clinical article J Neurosurg 125:730–736, 2016

Beta-blocker therapy and impact on outcome after aneurysmal : a cohort study

Nohra Chalouhi, MD,1 Badih Daou, MD,1 Toshimasa Okabe, MD,2 Robert M. Starke, MD,1,3 Richard Dalyai, MD,1 Cory D. Bovenzi, BS,1 Eliza Claire Anderson, MD,1 Guilherme Barros, BS,1 Adam Reese, BA,1 Pascal Jabbour, MD,1 Stavropoula Tjoumakaris, MD,1 Robert Rosenwasser, MD,1 Walter K. Kraft, MD,2 and Fred Rincon, MD, MSc1,4

Departments of 1Neurosurgery, 2Medicine, and 4Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania; and 3Department of Neurosurgery, University of Virginia Health System, Charlottesville, Virginia

Objective Cerebral vasospasm (cVSP) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on outcome. Beta blockers (BBs) may blunt the sympathetic effect and catecholamine surge as- sociated with ruptured cerebral aneurysms and prevent cardiac dysfunction. The purpose of this study was to investigate the association between preadmission BB therapy and cVSP, cardiac dysfunction, and in-hospital mortality following aSAH. Methods This was a retrospective cohort study of patients with aSAH who were treated at a tertiary high-volume neurovascular referral center. The exposure was defined as any preadmission BB therapy. The primary outcome was cVSP assessed by serial transcranial Doppler with any mean flow velocity ≥ 120 cm/sec and/or need for endovascular intervention for medically refractory cVSP. Secondary outcomes were cardiac dysfunction (defined as cardiac troponin-I elevation > 0.05 mg/L, low left ventricular ejection fraction [LVEF] < 40%, or LV wall motion abnormalities [LVWMA]) and in-hospital mortality. Results The cohort consisted of 210 patients treated between February 2009 and September 2010 (55% were women), with a mean age of 53.4 ± 13 years and median Hunt and Hess Grade III (interquartile range III–IV). Only 13% (27/210) of patients were exposed to preadmission BB therapy. Compared with these patients, a higher percentage of patients not exposed to preadmission BBs had transcranial Doppler-mean flow velocity ≥ 120 cm/sec (59% vs 22%; p = 0.003). In multivariate analyses, lower Hunt and Hess grade (OR 3.9; p < 0.001) and preadmission BBs (OR 4.5; p = 0.002) were negatively associated with cVSP. In multivariate analysis, LVWMA (OR 2.7; p = 0.002) and low LVEF (OR 1.1; p = 0.05) were independent predictors of in-hospital mortality. Low LVEF (OR 3.9; p = 0.05) independently predicted medically refractory cVSP. The in-hospital mortality rate was higher in patients with LVWMA (47.4% vs 14.8%; p < 0.001). Conclusions The study data suggest that preadmission therapy with BBs is associated with lower incidence of cVSP after aSAH. LV dysfunction was associated with higher medically refractory cVSP and in-hospital mortality. BB therapy may be considered after aSAH as a cardioprotective and cVSP preventive therapy. http://thejns.org/doi/abs/10.3171/2015.7.JNS15956 Key Words stroke; delayed cerebral ; transcranial Doppler; ultrasound; vascular disorders

erebral vasospasm (cVSP) is a frequent compli- deficits occur in up to 50% of patients with angiographic cation of aneurysmal subarachnoid hemorrhage cVSP, often causing stroke or death despite maximal ther- (aSAH) and occurs in 30%–70% of these patients, apy.10 mostC commonly between index Days 3 and 12. cVSP could Despite several research efforts, cVSP has remained lead to either permanent morbidity or death in up to 20% incompletely understood from both the pathogenic and of patients with aSAH.11 Delayed ischemic neurological therapeutic perspectives.8 A number of medical therapies

Abbreviations aSAH = aneurysmal subarachnoid hemorrhage; AUC = area under the receiver operating characteristic curve; BB = ; cTi = cardiac troponin- I; cVSP = cerebral vasospasm; DCI = delayed cerebral ischemia; HH = Hunt and Hess; LVEF = left ventricular ejection fraction; LVWMA = LV wall motion abnormalities; mFV = mean flow velocity; NSM = neurogenic stunned myocardium; TCD = transcranial Doppler. submitted April 26, 2015. accepted July 17, 2015. include when citing Published online January 22, 2016; DOI: 10.3171/2015.7.JNS15956.

