 CT Score 3/4

83 ± 32 81 ± 28

80 ± 26 82 ± 28

0.212 0.675

112 ± 38 113 ± 40

99 ± 39 99 ± 38

b0.001 b0.001

104 ± 41 109 ± 41

99 ± 37 100 ± 37

0.144 0.003

Aneurysm anatomy ACA/ACom

79 ± 25

83 ± 28

0.079

101 ± 37

103 ± 39

0.483

101 ± 36

103 ± 38

0.473

Aneurysm treatment Endovascular

84 ± 28

85 ± 28

0.702

107 ± 38

115 ± 42

0.046

107 ± 38

115 ± 39

0.038

Values represent means ±SD of the maximum Vm in cms/s, with (+) or (−) denoting the presence or absence of stated variable. Analyses performed using Pearson's correlation coefficient and the Student's (two-tailed) t-test. p-values b 0.1 are bolded. Data indicate an inverse association between age and ACA velocities during the early/late and overall time periods, greater velocities with tobacco use during all time periods, greater velocities with worse mRs score in the late & overall time periods, greater velocities with severe H/H grade during the late time period, and greater velocities with surgical treatment during the late and overall time periods.

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Table 4 Multivariate regression analyses for independent predictors of ACA velocity elevations and for low index velocities. Early

Velocity elevations Age Caucasian H/H Grade mFS Score 3/4 ACA/ACom

Late

Overall

PE/OR (95% CI)

p

PE/OR (95% CI)

p

PE/OR (95% CI)

p

NS 7.70 (2.58–12.8) 6.10 (0.76–11.5) NS -4.99 (−10.1–0.12)

0.003 0.025 10.9 (3.63–18.2) 0.056

−0.57 (−0.85 to −0.30) 10.2 (3.16–17.2) 7.11 (−0.20–14.4) 0.003 -9.96 (−16.9 to −2.96)

b0.001 0.005 0.057 9.57 (2.63–16.5) 0.005

−0.48 (−0.74 to −0.22) 10.4 (3.71–17.1) 7.32 (0.34–14.3) 0.007 −8.99 (−15.7 to −2.31)

b0.001 0.002 0.040

0.001 0.005

1.04 (1.01–1.06) 0.50 (0.30–0.82) 1.94 (1.19–3.17)

0.001 0.007 0.008

1.04 (1.02–1.06) 0.39 (0.24–0.62) 3.32 (2.07–5.34)

0.001 b0.001 b0.001

Low index velocities Age NS Caucasian 0.46 (0.28–0.73) ACA/ACom 1.94 (1.22–3.09)

0.008

Table presents the most consistent independent predictors of ACA velocity elevations and of low index velocities – additional less consistent predictors for these outcomes are presented in text. Linear regression modeling was used for the determination of velocity elevation predictors (analyzed as a continuous outcome measure), whereas logistic regression modeling was used for identification of low index velocity predictors (analyzed as a nominal outcome measure). Analogously, values represent parameter estimates (PE) or odds ratios (OR) with respective confidence intervals (95% CI) and concurrent p-values (p). All p-values b0.05 are bolded. Analyses identify age as an inverse independent predictor of ACA velocity elevation during the early/late and overall time periods, Caucasian race as a positive independent predictor of ACA velocity elevation during the early/late and overall investigational periods, severe H/H grade as a velocity predictor early and overall, worse mFs score as a predictor during the late and overall periods, and ACA/ACom aneurysm as a negative predictor late and overall. Analyses also identify older age as an independent predictor of low index velocities during the later and overall investigative time periods, non-Caucasian race as an independent predictor during the early/late and overall time periods, and ACA/ACom aneurysm location as an independent predictor during all time periods.

