Differences in Pressure Within the Sac of Human Ruptured and Nonruptured Cerebral Aneurysms

Differences in Pressure Within the Sac of Human Ruptured and Nonruptured Cerebral Aneurysms Abstract BACKGROUND Hemodynamics plays a critical role in the development, growth, and rupture of intracranial aneurysms. This data could be vital in determining individual aneurysm rupture risk and could facilitate our understanding of aneurysms. OBJECTIVE To present the largest prospective cross-sectional cohort study of intrasaccular pressure recordings of ruptured and nonruptured intracranial aneurysms and describe the hemodynamic differences that exist between ruptured and nonruptured aneurysms. METHODS During endovascular treatment, a standard 1.8-Fr 200 m length microcatheter was navigated into the dome of the aneurysm prior to coil embolization. With the microcatheter centralized within the dome of the aneurysm, an arterial pressure transducer was attached to the proximal end of the microcatheter to measure the stump pressure inside the aneurysm dome. RESULTS In 68 aneurysms (28 ruptured, 40 nonruptured), we observed that ruptured cerebral aneurysms had a lower systolic and mean arterial pressure compared to nonruptured cohort (P = .0008). Additionally, the pulse pressures within the dome of ruptured aneurysms were significantly more narrow than that of unruptured aneurysms (P = .0001). These findings suggest that there may be an inherent difference between ruptured and nonruptured aneurysms and such recordings obtained during routine digital subtraction angiography could potentially become a widely applied technique to augment risk stratification of aneurysms. CONCLUSION Our preliminary data present new evidence distinguishing ruptured from unruptured aneurysms that may have a critical role as a predictive parameter to stratify the natural history of nonruptured intracranial aneurysms and as a new avenue for future investigation. Cerebral aneurysm, Stump pressure, Hemodynamics, Computational fluid dynamics, Pressure, Rupture ABBREVIATIONS ABBREVIATIONS CH cerebral hemodynamics DBP diastolic blood pressure EVDs external ventricular drain IA intracranial aneurysm ICP intracranial pressure ISP intrasaccular pressure MAP mean arterial blood pressure NRIA nonruptured intracranial aneurysms RIA ruptured intracranial aneurysms SAH subarachnoid haemorrhage WSS wall shear stress Each year in the United States approximately 27 000 patients suffer from subarachnoid hemorrhage (SAH) secondary to rupture of an intracranial aneurysm (IA).1 The prevalence of IAs in the general population may be as high as 5% with a small minority suffering from rupture.2 Ruptured intracranial aneurysms (RIAs) are devastating with an estimated 1-yr mortality rate of almost 50%. Of those patients who survive, only 10% return to their neurological and cognitive baseline.3–5 Given the high morbidity and mortality, nonruptured intracranial aneurysms (NRIAs) are treated preventatively in high-risk patients. The risk of treating NRIA has to be carefully balanced with the natural history of each individual patient and aneurysm. At present, our risk assessments are based on crude factors such as age, smoking, hypertension, size, location, personal and family history, and genetic predispositions. Although these factors provide general predictive values, they are limited in individualized care.6,7 For example, ruptured aneurysms are frequently smaller than the recommended size for treatment suggested by data from the International Study of Unruptured Intracranial Aneurysms.8–10 In attempts to further individualize risk stratification, various authors have found associations between cerebral hemodynamics (CH) and rupture risk. Hemodynamics plays a critical role in the development, growth, and rupture of IAs.11,12 These data could be vital in determining individual aneurysm rupture risk and thereby facilitating our understanding and discrimination of high- versus low-risk aneurysms. Up to this point, our knowledge of CH has been based largely on animal or computational aneurysm models. Recordings of hemodynamic parameters within human aneurysm sacs have been limited to ex vivo magnetic resonance imaging and to date this technique has had little application and is of unknown significance in clinical practice.13 Very few studies have direct recordings of human aneurysm hemodynamic parameters in vivo, and to our knowledge no such studies have been performed in ruptured aneurysms. We hypothesized that hemodynamic differences exist between RIA and NRIA, which may facilitate risk stratification and further our understanding of cerebral aneurysms and present the largest prospective cross-sectional cohort of intrasaccular pressure (ISP) recordings of RIA and NRIAs. METHODS All patients at our institution who underwent endovascular coiling (with or without stent or balloon assistance) of both RIA and NRIA from July 2016 to 2017 were eligible and included in the study. Patient data were retrospectively evaluated in this cross-sectional cohort study. This study was approved by our Institutional Review Board . Informed consent for endovascular treatment and examinations was obtained from each patient. A total of 71 patients’ data were collected for review. All procedures were performed under general anesthesia with arterial pressure monitoring and systemic heparinization on a bi-plane angiographic unit. Oral endotracheal intubation was facilitated with standard muscle relaxation and mechanical ventilation was adjusted to maintain end-tidal PCO2 at 32 to 35 mm Hg. Systemic blood pressure was maintained at clinically desired levels (systolic pressure of between 90 and 140 mm Hg) in all cases. A 6-Fr shuttle (Cook Group, Bloomington, Indiana), 5 or 6-Fr guide catheter, and standard coiling microcatheter were used for aneurysm coil embolization and pressure monitoring. Once the standard 1.8-Fr 200 m length microcatheter (Headway 17 [Microvention, INC Aliso Viejo, California] in most cases, one with Echelon 10 [Medtronic, Dublin Ireland]), was navigated into the dome of the aneurysm prior to coil embolization, an arterial pressure transducer was attached to the proximal-end of the microcatheter to measure ISP. Pressure transducers are zeroed at the level of the right atrium. The microcatheter was carefully positioned under continuous fluoroscopic guidance to avoid interference from and damage to the vessel wall. To avoid potential added risk of adverse events, we excluded patients in whom the primary intervention did not include catheterization of the aneurysm dome. Pressure measurements were performed for an estimated 60 s and only considered valid when a clear systole and diastole profile was observed. Transducer rezeroing and line reprepping were performed in the absence of systole and diastole profiles prior to data exclusion. A total of 4 patients were initially eligible but ultimately excluded in