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Unauthenticated | Downloaded 10/06/21 04:45 PM UTC Beta blockers and outcome after aSAH have been proposed and evaluated for cVSP both at the vated or showed a trend toward elevation, or with increas- basic and translational levels. No single treatment modal- ing Lindegaard ratios. If patients developed a new focal ity has proven efficacious, with often conflicting trial re- neurological deficit, a CT scan was obtained to eliminate a sults.1 Currently, the strongest evidence supports the use of diagnosis of hydrocephalus or rebleeding. Hyperdynamic prophylactic oral for the prevention of delayed therapy was then maximized to the point of elevating the cerebral ischemia (DCI). Other therapies, including cal- mean arterial pressure by 20%. If patients did not dem- cium channel blockers (nicardipine), receptor onstrate neurological reversal within 60 minutes, they antagonists, magnesium, and statins, have failed to prove were transferred to the endovascular suite for emergency any efficacy.1,22 Although hyperdynamic therapy has been angiography and potential intervention with balloon an- historically advocated for the management of cVSP,1,22 re- gioplasty and/or spasmolytic agents. cent studies have shown that only induced is associated with improved cerebral blood flow.7,15 Data Collection The impact of beta-blocker (BB) therapy on the oc- Electronic medical records were reviewed to determine currence of cVSP has not been studied. Data concerning patients’ demographic data, HH and Fisher grades, comor- the impact of cardiac abnormalities on the occurrence of 19 bidities (i.e., hypertension or a history of ischemic heart cVSP have also been limited. In fact, cardiac function ab- disease), and preadmission antihypertensive drug thera- normalities are common following aSAH (in up to 33% of py, including BBs. The left ventricular ejection fraction cases) and may influence clinical outcomes and the occur- 20 (LVEF) and the presence of LV wall motion abnormalities rence of cVSP. The purpose of the present study was to (LVWMA) upon admission were assessed by the admis- assess the impact of preadmission BB therapy and cardiac sion echocardiograms and interpreted by a board-certified function abnormalities on the incidence of cVSP and in- cardiologist. The TCD data of all patients with aSAH were hospital mortality following aSAH. We hypothesized that collected prospectively and maintained in a computerized preadmission exposure to BBs would be associated with database. a lower incidence of cVSP and lower cardiac dysfunction and in-hospital mortality. Exposure and Outcome Measures The exposure was defined as any preadmission BB Methods therapy (metoprolol, atenolol, carvedilol, or others), which Study Population was discontinued upon admission to the hospital. The pri- Thomas Jefferson University’s institutional review mary outcome cVSP was defined as any serial TCD with board approved the study protocol. Patients treated for mFV ≥ 120 cm/sec. For the analysis, we also used a sec- aSAH between February 2009 and September 2010 at our ond a