aSAH is predominantly determined by VS, given that greater Vm were not observed in infarct-positive vessels during any time period. By contrast, the fact that iVm were substantially lower than the corresponding Vm of infarct-negative vessels raises the possibility that non-VS processes may contribute to causing ACA infarction. Our investigation did not specifically assess the accuracy of ACA velocities for detecting angiographic VS or symptomatic VS, and therefore our findings cannot address the reliability of ACA velocities for these two outcome measures. In addition, no prior studies like ours have been performed, so there is no precedent available in the medical literature to provide direct comparison. Nevertheless, our findings are somewhat comparable to several previous TCUS investigations. In the 2009 investigation by Kincaid et al., an ACA velocity of 130 cms/s resulted in an AUC of 0.61 for the identification of angiographic VS, which is not dissimilar to the AUC of 0.55 for a velocity of 100 cms/s from our current investigation [22]. In the 2002 report by Suarez et al., a velocity of 120 cms/s provided a S/S of 0.45/0.84 for symptomatic VS, similar to the 0.35/0.73 findings from our investigation using the same velocity [23]. Our findings differ, however, from those of Westermaier et al. in 2014 who assessed the S/S of all intracranial vessels cumulatively for identifying cerebral infarction, using 140 cms/s for supratentorial and 90 cms/s for posterior fossa vessels [24]. Greater sensitivity over specificity (0.90/0.60) was observed, possibly related to the greater sensitivity and lower specificity of TCUS for detecting VS in the middle cerebral and basilar arteries [25]. Pertinent to our investigation are prior works that reveal a dissociation between velocities, cerebral perfusion measures and neurological injury. In the 2003 report by Minhas et al. of SAH patients exhibiting delayed neurological deficits, MCA velocities failed to correlate with PET measured cerebral perfusion or with the presence of focal or global

neurological symptoms [26]. Elevated MCA velocities variably corresponded to normal, ischemic or hyperemic areas on PET. An earlier report by Clyde et al. correlated elevated arterial velocities to greater local perfusion in multiple intracranial vessels/territories, including the ACA, as measured by Xenon CT imaging [27]. Additionally, arteries with recent velocity increases demonstrated no substantial perfusion changes, and whereas focal neurological deficits corresponded to MCA territory reductions in perfusion, MCA velocities on TCUS remained unchanged. In these two investigations, lower MCA velocities correlated to lower MCA territory perfusion, and in the latter investigation lower velocities correlated to lower perfusion values in multiple arterial territories including the ACA. Our findings also reveal that ACA velocity elevations are predicted by younger age, female gender, Caucasian race, worse H/H grade, severe mFs score, non-ACA/ACom aneurysm location, and surgical treatment. Findings complement prior investigations that identified younger age [28,29], female gender [9,10], worse H/H grade [20,29], severe mFs score [9,20,30,31], and surgical treatment [9,10] as independent predictors of VS. The identification of Caucasian race as a positive predictor and of ACA/ACom aneurysm location as a negative predictor of velocity elevations have not been previously described, but the existence of an inverse association between velocities and local aneurysmal rupture, with vascular injury and regional thrombosis, is conceptually plausible. The similar risk factors between ACA velocity elevations and angiographic VS reinforce the notion that velocity elevations represent markers of, and are therefore of utility in detecting, cerebral VS. Conversely, and not unexpectedly, the most consistent predictors of low (index) ACA velocities in our investigation were older age, nonCaucasian race and ACA/ACom aneurysm location. In turn, low velocities emerged as powerful predictors of infarction during all time

Table 5 Multivariate logistic regression analyses to identify independent predictors of ACA infarctions. Early OR (95% CI) Male H/H Grade Vm b N ACA/ACom Surgery

NS 2.26 (1.02–5.01) 4.18 (1.77–9.84) 2.79 (1.24–6.26) NS

Late

Overall

p

OR (95% CI)

p

OR (95% CI)

p

0.045 0.001 0.013

0.26 (0.09–0.76) 11.98 (4.21–34.1) 6.58 (2.35–18.4) 16.6 (5.28–52.1) 2.39 (1.27–4.51)