the study due to invalid transducer recordings for a total of 67 patients’ data that were analyzed. We simultaneously recorded blood pressure, heart rate, intracranial pressure (ICP; when applicable), and oxygen saturations. Any external ventricular drain (EVDs) were clamped and intravascular balloons were deflated during pressure monitoring to prevent external changes in blood flow and vessel compliance. Statistical Analysis Descriptive statistical analyses, including systolic, diastolic, pulse pressure (PP), mean arterial, and ISPs with standard deviations are presented. Continuous variables were also matched to systemic values as a ratio to account for potential variations in systemic parameters that may affect intrasaccular recordings. Independent sample 2-tailed t-tests were used to compare differences in continuous variables between ruptured and nonruptured groups. P-values <.05 were considered significant. JASP statistical analysis for Windows-version 8.2 was used for all analyses (Affero General Public License, University of Amsterdam, Amsterdam, The Netherlands). RESULTS Patient and Aneurysm Demographics A total of 67 patients (53 female, 79.1%; 14 male, 20.9%) were treated during the analyzed period for 68 aneurysms. There is a predominance of the female gender. The average age at treatment was 58.4 yr. Out of 68 aneurysms, 28 (41.1%) were ruptured and 40 (58.9%) nonruptured. All patients presenting with SAH were treated within 24 hr of presentation. Most aneurysms were located in the anterior circulation (78%) with anterior communicating artery complex accounting for the most-common aneurysm location (29.4%). In terms of aneurysm morphology, the majority were saccular (98.5%) while 1 was fusiform (1.5%). The mean aneurysm size was 6.51 ± 4.05 mm with a 3.34 ± 1.62 mm neck. The mean aneurysm diameter in NRIAs was 7.0 mm compared to 5.6 mm in ruptured cases. Smaller diameter NRIAs were treated in patients with high-risk clinical or radiographic features. There was no difference in aneurysm characteristics between ruptured and nonruptured cohorts except a higher American Society of Anesthesiology physical status classification of severity of illness seen in RIA patients (Table 1). TABLE 1. Patient Demographics and Aneurysm Characteristics Age  58.4 ± 12.3    Sex  14 male, 53 female    Aneurysm Location  29.4% ACOM, 22.0% posterior circulation    Diameter  6.5 ± 4.1 mm    Neck  3.3 ± 1.6 mm  Systemic vs Intra Saccular  Systemic SBP  113.8 ± 15.0 mm Hg  P < .001  Systemic DBP  57.3 ± 10.4 mm Hg  P < .001  Systemic PP  56.6 ± 13.7 mm Hg  P < .001  Systemic MAP  76.0 ± 10.1 mm Hg  P = .02  Heart rate  63.6 ± 14.8    Aneurysm SBP  95.1 ± 18.1 mm Hg    Aneurysm DBP  79.9 ± 16.3 mm Hg    Aneurysm PP  15.2 ± 13.8 mm Hg    Aneurysm MAP  82.5 ± 21.2 mm Hg    Rupture status  28 ruptured, 40 unruptured  Ruptured vs Non-ruptured  Diameter (ruptured)  6.1 ± 3.3 mm  P = .90  Neck (ruptured)  2.9 ± 0.9 mm  P = .77  Systolic BP (ruptured)  110.8 ± 16.1 mm Hg  P = .82  Diastolic BP (ruptured)  58.8 ± 12.6 mm Hg  P = .87  Heart rate (ruptured)  73.3 ± 15.8  P = .33  Systemic PP (ruptured)  52.0 ± 11.9 mm Hg  P = .69  MAP (ruptured)  76.1 ± 12.7 mm Hg  P = .87  Diameter (unruptured)  6.8 ± 4.5 mm    Neck (unruptured)  3.6 ± 1.9 mm    Systolic BP (unruptured)  115.8 ± 14.0 mm Hg    Diastolic BP (unruptured)  56.3 ± 8.6 mm Hg    Heart rate (unruptured)  56.6 ± 9.1    Systemic PP (unruptured)  59.8 ± 14.2 mm Hg    MAP (unruptured)  76.5 ± 8.1 mm Hg    Saturation (%)  99.1 ± 1.8    ICP (from external ventricular drain)  17.1 ± 11.9 mm Hg      Unruptured (n = 40)  Ruptured (n = 28)  P value  Age  59 ± 13 yr  58 ± 11 yr  .74  Sex  85% female  71% female    Race  80% Caucasian  86% Caucasian    Location  68% anterior circulation  82% anterior circulation    Aneurysm size (mm)  7.0 ± 4.8 mm  5.6 ± 3.3 mm  .19  Family History  15%  3.6%    Diabetes  15%  3.6%    Hypertension  62.5%  60.7%    EGFR  95.3 ± 24.1  109.8 ± 43.4  .08  Smoking  32.5%  71%    BMI  30 ± 5.7  28 ± 4.9  .14  ASA class  2.6 ± 0.5  3.5 ± 0.8  .0001  Phenylephrine  5.5 ± 5.7 mcg/kg/min  5.0 ± 4.5 mcg/kg/min  .70  Ephedrine  7.0 ± 11.8 mg  4.8 ± 10.4 mg  .43  Ventriculostomy  0  22    Age  58.4 ± 12.3    Sex  14 male, 53 female    Aneurysm Location  29.4% ACOM, 22.0% posterior circulation    Diameter  6.5 ± 4.1 mm    Neck  3.3 ± 1.6 mm  Systemic vs Intra Saccular  Systemic SBP  113.8 ± 15.0 mm Hg  P < .001  Systemic DBP  57.3 ± 10.4 mm Hg  P < .001  Systemic PP  56.6 ± 13.7 mm Hg  P < .001  Systemic MAP  76.0 ± 10.1 mm Hg  P = .02  Heart rate  63.6 ± 14.8    Aneurysm SBP  95.1 ± 18.1 mm Hg    Aneurysm DBP  79.9 ± 16.3 mm Hg    Aneurysm PP  15.2 ± 13.8 mm Hg    Aneurysm MAP  82.5 ± 21.2 mm Hg    Rupture status  28 ruptured, 40 unruptured  Ruptured vs Non-ruptured  Diameter (ruptured)  6.1 ± 3.3 mm  P = .90  Neck (ruptured)  2.9 ± 0.9 mm  P = .77  Systolic BP (ruptured)  110.8 ± 16.1 mm Hg  P = .82  Diastolic BP (ruptured)  58.8 ± 12.6 mm Hg  P = .87  Heart rate (ruptured)  73.3 ± 15.8  P = .33  Systemic PP (ruptured)  52.0 ± 11.9 mm Hg  P = .69  MAP (ruptured)  76.1 ± 12.7 mm Hg  P = .87  Diameter (unruptured)  6.8 ± 4.5 mm    Neck (unruptured)  3.6 ± 1.9 mm    Systolic BP (unruptured)  115.8 ± 14.0 mm Hg    Diastolic BP (unruptured)  56.3 ± 8.6 mm Hg    Heart rate (unruptured)  56.6 ± 9.1    Systemic PP (unruptured)  59.8 ± 14.2 mm Hg    MAP (unruptured)  76.5 ± 8.1 mm Hg    Saturation (%)  99.1 ± 1.8    ICP (from external ventricular drain)  17.1 ± 11.9 mm Hg      Unruptured (n = 40)  Ruptured (n = 28)  P value  Age  59 ± 13 yr  58 ± 11 yr  .74  Sex  85% female  71% female    Race  80% Caucasian  86% Caucasian    Location  68% anterior circulation  82% anterior circulation    Aneurysm size (mm)  7.0 ± 4.8 mm  5.6 ± 3.3 mm  .19  Family History  15%  3.6%    Diabetes  15%  3.6%    Hypertension  62.5%  60.7%    EGFR  95.3 ± 24.1  109.8 ± 43.4  .08  Smoking  32.5%  71%    BMI  30 ± 5.7  28 ± 4.9  .14  ASA class  2.6 ± 0.5  3.5 ± 0.8  .0001  Phenylephrine  5.5 ± 5.7 mcg/kg/min  5.0 ± 4.5 mcg/kg/min  .70  Ephedrine  7.0 ± 11.8 mg  4.8 ± 10.4 mg  .43  Ventriculostomy  0  22    SBP—Systolic blood pressure, DBP—Diastolic blood pressure, PP—Pulse pressure, MAP—Mean arterial pressure, ICP—Intracranial pressure, EGFR—Estimated glomerular filtration rate, BMI—Body mass index, ASA—American Society of Anesthesiology severity scale. The middle column indicates average values with associated standard deviation (Avg ± SD). P values given on the right, a P value of <.05 was considered significant. View Large TABLE 1. Patient Demographics and Aneurysm Characteristics Age  58.4 ± 12.3    Sex  14 male, 53 female    Aneurysm Location  29.4% ACOM, 22.0% posterior circulation    Diameter  6.5 ± 4.1 mm    Neck  3.3 ± 1.6 mm  Systemic vs Intra Saccular  Systemic SBP  113.8 ± 15.0 mm Hg  P < .001  Systemic DBP  57.3 ± 10.4 mm Hg  P < .001  Systemic PP  56.6 ± 13.7 mm Hg  P < .001  Systemic MAP  76.0 ± 10.1 mm Hg  