priori definition of mFV ≥ 200 cm/sec. Medically hospital were included in the analysis. Exclusion criteria refractory cVSP was defined as TCD-mFV ≥ 120 cm/sec included traumatic or nonaneurysmal SAH and lack of ad- with clinical deterioration not responsive to medical ther- equate transcranial Doppler (TCD) windows. Per institu- apy and requiring an endovascular intervention. Second- tional protocol, aSAH was diagnosed based on the results ary outcomes were cardiac dysfunction (defined as cTi > of admission CT or MRI, or the presence of xanthochro- 0.05 mg/L, or LVEF < 40%, or LVWMA) and in-hospital mia in CSF. mortality. In all patients, an arterial line was placed at the time of admission, outpatient antihypertensive medications were Statistical Analysis discontinued, and a nicardipine infusion was started to Data are presented as the mean and range for continu- keep the mean arterial pressure < 90 mm Hg preopera- ous variables, and as the count and proportion for cate- tively. Patients with Hunt and Hess (HH) Grades ≥ III re- gorical variables. Differences were assessed by unpaired ceived a ventriculostomy for CSF drainage. All patients t-tests, Wilcoxon rank-sum tests, and chi-square or Fish- received nimodipine from index Day 0, and blood transfu- er’s exact tests as appropriate, based on their distributions. sions were given to maintain the hemoglobin level at ≥ 10 Bivariate analysis was used to test covariates predictive of mg/dl. Routine echocardiogram, electrocardiogram, and the following dependent variables: TCD-mFV ≥ 120 cm/ cardiac enzymes were generally measured at the time of sec in any vessel, TCD-mFV ≥ 200 cm/sec in any ves- admission and as necessary during the hospital stay. Car- sel, medically refractory cVSP, cardiac dysfunction, and diac troponin-I (cTi) levels > 0.05 ng/ml were considered in-hospital mortality. The following variables were tested abnormal. Digital subtraction angiography was performed for their predictive value: age, HH grade, Fisher grade, in all patients and aneurysms were secured within 24 hours hypertension, ischemic heart disease, preadmission anti- of admission by coil embolization or by surgical clipping. hypertensive medication, preadmission BBs, peak cTi val- In the neuro-intensive care unit, TCD ultrasonography ue, LVEF, and LVWMA. The Youden index was used to of the bilateral middle cerebral , anterior cerebral determine the optimal dichotomization level for continu- arteries, and posterior cerebral arteries was performed ous variables. Interaction and confounding was assessed daily on aSAH index Days 1–14 by experienced techni- through stratification and relevant expansion of covariates. cians. The mean flow velocity (mFV) was measured Factors predictive in bivariate analysis (p < 0.20)2 were through a transsphenoidal window with a 2-MHz trans- entered into a multivariate logistic regression analysis. A ducer. Patients were treated prophylactically with induced p value of ≤ 0.05 was considered statistically significant. hypertension when their velocities on TCD became ele- Using the C statistic, we calculated the receiver operating