0.014 b0.001 b0.001 b0.001 0.007

0.29 (0.12–0.75) 9.86 (4.08–23.8) 7.99 (3.45–18.5) 14.1 (5.48–36.3) 2.31 (1.33–4.00)

0.010 b0.001 b0.001 b0.001 0.003

Values represent odds ratios (OR) with confidence intervals (95% CI) and concurrent p-values (p). All p-values b 0.05 are bolded. Analyses incorporate low index velocity as a nominal variable – low index velocities (N) were b60 cms/s for the early, b70 cms/s for the later, and b70 cms/s for the overall investigative time periods. Predictors of infarction include female gender, worse H/H grade, ACA/ACom aneurysm, surgical treatment, and low index velocity.

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periods, as did severe H/H grade and ACA/ACom aneurysm location; female gender and surgery were also predictors. Findings are consistent with a prior investigation that also identified worse H/H grade, ACA/ ACom aneurysm location and non-Caucasian race as predictors of ACA infarction following aSAH [32], and with investigations not focusing specifically on the ACA that identified increasing age [8], severe H/H grade [33], ipsivascular aneurysm location [34], and surgery [35] as infarct predictors. The inverse association between age and velocities may be related to the decline in cerebral flow that occurs with normal aging [14], due to various cardiovascular and hemodynamic reasons [36]. Differences between the predictors of velocity elevation and territorial infarction may explain the inaccuracy of increased velocities for predicting the development of ACA infarction, in that the influence of any common clinical risk factor may be diluted or negated by conflicting factors. Differences between the determinants of velocity elevation and territorial infarction may also imply that the two entities may be caused by different or only partly related pathophysiologic processes, and that infarction may be unrelated or only partially related to the occurrence of cerebral VS. Similarly, absence of velocity elevations among infarct-positive vessels may explain the neutral findings from per-period velocity range analyses, while generally lower velocities among infarct-positive vessels may explain the differences observed in peri-infarct velicity range analyses. Negative findings from the iACA/cACA ratio analyses may be explained by asymmetric anatomic configurations between the two ACA vessels, complex rheologic interdependence of the ACAs, common pathologic processes impacting the ACAs, and most importantly the frequency with which bilateral infarctions occurred in the majority of cases. Recent reports have implicated numerous non-VS causes of infarction following aSAH [5,17], including local thrombosis [37], cerebral edema [37], elevated intracranial pressure [38], endothelial dysfunction [34], impaired autoregulation [15], reduced perfusion [37], and cortical depolarization [5]. One new and particularly relevant investigation revealed that VS alone does not relate to the development of delayed cerebral ischemia, but instead that the combination of VS with impaired cerebral autoregulation was necessary [39]. Another new and intriguing investigation proposed distinctly separate mechanisms for VS and delayed cerebral ischemia, whereby VS results from myogenic dysfunction, and cerebral ischemia is caused by neurogenic autonomic dysregulation in the form of excessive sympathetic activity [40]. Failure of the endothelin antagonist clazosentan to convincingly decrease mortality/morbidity or cerebral infarction, despite consistently reducing moderate to severe VS, also provides evidence for a dissociation between VS and ischemia [41–43]. Limitations to our investigation include the inability to insonate all ACA vessels due to temporal cranial hyperostosis in certain patients [44], the lack of angle correction during velocity measurement [44], the inability of TCUS to detect distal arterial VS [44], and the frequent anatomic variability of the ACA/ACom complex, which may involve vascular aplasia or hypoplasia, fenestration, duplication, and asymmetric variation in arterial lumen diameter [45]. However, such limitations are unavoidable and intrinsic to the performance of routine TCUS, and represent constraints inherent to any given population. Conversely, the number of patients included, the frequent insonations performed twice daily, and the consistency of the results with past literature, represent attributes to the current investigation. Additional limitations may include the lack of angiography and MRI imaging for precise identification of VS and infarction, and the absence of any clinical correlation for infarction occurrence. However, the performance of serial angiograms and cerebral MRI imaging is logistically impossible, and pose greater risks to patients than do bedside TCUS screens and portable CT scans. Since imaging evidence of infarction may not always present with a clinical correlate, and because examination of severely impaired patients may limit clinical detection of infarction [24], an objective radiographic definition of infarction was preferred. The absence of routine