P = .02  Heart rate  63.6 ± 14.8    Aneurysm SBP  95.1 ± 18.1 mm Hg    Aneurysm DBP  79.9 ± 16.3 mm Hg    Aneurysm PP  15.2 ± 13.8 mm Hg    Aneurysm MAP  82.5 ± 21.2 mm Hg    Rupture status  28 ruptured, 40 unruptured  Ruptured vs Non-ruptured  Diameter (ruptured)  6.1 ± 3.3 mm  P = .90  Neck (ruptured)  2.9 ± 0.9 mm  P = .77  Systolic BP (ruptured)  110.8 ± 16.1 mm Hg  P = .82  Diastolic BP (ruptured)  58.8 ± 12.6 mm Hg  P = .87  Heart rate (ruptured)  73.3 ± 15.8  P = .33  Systemic PP (ruptured)  52.0 ± 11.9 mm Hg  P = .69  MAP (ruptured)  76.1 ± 12.7 mm Hg  P = .87  Diameter (unruptured)  6.8 ± 4.5 mm    Neck (unruptured)  3.6 ± 1.9 mm    Systolic BP (unruptured)  115.8 ± 14.0 mm Hg    Diastolic BP (unruptured)  56.3 ± 8.6 mm Hg    Heart rate (unruptured)  56.6 ± 9.1    Systemic PP (unruptured)  59.8 ± 14.2 mm Hg    MAP (unruptured)  76.5 ± 8.1 mm Hg    Saturation (%)  99.1 ± 1.8    ICP (from external ventricular drain)  17.1 ± 11.9 mm Hg      Unruptured (n = 40)  Ruptured (n = 28)  P value  Age  59 ± 13 yr  58 ± 11 yr  .74  Sex  85% female  71% female    Race  80% Caucasian  86% Caucasian    Location  68% anterior circulation  82% anterior circulation    Aneurysm size (mm)  7.0 ± 4.8 mm  5.6 ± 3.3 mm  .19  Family History  15%  3.6%    Diabetes  15%  3.6%    Hypertension  62.5%  60.7%    EGFR  95.3 ± 24.1  109.8 ± 43.4  .08  Smoking  32.5%  71%    BMI  30 ± 5.7  28 ± 4.9  .14  ASA class  2.6 ± 0.5  3.5 ± 0.8  .0001  Phenylephrine  5.5 ± 5.7 mcg/kg/min  5.0 ± 4.5 mcg/kg/min  .70  Ephedrine  7.0 ± 11.8 mg  4.8 ± 10.4 mg  .43  Ventriculostomy  0  22    Age  58.4 ± 12.3    Sex  14 male, 53 female    Aneurysm Location  29.4% ACOM, 22.0% posterior circulation    Diameter  6.5 ± 4.1 mm    Neck  3.3 ± 1.6 mm  Systemic vs Intra Saccular  Systemic SBP  113.8 ± 15.0 mm Hg  P < .001  Systemic DBP  57.3 ± 10.4 mm Hg  P < .001  Systemic PP  56.6 ± 13.7 mm Hg  P < .001  Systemic MAP  76.0 ± 10.1 mm Hg  P = .02  Heart rate  63.6 ± 14.8    Aneurysm SBP  95.1 ± 18.1 mm Hg    Aneurysm DBP  79.9 ± 16.3 mm Hg    Aneurysm PP  15.2 ± 13.8 mm Hg    Aneurysm MAP  82.5 ± 21.2 mm Hg    Rupture status  28 ruptured, 40 unruptured  Ruptured vs Non-ruptured  Diameter (ruptured)  6.1 ± 3.3 mm  P = .90  Neck (ruptured)  2.9 ± 0.9 mm  P = .77  Systolic BP (ruptured)  110.8 ± 16.1 mm Hg  P = .82  Diastolic BP (ruptured)  58.8 ± 12.6 mm Hg  P = .87  Heart rate (ruptured)  73.3 ± 15.8  P = .33  Systemic PP (ruptured)  52.0 ± 11.9 mm Hg  P = .69  MAP (ruptured)  76.1 ± 12.7 mm Hg  P = .87  Diameter (unruptured)  6.8 ± 4.5 mm    Neck (unruptured)  3.6 ± 1.9 mm    Systolic BP (unruptured)  115.8 ± 14.0 mm Hg    Diastolic BP (unruptured)  56.3 ± 8.6 mm Hg    Heart rate (unruptured)  56.6 ± 9.1    Systemic PP (unruptured)  59.8 ± 14.2 mm Hg    MAP (unruptured)  76.5 ± 8.1 mm Hg    Saturation (%)  99.1 ± 1.8    ICP (from external ventricular drain)  17.1 ± 11.9 mm Hg      Unruptured (n = 40)  Ruptured (n = 28)  P value  Age  59 ± 13 yr  58 ± 11 yr  .74  Sex  85% female  71% female    Race  80% Caucasian  86% Caucasian    Location  68% anterior circulation  82% anterior circulation    Aneurysm size (mm)  7.0 ± 4.8 mm  5.6 ± 3.3 mm  .19  Family History  15%  3.6%    Diabetes  15%  3.6%    Hypertension  62.5%  60.7%    EGFR  95.3 ± 24.1  109.8 ± 43.4  .08  Smoking  32.5%  71%    BMI  30 ± 5.7  28 ± 4.9  .14  ASA class  2.6 ± 0.5  3.5 ± 0.8  .0001  Phenylephrine  5.5 ± 5.7 mcg/kg/min  5.0 ± 4.5 mcg/kg/min  .70  Ephedrine  7.0 ± 11.8 mg  4.8 ± 10.4 mg  .43  Ventriculostomy  0  22    SBP—Systolic blood pressure, DBP—Diastolic blood pressure, PP—Pulse pressure, MAP—Mean arterial pressure, ICP—Intracranial pressure, EGFR—Estimated glomerular filtration rate, BMI—Body mass index, ASA—American Society of Anesthesiology severity scale. The middle column indicates average values with associated standard deviation (Avg ± SD). P values given on the right, a P value of <.05 was considered significant. View Large Patient and Aneurysm Hemodynamics A mean SBP of 113.7 mm Hg over a diastolic blood pressure (DBP) of 57.3 mm Hg with a PP of 56.6 mm Hg and an mean arterial blood pressure (MAP) of 76 mm Hg was obtained. The average heart rate was 63.5 beats per minute with a saturation of 99.1%. In patients presenting with a ventriculostomy, the average ICP during treatment was 17.1 mm Hg. In all cases, ISP was recorded using a standard 1.8-Fr 200 m length microcatheter attached to a transducer. A mean SBP of 95.1 mm Hg over a DBP of 79.9 mm Hg with a PP of 15.2 mm Hg and an MAP of 82.5 mm Hg was obtained. Intrasaccular systolic and PP were consistently lower than systemic recordings and higher diastolic and MAPs were observed compared to systemic recordings. This is a characteristic finding with measurements obtained from a long microcatheter due to increased impedance and destructive interference along the catheter length. There was no significant difference in baseline systemic or aneurysm hemodynamic parameters between ruptured and nonruptured groups (Table 1). Intrasaccular hemodynamic parameters are outlined in Table 2 comparing ruptured with nonruptured aneurysms. Hemodynamic variables were also matched to systemic values in order to account for potential variations in systemic parameters that may affect intrasaccular recordings. This ratio accounts for absolute as well as relative differences between groups and has been independently validated.14 Independent sample 2 tailed t-tests were used to compare differences in continuous variables between ruptured and nonruptured groups. TABLE 2. Aneurysm Intrasaccular Hemodynamics Parameter  Unruptured  Ruptured  P value  SBP    102 ± 16.4  84.8 ± 15.6  P < .001    % Sys  88 ± 13  76 ± 11  P < .001  DBP    81 ± 16  78.3 ± 16.9  P = .25    % Sys  145 ± 31  132 ± 23  P = .06  Pulse pressure    21 ± 15  6.58 ± 3.92  P < .001    % Sys  36 ± 24  13 ± 7  P < .001  MAP    88 ± 14  80.5 ± 16.4  P = .05    % Sys  115 ± 18  104 ± 16  P = .01  Parameter  Unruptured  Ruptured  P value  SBP    102 ± 16.4  84.8 ± 15.6  P < .001    % Sys  88 ± 13  76 ± 11  P < .001  DBP    81 ± 16  78.3 ± 16.9  P = .25    % Sys  145 ± 31  132 ± 23  P = .06  Pulse pressure    21 ± 15  6.58 ± 3.92  P < .001    % Sys  36 ± 24  13 ± 7  P < .001  MAP    88 ± 14  80.5 ± 16.4  P = .05    % Sys  115 ± 18  104 ± 16  P = .01  Average hemodynamic parameters between ruptured and unruptured aneurysm were analyzed using two-tailed T-test. P value of <.05 was considered significant. (% Sys—Percent of systemic values). View Large TABLE 2. Aneurysm Intrasaccular Hemodynamics Parameter  Unruptured  Ruptured  P value  SBP    102 ± 16.4  84.8 ± 15.6  P < .001    % Sys  88 ± 13  76 ± 11  P < .001  DBP    81 ± 16  78.3 ± 16.9  P = .25    % Sys  145 ± 31  132 ± 23  P = .06  Pulse pressure    21 ± 15  6.58 ± 3.92  P < .001    % Sys  36 ± 24  13 ± 7  P < .001  MAP    88 ± 14  80.5 ± 16.4  P = .05    % Sys  115 ± 18  104 ± 16  P = .01  Parameter  Unruptured  Ruptured  P value  SBP    102 ± 16.4  84.8 ± 