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Unauthenticated | Downloaded 10/06/21 04:45 PM UTC N. Chalouhi et al. characteristic for each of the primary outcomes of interest TABLE 1. HH grades in a cohort of 210 patients with aSAH using our a priori definitions (Fig. 1). Statistical analysis HH Grade No. of Patients (%) was performed using Stata version 10.0 (StataCorp). I 48 (22.85) Results II 12 (5.70) Baseline Characteristics III 84 (40.00) IV 48 (22.85) A total of 210 consecutive patients met the study cri- teria. The mean age was 53.4 ± 13.3 years (range 17–93 V 18 (8.60) years), 55% were women, 57% (120/210) had hypertension, Total 210 and 7% (15/210) had a history of ischemic heart disease. Of those with hypertension, 22% (26/120) were in the BB- exposed group versus 78% (94/120) in non–BB-exposed predicted TCD-mFV ≥ 120 cm/sec (p < 0.001). The pro- group (p < 0.001). Of those with ischemic heart disease, portion of patients with any TCD-mFV ≥ 200 cm/sec was 53% (8/15) were in the BB-exposed group versus 47% in lower in patients exposed to prehospital BBs (4% [1/27] the non–BB-exposed group (p < 0.001). Seventy-three vs 19% [34/183]; p = 0.04). The factors tested in bivariate patients (34.7%) were on preadmission antihypertensive and multivariate analysis for association with TCD-mFV medications, and 13% (27/210) were on BBs. The median ≥ 200 cm/sec are listed in Table 4. In multivariate analysis, HH grade on admission was III (interquartile range III– there was a strong trend for preadmission BBs (p = 0.07) IV). The HH and Fisher grades are listed in Tables 1 and to negatively predict TCD-mFV ≥ 200 cm/sec. 2. An echocardiogram was performed in 82% (174/210) of patients; the mean LVEF was 64% ± 12%, and 4% (8/210) Medically Refractory cVSP Requiring Endovascular Therapy of patients had an LVEF < 40%. Nineteen patients (9%) Fourteen patients (6.7%) required an endovascular in- had LVWMA of any type. Ninety-one patients (43%) had tervention for medically refractory cVSP (Fig. 3); none of a cTi > 0.05 mg/ml during their hospital stay. Among the these patients were taking prehospital BBs. The factors BB-exposed groups, there were no differences in the pro- tested in bivariate and multivariate analysis for associa- portion of patients with an LVEF < 40%, LVWMA, or cTi tion with medically refractory cVSP are listed in Table 5. > 0.05 mg/ml. In multivariate analysis, an mFV ≥ 120 cm/sec (p < 0.001) and an LVEF < 40% (p = 0.05) were independent predic- TCD-Defined cVSP tors of medically refractory cVSP. In the cohort, 54.3% (114/210) of patients had a TCD- mFV ≥ 120 cm/sec (Fig. 1) in any vessel and 17% (35/210) In-Hospital Mortality ≥ had a TCD-mFV 200 cm/sec (Fig. 2) in any vessel dur- The overall in-hospital mortality rate was 15.2% ing their hospital stay. The proportion of patients with any (32/210 patients). The rate of in-hospital mortality was ≥ TCD-mFV 120 cm/sec was lower in patients exposed to lower in patients with LVEF > 55% (17% [26/156 patients] prehospital BB therapy (22% [6/27] vs 59% [108/183]; p vs 33% [6/18 patients]; p = 0.002); in-hospital mortality = 0.003). The factors tested in bivariate and multivariate was lower in patients without LVWMA (15% [23/155 pa- ≥ analysis for association with TCD-mFV 120 cm/sec are tients] vs 47% [9/19 patients]; p < 0.001). The factors tested listed in Table 3. In multivariate analysis, preadmission in bivariate and multivariate analysis for association with BBs (p = 0.007) were an independent negative predictor in-hospital mortality are listed in Table 6. In multivariate ≥ of TCD-mFV 120 cm/sec. Higher HH grades (III–V) analysis, mFV ≥ 120 cm/sec (p = 0.003), HH Grades III–V (p < 0.001), LVWMA (p = 0.002), and LVEF < 40% (p = 0.05) were independent predictors of in-hospital mortality. Discussion The most important findings of this study are as fol- lows: 1) exposure to preadmission BB therapy is associ- ated with a lower incidence of cVSP by TCD in patients with aSAH; 2) LV dysfunction is an independent predictor of medically refractory cVSP requiring endovascular in-