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cerebral CT scans following interventional or surgical aneurysmal treatment may represent a limitation to identifying postprocedural ischemic complications but is not expected to impact the identification of subacute infarctions during which time VS is most prevalent. Regardless, statistical analyses were repeated excluding those hyperacute postprocedural cases. The complex nonlinear and nonuniform relationship between vessel stenosis, velocity and flow (Spencer Curve) represents an additional problem in relating intracranial velocities to perfusion [46]. Severe arterial stenosis may display elevated, normal (pseudonormalized) or reduced velocities, all of which may reflect reduced cerebral flow. Based on available cerebral perfusion imaging data, elevated velocities may correspond to normal, ischemic or hyperemic regions of cerebral flow, while lower velocities appear to represent low flow. Given findings linking lower velocities to infarction, iVm may reflect markedly reduced flow at the extreme terminal end of the velocity-flow curve, as may be seen in cases of severe or critical VS. However, given the absence of increased velocities among infarct patients during any time period, lower velocities may merely indicate decreased perfusion to an ischemic region, and therefore may simply serve as a marker of ACA infarction [47]. 5. Conclusion Following aSAH, ACA velocity elevations (and velocity ratios/ranges) do not anticipate the development of ACA infarctions, whereas lower velocities are moderately accurate and independently predict the occurrence of infarction. Predictors of ACA velocity elevations are generally similar to those that predict angiographic VS, whereas predictors of lower velocities more closely resemble those that predict infarction. This investigation raises the possibility that ACA velocity elevations may relate to VS (as evidenced in the medical literature) but that lower ACA velocities may relate more to actual infarction. ACA velocities below, or decreasing velocities approaching, the index values may require greater clinical attention and additional investigation than elevated velocities that traditionally define cerebral VS. More meticulous and more frequent clinical examinations, and additional confirmatory diagnostic imaging such as CT or MR angiography and perfusion, may be indicated. The presence of an ACA/ACom aneurysm, severe H/H grade, surgical treatment, and female gender, may also raise concern for risk of infarction. Funding This research did not receive any specific grants from funding agencies in the public/commercial/non-profit sectors. Disclosures/conflict of interest None. References [1] N.W. Dorsch, Cerebral arterial spasm–a clinical review, Br. J. Neurosurg. 9 (1995) 403–412. [2] R.H. Wilkins, Cerebral vasospasm, Crit. Rev. Neurobiol. 6 (1990) 51–77. [3] M.E. Baldwin, R.L. Macdonald, D. Huo, et al., Early vasospasm on admission angiography in patients with aneurysmal subarachnoid hemorrhage is a predictor for inhospital complications and poor outcome, Stroke 35 (2004) 2506–2511. [4] M. Moussouttas, E.W. Lai, T.T. Huynh, et al., Association between acute sympathetic response, early onset vasospasm, and delayed vasospasm following spontaneous subarachnoid hemorrhage, J. Clin. Neurosci. 21 (2014) 256–262. [5] M. Vergouwen, D. Ilodigwe, L. Macdonald, Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm dependent and -independent effects, Stroke 42 (2011) 924–929. [6] A. Rosengart, K. Schultheiss, J. Tolentino, et al., Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage, Stroke 38 (2007) 2315–2321. [7] S. Juvela, J. Siironen, J. Kuhmonen, Hyperglycemia, excess weight, and history of hypertension as risk factors for poor outcome and cerebral infarction after aneurysmal suarachnoid hemorrhage, J. Neurosurg. 102 (2005) 998–1003.

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