15.6  P < .001    % Sys  88 ± 13  76 ± 11  P < .001  DBP    81 ± 16  78.3 ± 16.9  P = .25    % Sys  145 ± 31  132 ± 23  P = .06  Pulse pressure    21 ± 15  6.58 ± 3.92  P < .001    % Sys  36 ± 24  13 ± 7  P < .001  MAP    88 ± 14  80.5 ± 16.4  P = .05    % Sys  115 ± 18  104 ± 16  P = .01  Average hemodynamic parameters between ruptured and unruptured aneurysm were analyzed using two-tailed T-test. P value of <.05 was considered significant. (% Sys—Percent of systemic values). View Large We observed that RIAs have a lower SBP and MAP within the dome compared to NRIAs (P < .001 and P = .05, respectively). Additionally, the PP within the dome of RIAs were significantly narrower than that of NRIAs (P < .001). These findings suggest that there may be an inherent difference in hemodynamics between RIA and NRIAs. DISCUSSION NRIA have an estimated prevalence of 3% to 5% in the general population with up to 30% of these patients harboring multiple aneurysms.2,15 Current treatment paradigms are guided by estimated rupture risk, patient age, and associated comorbidity. Patients with larger aneurysms, family history, or personal history of ruptured IAs are felt to be at higher risk, while patients with smaller (less than 10 mm) aneurysms without significant associated risk factors have low risk of rupture and can be followed conservatively.9,10 Conflicting data exist however, as the majority of RIAs are small with a median size of 7 mm. Therefore, the optimal management strategy of small NRIAs is controversial.16 As NRIAs are being increasingly detected due to the improvement and increased utilization of cerebrovascular imaging, there is increased “pressure” to explore new methods of improving risk stratification of NRIAs. In attempts to further individualize rupture risk, CH has been extensively evaluated using a combination of invasive and noninvasive modalities both in vivo and ex vivo. Various authors have found significant associations between CH and aneurysm rupture risk that may prove vital in clinical decision making and facilitate our understanding and discrimination between RIAs and NRIAs.11,12 CH studies suggest that aneurysms form as a result of chronic exposure to high wall shear stress (WSS) that is often seen at the branch-point of vessels or along a lateral outward curve. This theory explains why aneurysms are commonly found at their bifurcations or branching points. Chronically high WSS results in elastin degradation, disruption of the internal elastic lamina, and apoptosis of the vascular smooth muscle.17,18 Compensatory responses to repeated microtrauma from high WSS result in vessel wall outpouching, remodeling, and ultimately dilation and aneurysm formation. Enlargement and rupture appears to incorporate the same physics combined with inflammation of the vessel wall. Aneurysm rupture occurs at areas of focal endothelial weakening in the dome that develops secondary to chronic exposure to low WSS; however, this has been an area of controversy.17,19–21 WSS is a vector whose scale and direction are driven by the pulsatility and flow of blood while the circumferential stress on blood vessels is determined by the variations of blood pressure and blood flow during the cardiac cycle. Therefore, the parameters affecting local WSS include SBP, DBP, and the velocity and angle of the blood flow vector.22,23 Recently, bifurcation/inflow angle, bottle-neck-ratio, neck-deviation, and other morphometric parameters have been studied to help distinguish between RIA and NRIAs.24-27 These studies highlight the need for improved patient-specific parameters to differentiate between high- and low-risk aneurysms but also further emphasize WSS and CH as an important influencer of aneurysm growth and rupture. Much of our understanding of WSS and CH has been based largely on animal or computational aneurysm models. Recordings of hemodynamic parameters within human aneurysm sacs have been predominantly limited to ex vivo imaging with very few studies citing human invasive in vivo measurements. To the best of our knowledge no such invasive investigation has been performed on RIAs. We prospectively evaluated the ISPs within RIA and NRIAs in a cross-sectional cohort of patients undergoing endovascular surgery. We observed a significant decrease in SBP, MAP, and PP within the domes of RIAs compared to their nonruptured cohorts. When hemodynamic variables were matched to systemic values to account for absolute as well as relative differences between groups and to account for potential variations in systemic parameters that may affect intrasaccular recordings, statistical significance was maintained. These data suggest that there may be an inherent difference in hemodynamics between ruptured and nonruptured aneurysms (Table 2). Our findings were initially counterintuitive, as one would predict a higher SBP and MAP within the dome of an aneurysm would increase the rate of rupture, just as a higher pressure would contribute to the expansion and ultimate rupture of a plastic balloon. On the contrary, our findings demonstrated a lower MAP and SBP within the domes of ruptured aneurysms. This apparent paradox could be explained by the consequence of vascular remodeling changing the composition of the vessel wall leading to enlargement of the aneurysm sac via secondary inflammation. As the radius of the aneurysmal sac increases, the overall pressure distributed against the wall of the aneurysm decreases as an offsetting mechanism to prevent further endothelial vessel wall injury also known as “stress-relaxation”.28 This mechanism may be akin to the process of developing poststenotic dilatations commonly seen within the aorta and proximal internal carotid artery secondary to flow disturbances and abnormal WSS produced by atherosclerosis and arteriosclerosis.29-31 “Stress-relaxation” is due to a decrease in the vessel wall thickness that results in increased compliance and loss of pressure variability seen as a narrow PP. As described by LaPlace's law, as a vessel wall thins out or diameter expands, there is an increase in wall tension needed to withstand a given internal pressure thereby elucidating the mechanism of increased risk of subsequent aneurysm rupture. As a vessel wall remodels secondary to turbulent flow, changes in regional hemodynamics ensue with the development of local stasis within the aneurysm dome that increases local inflammation and subsequent rupture. It may be a decrease in local ISP that corresponds to the stasis seen in remodeling and higher risk aneurysms. Intrasaccular WSS is a dynamic process supported by decreases seen in WSS at the site of secondary bleb formation along the aneurysm dome.32,33 Local WSS is typically lowest at the apex of an aneurysm dome compared to its neck.25,34,35 Low WSS induces stagnation of blood that precipitates thrombus formation and secondary inflammation via macrophage infiltration, degradation of elastin, and