TABLE 2. Fisher grades in a cohort of 210 patients with aSAH Fisher Grade No. of Patients (%) 1 5 (2.4) 2 28 (13.3) 3 74 (35.3) FIG. 1. The area under the receiver operating characteristic curve (AUC) 4 103 (49.0) for TCD-mFV ≥ 120 cm/sec was 0.7312. Figure is available in color Total 210 online only.

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FIG. 2. The AUC for TCD-mFV ≥ 200 cm/sec was 0.6906. Figure is FIG. 3. The AUC for medically refractory vasospasm was 0.8113. Figure available in color online only. is available in color online only. tervention independent of prior BB exposure; and 3) LV of cerebral infarction from cVSP in a population of 119 dysfunction and LVWMA are strongly associated with patients with aSAH.20 The authors found that neurogenic in-hospital mortality in patients with aSAH. We did not LV dysfunction from aSAH increases the risk of cerebral find an association between preadmission BB therapy and infarction from cVSP and that this risk increases with the cardiac dysfunction. Although protective cardiac effects severity of cVSP. Additionally, a higher incidence of hy- from BBs have been suggested by others,6,12,17 our novel potension requiring vasopressors and pulmonary edema observation points to additional beneficial effects of BBs was noted in patients with LV dysfunction. Interestingly, in the setting of aSAH that may extend beyond cardiac the authors noted that none of the patients with LV dys- protection, as we explain below. function were on preadmission antihypertensive medica- In our study, the incidence of cVSP (by TCD criteria) tion compared with 35% of those without LV dysfunction, was reduced by 3-fold and severe cVSP by 6-fold in the suggesting that antihypertensive medication may confer BB-exposed group after adjustment for cardiac dysfunc- cardioprotective effects following aSAH.20 tion. None of the patients taking BBs developed medically In another study, the same group also demonstrated that refractory cVSP requiring an endovascular intervention. cTi elevation after aSAH is associated with an increased The mechanisms that may explain this finding are not risk of DCI and death or poor functional outcome at dis- clearly understood. Primary and secondary cardiac abnor- charge.16 A more recent study by Liang et al.12 found that malities are common in patients with aSAH, and the onset prehospital BB exposure was associated with lower risk of cVSP after aSAH has been associated with cardiac dys- of developing neurogenic stunned myocardium (NSM) in function.20,21 Although we found a significant proportion patients with aSAH. The authors examined a group of 130 of cardiac dysfunction in our cohort (up to 43%), this was patients with aSAH, among whom 18 (13.8%) developed not associated with our prespecified end point of cVSP. NSM, and noted that none of the 22 patients taking pre- In a recent study, Temes et al. examined the incidence hospital BBs developed NSM.12

TABLE 3. Univariate and multivariate analyses of predicting factors for TCD-mFV ≥ 120 cm/sec Multivariate Variable* Univariate p Value OR 95% CI p Value Age 0.3 HH Grades III–V† 0.01 4.2 2.1–8.5 <0.001 Hypertension 0.02 Ischemic heart disease 0.1 BB therapy† 0.003 0.2 0.05–0.8 0.007 Preadmission antihypertensive medication 0.02 Positive troponin 0.1 LVWMA 0.5 LVEF >70% 0.1 Fisher Grades 3–4 0.08 * Higher HH grades (p = 0.01), no hypertension (p = 0.02), no ischemic heart disease (p = 0.1), no preadmission BB therapy (p = 0.003), no preadmission antihypertensive medication (p = 0.02), positive troponin (p = 0.1), and LVEF ≤ 70% (p = 0.1) predicted TCD-mFV ≥ 120 cm/sec. † Predictive factors in multivariate analysis.

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TABLE 4. Univariate and multivariate analyses of predicting factors for TCD-mFV ≥ 200 cm/sec Multivariate Variable* Univariate p Value OR 95% CI p Value Age 0.3 HH Grades III–V 0.1 2.5 0.8–7 0.08 Hypertension 0.3 Ischemic heart disease 0.7 BB therapy 0.04 0.2 0.02–1.2 0.07 Preadmission antihypertensive medication 0.4 Positive troponin 0.6 LVWMA 0.8 LVEF >70% 0.09 0.4 0.1–1.5 0.2 Fisher Grades 3–4 0.3 * The following factors were predictive of TCD-mFV ≥ 200 cm/sec in univariate analysis: higher HH Grades (III–V), no preadmission BB thera- py, and LVEF ≤ 70%.