apoptosis of vascular smooth muscle.32,36–38 Low WSS has been associated with known points of rupture further confirmed by studies where hemodynamic parameters were obtained auspiciously just prior to the event of rupture.39–44 A narrow intrasaccular PP observed within the dome of ruptured aneurysms also corroborates LaPlace's law and the “stress-relaxation” theory of an enlarging or fragile aneurysm. Decreasing aneurysm wall thickness induces increased compliance and loss of pressure variability that is manifested as a narrow PP. Measuring intrasaccular PPs may therefore raise suspicion to growing or fragile aneurysms. A narrow PP seen in RIAs also supports the hypothesis that areas of low WSS and resultant stasis can precipitate inflammation and secondary aneurysm rupture. Decreased PP can facilitate decreased outflow and local pooling of blood that may be observed on diagnostic angiography as contrast stasis within a secondary bleb. Low ISPs and narrow PPs may therefore serve as a potential surrogate marker for low WSS and assist in predicting aneurysm risk. Morphological parameters associated with RIA have been investigated. Meaningful parameters associated with higher risk of SAH include higher size ratio, height-width ratio, undulation index, nonsphericity index, ellipticity index, aneurysm, and parent vessel angles.45,46 Unfortunately, CH studies are not widely available and to date this technique and the use of morphological parameters have had little application in clinical practice.13 In contrast, measurement of ISP is extremely commonplace within neuroendovascular surgery and has been used as an adjunct during venography for diagnosing pseudotumor cerebri and balloon test occlusion. Measuring ISPs may have diagnostic utility and may serve as a surrogate for detecting low WSS. As previously discussed, parameters that affect local WSS include blood pressure and velocity, which are directly influenced by the SBP and DBP locally within the aneurysm dome. Such recordings obtained during angiography could potentially become a widely applied technique to augment risk stratification of NRIAs. In our cohort of RIA, only 3 of 28 cases were found to have a PP of greater than 10 mm Hg, whereas in the NRIA cohort 9 of 40 aneurysms had a PP below 10 mm Hg. In Table 3, we present the patient characteristics of those NRIA with narrow PP. In this group, 7 of 8 patients had strong family history, history of previous aneurysm rupture, multiple IAs, or developed a new cranial neuropathy likely from enlargement of the aneurysm. Only one patient did not have a high-risk factor for rupture. This is in contrast to the remaining NRIA cohort with high PPs, where 17 of 32 patients did not have high-risk factors. TABLE 3. Demographic and Angiographic Characteristics of Patients With NRIAs With Low Pulse Pressure Age  Sex  Location  Morphology  Neck  Size  A-SBP  A-DBP  PP  High-risk features  79  F  MCA  Saccular  2 mm  2.5 × 2.5 × 3 mm  106  100  6  Has 6 aneurysms and strong family history of rupture  57  F  P2  Saccular  2 mm  2 × 2 × 2.5 mm  105  101  4  Previous ruptured MCA  44  F  Paraclinoid  Multilobulated  3 mm  9 × 6 × 6 mm  91  84  7  Developed new cranial neuropathy, suspect enlarging aneurysm  51  F  Paraclinoid  Saccular  2.5 mm  3.5 × 3 × 2.5 mm  90  82  8  None  35  F  ACOM  Dysplastic with recurrent bleb  2 mm  2 × 2.5 × 2 mm  84  81  3  Previous rupture s/p coiling and new recurrence adjacent to previous neck  46  F  Paraclinoid  Multilobulated  3 mm  8 × 6 × 6 mm  90  84  6  Has multiple intracranial aneurysms  58  F  ACOM  Multilobulated  5 mm  8 × 12 × 6 mm  98  94  4  Strong family history of rupture  63  F  PCOM  Multilobulated  3 mm  3 × 2 × 6 mm  87  78  9  Has multiple intracranial aneurysms and strong family history of aneurysm rupture  Age  Sex  Location  Morphology  Neck  Size  A-SBP  A-DBP  PP  High-risk features  79  F  MCA  Saccular  2 mm  2.5 × 2.5 × 3 mm  106  100  6  Has 6 aneurysms and strong family history of rupture  57  F  P2  Saccular  2 mm  2 × 2 × 2.5 mm  105  101  4  Previous ruptured MCA  44  F  Paraclinoid  Multilobulated  3 mm  9 × 6 × 6 mm  91  84  7  Developed new cranial neuropathy, suspect enlarging aneurysm  51  F  Paraclinoid  Saccular  2.5 mm  3.5 × 3 × 2.5 mm  90  82  8  None  35  F  ACOM  Dysplastic with recurrent bleb  2 mm  2 × 2.5 × 2 mm  84  81  3  Previous rupture s/p coiling and new recurrence adjacent to previous neck  46  F  Paraclinoid  Multilobulated  3 mm  8 × 6 × 6 mm  90  84  6  Has multiple intracranial aneurysms  58  F  ACOM  Multilobulated  5 mm  8 × 12 × 6 mm  98  94  4  Strong family history of rupture  63  F  PCOM  Multilobulated  3 mm  3 × 2 × 6 mm  87  78  9  Has multiple intracranial aneurysms and strong family history of aneurysm rupture  MCA—Middle cerebral artery, P2—Segment 2 of posterior cerebral artery, ACOM—Anterior communicating artery, PCOM—Posterior communicating artery. View Large TABLE 3. Demographic and Angiographic Characteristics of Patients With NRIAs With Low Pulse Pressure Age  Sex  Location  Morphology  Neck  Size  A-SBP  A-DBP  PP  High-risk features  79  F  MCA  Saccular  2 mm  2.5 × 2.5 × 3 mm  106  100  6  Has 6 aneurysms and strong family history of rupture  57  F  P2  Saccular  2 mm  2 × 2 × 2.5 mm  105  101  4  Previous ruptured MCA  44  F  Paraclinoid  Multilobulated  3 mm  9 × 6 × 6 mm  91  84  7  Developed new cranial neuropathy, suspect enlarging aneurysm  51  F  Paraclinoid  Saccular  2.5 mm  3.5 × 3 × 2.5 mm  90  82  8  None  35  F  ACOM  Dysplastic with recurrent bleb  2 mm  2 × 2.5 × 2 mm  84  81  3  Previous rupture s/p coiling and new recurrence adjacent to previous neck  46  F  Paraclinoid  Multilobulated  3 mm  8 × 6 × 6 mm  90  84  6  Has multiple intracranial aneurysms  58  F  ACOM  Multilobulated  5 mm  8 × 12 × 6 mm  98  94  4  Strong family history of rupture  63  F  PCOM  Multilobulated  3 mm  3 × 2 × 6 mm  87  78  9  Has multiple intracranial aneurysms and strong family history of aneurysm rupture  Age  Sex  Location  Morphology  Neck  Size  A-SBP  A-DBP  PP  High-risk features  79  F  MCA  Saccular  2 mm  2.5 × 2.5 × 3 mm  106  100  6  Has 6 aneurysms and strong family history of rupture  57  F  P2  Saccular  2 mm  2 × 2 × 2.5 mm  105  101  4  Previous ruptured MCA  44  F  Paraclinoid  Multilobulated  3 mm  9 × 6 × 6 mm  91  84  7  Developed new cranial neuropathy, suspect enlarging aneurysm  51  F  Paraclinoid  Saccular  2.5 mm  3.5 × 3 × 2.5 mm  90  82  8  None  35  F  ACOM  Dysplastic with recurrent bleb  2 mm  2 × 2.5 × 2 mm  84  81  3  Previous rupture s/p coiling and new recurrence adjacent to previous neck  46  F  Paraclinoid  Multilobulated  3 mm  8 × 6 × 6 mm  90  84  6  Has multiple intracranial aneurysms  58  F  ACOM  Multilobulated  5 mm  8 × 12 × 6 mm  98  94  4  Strong family history of rupture  63  F  PCOM  Multilobulated  3 mm  3 × 2 × 6 mm  87  78  9  Has multiple intracranial aneurysms and strong family history of aneurysm rupture  MCA—Middle cerebral artery, P2—Segment 2 of posterior cerebral artery, ACOM—Anterior communicating artery, PCOM—Posterior communicating artery. View Large Could NRIAs with narrow PP represent a subgroup of NRIA that are at higher risk of future rupture? Additionally, could this information be used to help intraoperatively predict the culprit aneurysm in a case of SAH in the setting of multiple IAs? Limitations The accuracy and precision of transducing microcatheter stump pressures have been independently validated in both animal and human studies but the largest limitation of this study remains the use of a long and narrow microcatheter for the measurement of ISPs.14,47-49 Although a relatively well-established technique in endovascular surgery, pressure recordings via a microcatheter have inherent biases. There is a substantial impedance and destructive interference effect on the accuracy of measurements—a theoretical dampening effect transmitted through length of the catheter to the pressure transducer attached to the hub. As previously mentioned, we consistently observed lower ISPs, narrow PPs, and higher DBP and MAPs compared to systemic radial artery recordings. This is a characteristic finding of increased impedance and destructive interference of measuring pressures across the length of a long and narrow tube. Despite these inherent biases, the precision of measurements comparing RIAs and NRIAs should be retained. All data were accumulated using a standard 1.8-French coiling microcatheter of the same brand, length, and make except 2 cases that were of the same length and diameter but of a different manufacturer. Partial occlusion of the aneurysm neck by the microcatheter during ISP recordings may also bias the results with larger aneurysm necks having reduced effects. There was no difference in aneurysm neck diameter between the RIA and NRIA cohorts. In the index case, the same microcatheter was used in both aneurysms and produced readings that were consistent with our overall findings. Other limitation of this study include a small sample size, the location of the microcatheter placement during data collection, as well as the presence of an EVD or intravascular balloon during measurements that could have a dampening effect on ISP recordings. To the best of our ability, we centralized the microcatheter within the dome of the aneurysm during data collection. The EVD was clamped and any intravascular balloon was deflated during recording to prevent any loss of resistance. Not all RIAs had an EVD placed during data collection although the majority did (6/28 patients did not). Only 3 out of 67 patients (all ruptured cases) were treated with the assistance of an intravascular balloon. Alternatively, our findings of lower ISPs could also be an effect of aneurysm rupture rather than a cause. In the acute setting after SAH, ICP rises rapidly to reduce transmural pressure and facilitate thrombus formation at the rupture site to achieve hemostasis.50 Local thrombosis and vasospasm within the aneurysm wall may confound ISPs by reducing the inflow and compliance of the local vessel wall. Increased ICP also results in autonomic dysregulation and global hypoperfusion that may manifest lower ISPs. Subsequent to the acute stage of SAH, which typically lasts only a few minutes, elevated ICP begins to resolve and secondary injury is induced.50,51 Secondary injury that develops within 4 h after SAH produces cerebral ischemia and secondary edema.51 Cerebral edema after SAH may reduce cerebral compliance reflected as a decrease in PP. Therefore, lower and narrower ISPs may simply be a result of recent SAH. In our cohort, increased ICP after aneurysm rupture was managed medically and with the use of an external ventricular drain. ICP was maintained below 25 mm Hg in all cases with a mean of 17 mm Hg. A good waveform was demonstrated on the ICP monitor in all cases that suggests adequate cerebral compliance. Although the intricate mechanisms after SAH may confound ISP recordings, ISPs could still prove to be a useful technique in helping distinguish between RIAs and NRIAs when multiple are present. The rupture effect as a cause of lower and narrower ISPs does not explain the observation of a small subset of morphologically and clinically high-risk appearing group of NRIAs with narrow PPs. The role of PP and WSS in aneurysm formation and rupture has not been conclusively elucidated. Future studies are needed to expound upon these preliminary findings. CONCLUSION Cerebral hemodynamics is critical to the understanding of cerebral aneurysm formation, progression, and rupture. Decreased WSS may be an important predictive parameter to augment risk stratification of NRIA; however, computational fluid dynamic studies are not widely available. We present the largest prospective cross-sectional cohort of ISP recordings of RIA and NRIAs and found lower overall stump pressures and narrow PPs observed within the domes of RIAs compared to NRIAs. Future studies are needed to validate these findings but our preliminary data present new evidence that may have a critical role as a predictive parameter to stratify the natural history of NRIA and is a new avenue for future investigation. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes Oral Abstract Presentation at the Annual Congress of Neurological Surgeons Society Meeting, Boston, Massachusetts, October 10th, 2017. REFERENCES 1. Schievink WI. Intracranial aneurysms. N Engl J Med . 1997; 336( 1): 28- 40. 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Neurol Res . 2006; 28( 4): 381- 398. Google Scholar CrossRef Search ADS PubMed  51. Trojanowski T. Blood-brain barrier changes after experimental subarachnoid haemorrhage. Acta neurochir . 1982; 60( 1–2): 45- 54. Google Scholar CrossRef Search ADS PubMed  COMMENTS Since ISUIA (the The International Study of Unruptured Intracranial Aneurysms), one major deciding factor for intervening on unruptured intracranial aneurysms is the size. As our diagnostic capabilities become more sophisticated, there is an increasing demand to more safely identify high-risk features in unruptured aneurysms. In this paper, the authors elegantly, albeit invasively, measure intrasaccular pressures of both ruptured and unruptured aneurysms. They note significantly lower intrasaccular pressures and narrow pulse pressures were found in the ruptured aneurysm cohort as compared to the unruptured aneurysm cohort. Although a noninvasive test would be ideal, measuring intrasaccular pressures in an unruptured aneurysm may add more prognostic information regarding the danger posed by the aneurysm. Moving forward, the authors should be commended on their work and further data should be compiled to determine the usefulness of intrasaccular measurements. Daniel Felbaum Erol Veznedaroglu Pennington, New Jersey The discovery of modern, reliable predictors for intracranial aneurysm