3,14 It is thought that BBs decrease the risk of developing (CMRGluc). An early experiment conducted in 1974 by NSM and cardiac dysfunction by reducing the impact of Meyer et al. demonstrated that systemic administration of the catecholamine surge that occurs with aneurysm rup- the BB in patients with ischemic stroke re- ture.17 However, it is unclear how they prevent cVSP, as sulted in reductions of cerebral oxidative metabolism.14 independently shown by our study. Perhaps the difference This effect may be enhanced because endogenous norepi- between prior studies and our study relates to the method- nephrine is peripherally released and can cross into brain ological definitions for cVSP.12,16,20 We used a TCD defini- tissue through the disrupted blood-brain barrier, which tion and not the classic composite end point of DCI. To this may abnormally stimulate cerebral glucose and oxygen end, we might have misclassified patients who developed metabolism. The study by Meyer et al. also demonstrated DCI and who may not have had elevated velocities in seri- that besides CMRO2 reductions, b blockade improved au- al TCD assessments. Thus, we could have underestimated toregulation capacity of infarcted brain tissue.14 Because the true incidence of stroke related to cVSP, which is in cerebral autoregulation is impaired after aSAH and this fact associated with cardiac dysfunction after aSAH.20 is a risk factor for cVSP,9 it is possible that 1) coupling of Earlier studies on the molecular mechanisms of cere- CMRO2 and cerebral blood flow in the setting of metabol- bral metabolism and autoregulation have demonstrated ic stress and 2) maintenance of cerebral autoregulation are that cerebral vessels are innervated similarly to other vas- molecular properties of BBs that could potentially explain cular beds.18 Pharmacological studies have determined the association found in our study. that catecholamines can stimulate carbohydrate me- We also found that the odds of developing medically tabolism in the brain as well as in the peripheral tissues; refractory cVSP requiring an endovascular intervention therefore, blocking this action might reduce the overall were 4 times higher when the LVEF was < 40%. This find- cerebral metabolic rate of oxygen (CMRO2) and glucose ing suggests that the normal hyperdynamic response to

TABLE 5. Univariate and multivariate analyses of predicting factors for medically refractory cVSP Multivariate Variable* Univariate p Value OR 95% CI p Value Age 0.8 HH Grades III–V 0.4 Hypertension 0.1 Ischemic heart disease 0.9 BB therapy 0.6 Preadmission antihypertensive medication 0.7 Positive troponin 0.9 LVWMA 0.8 LVEF <40%† 0.06 3.9 1.1–101 0.05 Fisher Grades 3–4 0.3 mFV ≥120 cm/sec† <0.001 6.8 2.1–22.2 <0.001 * The following factors were predictive of medically refractory cVSP in univariate analysis: no hypertension, ejection fraction < 40%, and mFV ≥ 120 cm/sec. † Predictive factors in multivariate analysis.

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TABLE 6. Univariate and multivariate analyses of predicting factors for in-hospital mortality Multivariate Variable* Univariate p Value OR 95% CI p Value Age 0.8 HH Grades III–V† <0.001 4.2 2.3–7.6 <0.001 Hypertension 0.1 Ischemic heart disease 0.2 BB therapy 0.14 Preadmission antihypertensive medication 0.8 Positive troponin 0.001 LVWMA† <0.001 2.7 1.4–5.1 0.002 LVEF <40%† 0.002 1.1 0.99–1.2 0.05 Fisher Grades 3–4 0.3 mFV ≥120 cm/sec† <0.001 5.1 2.0–14 0.003 * The following factors were predictive of in-hospital mortality in univariate analysis: higher HH grades, history of ischemic heart disease, no preadmission BB therapy, positive troponin, lower LVEF, LVMWA, and mFV ≥ 120 cm/sec in any vessel. † Predictive factors in multivariate analysis. aSAH protects against cVSP, and that cardiac dysfunction cVSP after aSAH.13 Fifth, we did not analyze the occur- increases this risk. Also, the finding suggests that patients rence of DCI. Instead, we chose to use medically refrac- with cardiac dysfunction are unlikely to respond to or tol- tory cVSP requiring an endovascular intervention, which erate hyperdynamic therapy. Thus, these patients are more may represent a form of DCI. Therefore, our results should likely to require an endovascular procedure for reversal of be interpreted with this in mind. Finally, because this was medically refractory cVSP. This finding is in agreement a single-center study, whether our results are generalizable with that of Temes et al.;20 however, we suspect that our in- to other populations can always be argued as a potential ability to link cardiac dysfunction with cVSP in our cohort limitation. However, our study provides potentially useful was related to the small number of patients with a recorded information for future research in the field of aSAH. LVEF < 40%. Finally, the results of our study confirm that cardiac Conclusions dysfunction carries a poor prognostic value, not only in terms of medically refractory cVSP but also in terms of The results of this study show that preadmission BB in-hospital mortality. The in-hospital mortality was more exposure is associated with decreased incidence of cVSP than twice as high in the presence of LVWMA or low- in patients with aSAH. LV dysfunction was also associated er LVEF. These findings further highlight the impact of with medically refractory cVSP and in-hospital mortality. cardiac dysfunction on outcome after aSAH. A screening The findings suggest that BBs may be a promising thera- echocardiogram appears to be necessary in patients with peutic avenue for prevention of cVSP and may need to be aSAH at the time of admission or in the event of initial continued or started in patients with aSAH. A controlled cardiac troponin elevation, , or arrhythmias/ randomized clinical trial may be necessary to confirm this electrocardiogram abnormalities. observation.