rupture has captivated many academic cerebrovascular neurosurgeons and neurointerventionalists, acknowledging the fact that we continue to rely on traditional markers of high rupture risk (ie, size, irregular morphology) to determine the necessity of aneurysm treatment. Fortunately, as imaging techniques and computational analyses advance, many have isolated specific cerebrovascular hemodynamic parameters as potential biomarkers in identifying high-risk aneurysm. In the current manuscript, the authors assess the differences in arterial and aneurysmal blood pressures in patients with either ruptured or unruptured intracranial aneurysms. In their retrospective review of 67 patients, the authors observed a significantly decreased systolic, mean arterial, and pulse pressures in ruptured aneurysms, compared to unruptured aneurysms undergoing elective treatment. As discussed, the authors posit that this decrease in intrasaccular pressures may be associated with aneurysmal vascular remodeling, inflammation, and higher rupture risk. Extrapolated as a potential biomarker, the use of routine intrasaccular pressure (ISP) monitoring could serve a dual purpose. First, in determination of elective aneurysm treatment, aneurysms with low ISPs might be considered for treatment, even if other high-risk features are absent. Second, in patients with subarachnoid hemorrhage and multiple aneurysms present, the culprit ruptured aneurysm may have lower ISP than the others, and thus be isolated for immediate treatment. However, 2 considerations should be made prior to incorporating routine ISP monitoring for aneurysm risk stratification. First, we must consider the added procedural time and risk of aneurysmal pressure monitoring. While it may be exceedingly low, the risk would still be non-zero, and should be further discussed with patients undergoing angiography. Second, we must acknowledge that this procedure will be obviously self-selecting for patients who are already undergoing cerebral angiography, and thus representing a pool of patients at higher than average risk. Ideally, such a biomarker would be non-invasive, such as with MR vessel wall imaging or quantitative hemodynamic analysis, in order to totally preclude the inherent procedural risks of angiography. Kurt Yaeger J Mocco New York, New York Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Differences in Pressure Within the Sac of Human Ruptured and Nonruptured Cerebral Aneurysms

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Publisher
Congress of Neurological Surgeons
Copyright
Copyright © 2018 by the Congress of Neurological Surgeons
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1093/neuros/nyy182
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Abstract

Abstract BACKGROUND Hemodynamics plays a critical role in the development, growth, and rupture of intracranial aneurysms. This data could be vital in determining individual aneurysm rupture risk and could facilitate our understanding of aneurysms. OBJECTIVE To present the largest prospective cross-sectional cohort study of intrasaccular pressure recordings of ruptured and nonruptured intracranial aneurysms and describe the hemodynamic differences that exist between ruptured and nonruptured aneurysms. METHODS During endovascular treatment, a standard 1.8-Fr 200 m length microcatheter was navigated into the dome of the aneurysm prior to coil embolization. With the microcatheter centralized within the dome of the aneurysm, an arterial pressure transducer was attached to the proximal end of the microcatheter to measure the stump pressure inside the aneurysm dome. RESULTS In 68 aneurysms (28 ruptured, 40 nonruptured), we observed that ruptured cerebral aneurysms had a lower systolic and mean arterial pressure compared to nonruptured cohort (P = .0008). Additionally, the pulse pressures within the dome of ruptured aneurysms were significantly more narrow than that of unruptured aneurysms (P = .0001). These findings suggest that there may be an inherent difference between ruptured and nonruptured aneurysms and such recordings obtained during routine digital subtraction angiography could potentially become a widely applied technique to augment risk stratification of aneurysms. CONCLUSION Our preliminary data present new evidence distinguishing ruptured from unruptured aneurysms that may have a critical role as a predictive parameter to stratify the natural history of nonruptured intracranial aneurysms and as a new avenue for future investigation. Cerebral aneurysm, Stump pressure, Hemodynamics, Computational fluid dynamics, Pressure, Rupture ABBREVIATIONS ABBREVIATIONS CH cerebral hemodynamics DBP diastolic blood pressure EVDs external ventricular drain IA intracranial aneurysm ICP intracranial pressure ISP intrasaccular pressure MAP mean arterial blood pressure NRIA nonruptured intracranial aneurysms RIA ruptured intracranial aneurysms SAH subarachnoid haemorrhage WSS wall shear stress Each year in the United States approximately 27 000 patients suffer from subarachnoid hemorrhage (SAH) secondary to rupture of an intracranial aneurysm (IA).1 The prevalence of IAs in the general population may be as high as 5% with a small minority suffering from rupture.2 Ruptured intracranial aneurysms (RIAs) are devastating with an estimated 1-yr mortality rate of almost 50%. Of those patients who survive, only 10% return to their neurological and cognitive baseline.3–5 Given the high morbidity and mortality, nonruptured intracranial aneurysms (NRIAs) are treated preventatively in high-risk patients. The risk of treating NRIA has to be carefully balanced with the natural history of each individual patient and aneurysm. At present, our risk assessments are based on crude factors such as age, smoking, hypertension, size, location, personal and family history, and genetic predispositions. Although these factors provide general predictive values, they are limited in individualized care.6,7 For example, ruptured aneurysms are frequently smaller than the recommended size for treatment suggested by data from the International Study of Unruptured Intracranial Aneurysms.8–10 In attempts to further individualize risk stratification, various authors have found associations between cerebral hemodynamics (CH) and rupture risk. Hemodynamics plays a critical role in the development, growth, and rupture of IAs.11,12 These data could be vital in determining individual aneurysm rupture risk and thereby facilitating our understanding and discrimination of high- versus low-risk aneurysms. Up to this point, our knowledge of CH has been based largely on animal or computational aneurysm models. Recordings of hemodynamic parameters within human aneurysm sacs have been limited to ex vivo magnetic resonance imaging and to date this technique has had little application and is of unknown significance in clinical practice.13 Very few studies have direct recordings of