Limitations of the Study Acknowledgments We acknowledge the limitations of our study. First, our Dr. Rincon has received salary support from the American analysis is observational in nature, limiting the inferences Heart Association (AHA 12CRP12050342). that can be made about causal relationships. Second, TCD References and echocardiograms were performed for clinical purpos- es and did not use a standardized research protocol and 1. Adamczyk P, He S, Amar AP, Mack WJ: Medical manage- ment of cerebral vasospasm following aneurysmal subarach- data collected retrospectively. To this end, our study may noid hemorrhage: a review of current and emerging therapeu- have suffered from selection bias. Third, on the basis of tic interventions. Neurol Res Int 2013:462491, 2013 clinical indications, echocardiograms were not performed 2. Altman DG: Practical Statistics for Medical Research. serially or in all patients; thus, our analysis is based on Boca Raton, FL: Chapman & Hall/CRC, 1999 the initial echocardiogram upon admission to the hospital. 3. Aqyagi M, Deshmukh VD, Meyer JS, Kawamura Y, Tagashi- However, experience suggests that the initial cardiac dys- ra Y: Effect of beta-adrenergic blockade with propranolol on function after aSAH is associated with poor outcome and cerebral blood flow, autoregulation and CO2 responsiveness. 4,21 Stroke 7:291–295, 1976 that it improves over time. Fourth, in accordance with 4. Banki N, Kopelnik A, Tung P, Lawton MT, Gress D, Drew our center’s clinical practice, we assessed cVSP mainly B, et al: Prospective analysis of prevalence, distribution, on the basis of TCD criteria. Although the sensitivity and and rate of recovery of left ventricular systolic dysfunction predictive value of TCD are not perfect,5 the technique re- in patients with subarachnoid hemorrhage. J Neurosurg mains a practical and widely used method for screening 105:15–20, 2006

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5. Carrera E, Schmidt JM, Oddo M, Fernandez L, Claassen J, 17. Neil-Dwyer G, Walter P, Cruickshank JM, Doshi B, Seder D, et al: Transcranial Doppler for predicting delayed O’Gorman P: Effect of propranolol and phentolamine on cerebral ischemia after subarachnoid hemorrhage. Neurosur- myocardial necrosis after subarachnoid haemorrhage. BMJ gery 65:316–324, 2009 2:990–992, 1978 6. Cruickshank JM, Neil-Dwyer G, Degaute JP, Hayes Y, 18. Nelson E, Rennels M: Innervation of intracranial arteries. Kuurne T, Kytta J, et al: Reduction of stress/catecholamine- Brain 93:475–490, 1970 induced cardiac necrosis by beta 1-selective blockade. Lan- 19. Okabe T, Kanzaria M, Rincon F, Kraft WK: Cardiovascular cet 2:585–589, 1987 protection to improve clinical outcomes after subarachnoid 7. Dankbaar JW, Slooter AJ, Rinkel GJ, Schaaf IC: Effect of hemorrhage: is there a proven role? Neurocrit Care 18:271– different components of triple-H therapy on cerebral perfu- 284, 2013 sion in patients with aneurysmal subarachnoid haemorrhage: 20. Temes RE, Tessitore E, Schmidt JM, Naidech AM, Fernan- a systematic review. Crit Care 14:R23, 2010 dez A, Ostapkovich ND, et al: Left ventricular dysfunction 8. Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller and cerebral infarction from vasospasm after subarachnoid T, Ley KF, et al: Cerebral vasospasm after subarachnoid hemorrhage. Neurocrit Care 13:359–365, 2010 hemorrhage: putative role of inflammation. Neurosurgery 21. van der Bilt I, Hasan D, van den Brink R, Cramer MJ, van 53:123–135, 2003 der Jagt M, van Kooten F, et al: Cardiac dysfunction after 9. Frontera JA, Rundek T, Schmidt JM, Claassen J, Parra A, aneurysmal subarachnoid hemorrhage: relationship with out- Wartenberg KE, et al: Cerebrovascular reactivity and vaso- come. Neurology 82:351–358, 2014 spasm after subarachnoid hemorrhage: a pilot study. Neurol- 22. Velat GJ, Kimball MM, Mocco JD, Hoh BL: Vasospasm after ogy 66: 727–729, 2006 aneurysmal subarachnoid hemorrhage: review of randomized 10. Haley EC Jr, Kassell NF, Torner JC: The International Co- controlled trials and meta-analyses in the literature. World operative Study on the Timing of Aneurysm Surgery. The Neurosurg 76: North American experience. Stroke 23:205–214, 1992 446–454, 2011 11. Komotar RJ, Zacharia BE, Otten ML, Mocco J, Lavine SD: Controversies in the endovascular management of ce- rebral vasospasm after rupture and future directions for therapeutic approaches. Neurosurgery 62:897–907, 2008 Disclosures 12. Liang CW, Chen R, Macri E, Naval N: Preadmission beta- Dr. Tjoumakaris is a consultant for Stryker and Covidien. blockers are associated with decreased incidence of neu- rogenic stunned myocardium in aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 22:601–607, 2013 Author Contributions 13. Marshall SA, Nyquist P, Ziai WC: The role of transcranial Conception and design: Rincon, Kraft, Okabe, Chalouhi, Jabbour. Doppler ultrasonography in the diagnosis and management of Acquisition of data: Okabe, Chalouhi, Starke, Bovenzi, Ander- vasospasm after aneurysmal subarachnoid hemorrhage. Neu- son, Barros, Reese. Analysis and interpretation of data: Okabe, rosurg Clin N Am 21:291–303, 2010 Chalouhi, Dalyai. Drafting the article: Chalouhi, Daou, Okabe. 14. Meyer JS, Okamoto S, Sari A, Koto A, Itoh Y, Ericsson AD: Critically revising the article: Rincon, Chalouhi, Daou, Dalyai, Effects of beta-adrenergic blockade on cerebral autoregula- Tjoumakaris, Jabbour, Rosenwasser. Reviewed submitted version tion and chemical vasomotor control in patients with stroke. of manuscript: Rincon, Chalouhi, Daou, Okabe, Starke, Dalyai, Stroke 5:167–179, 1974 Reese, Jabbour. Approved the final version of the manuscript on 15. Muench E, Horn P, Bauhuf C, Roth H, Philipps M, Hermann behalf of all authors: Rincon. Statistical analysis: Starke. Study P, et al: Effects of hypervolemia and hypertension on regional supervision: Rincon, Kraft, Chalouhi, Rosenwasser, Tjoumakaris. cerebral blood flow, intracranial pressure, and brain tissue oxygenation after subarachnoid hemorrhage. Crit Care Med 35:1844–1852, 2007 Correspondence 16. Naidech AM, Kreiter KT, Janjua N, Ostapkovich ND, Parra Fred Rincon, Department of Neurological Surgery, Thomas Jef- A, Commichau C, et al: Cardiac troponin elevation, cardio- ferson University and Jefferson College of Medicine, Division of vascular morbidity, and outcome after subarachnoid hemor- Critical Care and Neurotrauma, 909 Walnut St., 3rd Fl., Philadel- rhage. Circulation 112:2851–2856, 2005 phia, PA 19107. email: [email protected].

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