human aneurysm hemodynamic parameters in vivo, and to our knowledge no such studies have been performed in ruptured aneurysms. We hypothesized that hemodynamic differences exist between RIA and NRIA, which may facilitate risk stratification and further our understanding of cerebral aneurysms and present the largest prospective cross-sectional cohort of intrasaccular pressure (ISP) recordings of RIA and NRIAs. METHODS All patients at our institution who underwent endovascular coiling (with or without stent or balloon assistance) of both RIA and NRIA from July 2016 to 2017 were eligible and included in the study. Patient data were retrospectively evaluated in this cross-sectional cohort study. This study was approved by our Institutional Review Board . Informed consent for endovascular treatment and examinations was obtained from each patient. A total of 71 patients’ data were collected for review. All procedures were performed under general anesthesia with arterial pressure monitoring and systemic heparinization on a bi-plane angiographic unit. Oral endotracheal intubation was facilitated with standard muscle relaxation and mechanical ventilation was adjusted to maintain end-tidal PCO2 at 32 to 35 mm Hg. Systemic blood pressure was maintained at clinically desired levels (systolic pressure of between 90 and 140 mm Hg) in all cases. A 6-Fr shuttle (Cook Group, Bloomington, Indiana), 5 or 6-Fr guide catheter, and standard coiling microcatheter were used for aneurysm coil embolization and pressure monitoring. Once the standard 1.8-Fr 200 m length microcatheter (Headway 17 [Microvention, INC Aliso Viejo, California] in most cases, one with Echelon 10 [Medtronic, Dublin Ireland]), was navigated into the dome of the aneurysm prior to coil embolization, an arterial pressure transducer was attached to the proximal-end of the microcatheter to measure ISP. Pressure transducers are zeroed at the level of the right atrium. The microcatheter was carefully positioned under continuous fluoroscopic guidance to avoid interference from and damage to the vessel wall. To avoid potential added risk of adverse events, we excluded patients in whom the primary intervention did not include catheterization of the aneurysm dome. Pressure measurements were performed for an estimated 60 s and only considered valid when a clear systole and diastole profile was observed. Transducer rezeroing and line reprepping were performed in the absence of systole and diastole profiles prior to data exclusion. A total of 4 patients were initially eligible but ultimately excluded in the study due to invalid transducer recordings for a total of 67 patients’ data that were analyzed. We simultaneously recorded blood pressure, heart rate, intracranial pressure (ICP; when applicable), and oxygen saturations. Any external ventricular drain (EVDs) were clamped and intravascular balloons were deflated during pressure monitoring to prevent external changes in blood flow and vessel compliance. Statistical Analysis Descriptive statistical analyses, including systolic, diastolic, pulse pressure (PP), mean arterial, and ISPs with standard deviations are presented. Continuous variables were also matched to systemic values as a ratio to account for potential variations in systemic parameters that may affect intrasaccular recordings. Independent sample 2-tailed t-tests were used to compare differences in continuous variables between ruptured and nonruptured groups. P-values <.05 were considered significant. JASP statistical analysis for Windows-version 8.2 was used for all analyses (Affero General Public License, University of Amsterdam, Amsterdam, The Netherlands). RESULTS Patient and Aneurysm Demographics A total of 67 patients (53 female, 79.1%; 14 male, 20.9%) were treated during the analyzed period for 68 aneurysms. There is a predominance of the female gender. The average age at treatment was 58.4 yr. Out of 68 aneurysms, 28 (41.1%) were ruptured and 40 (58.9%) nonruptured. All patients presenting with SAH were treated within 24 hr of presentation. Most aneurysms were located in the anterior circulation (78%) with anterior communicating artery complex accounting for the most-common aneurysm location (29.4%). In terms of aneurysm morphology, the majority were saccular (98.5%) while 1 was fusiform (1.5%). The mean aneurysm size was 6.51 ± 4.05 mm with a 3.34 ± 1.62 mm neck. The mean aneurysm diameter in NRIAs was 7.0 mm compared to 5.6 mm in ruptured cases. Smaller diameter NRIAs were treated in patients with high-risk clinical or radiographic features. There was no difference in aneurysm characteristics between ruptured and nonruptured cohorts except a higher American Society of Anesthesiology physical status classification of severity of illness seen in RIA patients (Table 1). TABLE 1. Patient Demographics and Aneurysm Characteristics Age  58.4 ± 12.3    Sex  14 male, 53 female    Aneurysm Location  29.4% ACOM, 22.0% posterior circulation    Diameter  6.5 ± 4.1 mm    Neck  3.3 ± 1.6 mm  Systemic vs Intra Saccular  Systemic SBP  113.8 ± 15.0 mm Hg  P < .001  Systemic DBP  57.3 ± 10.4 mm Hg  P < .001  Systemic PP  56.6 ± 13.7 mm Hg  P < .001  Systemic MAP  76.0 ± 10.1 mm Hg  P = .02  Heart rate  63.6 ± 14.8    Aneurysm SBP  95.1 ± 18.1 mm Hg    Aneurysm DBP  79.9 ± 16.3 mm Hg    Aneurysm PP  15.2 ± 13.8 mm Hg    Aneurysm MAP  82.5 ± 21.2 mm Hg    Rupture status  28 ruptured, 40 unruptured  Ruptured vs Non-ruptured  Diameter (ruptured)  6.1 ± 3.3 mm  P = .90  Neck (ruptured)  2.9 ± 0.9 mm  P = .77  Systolic BP (ruptured)  110.8 ± 16.1 mm Hg  P = .82  Diastolic BP (ruptured)  58.8 ± 12.6 mm Hg  P = .87  Heart rate (ruptured)  73.3 ± 15.8  P = .33  Systemic PP (ruptured)  52.0 ± 11.9 mm Hg  P = .69  MAP (ruptured)  76.1 ± 12.7 mm Hg  P = .87  Diameter (unruptured)  6.8 ± 4.5 mm    Neck (unruptured)  3.6 ± 1.9 mm    Systolic BP (unruptured)  115.8 ± 14.0 mm Hg    Diastolic BP (unruptured)  56.3 ± 8.6 mm Hg    Heart rate (unruptured)  56.6 ± 9.1    Systemic PP (unruptured)  59.8 ± 14.2 mm Hg    MAP (unruptured)  76.5 ± 8.1 mm Hg    Saturation (%)  99.1 ± 1.8    ICP (from external ventricular drain)  17.1 ± 11.9 mm Hg      Unruptured (n = 40)  Ruptured (n = 28)  P value  Age  59 ± 13 yr  58 ± 11 yr  .74  Sex  85% female  71% female    Race  80% Caucasian  86% Caucasian    Location  68% anterior circulation  82% anterior circulation    Aneurysm size (mm)  7.0 ± 4.8 mm  5.6 ± 3.3 mm  .19  Family History  15%  3.6%    Diabetes  15%  3.6%    Hypertension  62.5%  60.7%    EGFR  95.3 ± 24.1  109.8 ± 43.4  .08  Smoking  32.5%  71%    BMI  30 ± 5.7  28 ± 4.9  .14  ASA class  2.6 ± 0.5  3.5 ± 0.8  .0001  Phenylephrine  5.5 ± 5.7 mcg/kg/min  5.0 ± 4.5 mcg/kg/min  .70  Ephedrine  7.0 ± 11.8 mg  4.8 ± 10.4 mg  .43  Ventriculostomy  0  22    Age  58.4 ± 12.3    Sex  14 male, 53 female    Aneurysm Location  29.4% ACOM, 22.0% posterior circulation    Diameter  6.5 ± 4.1 mm    Neck  3.3 ± 1.6 mm  Systemic vs Intra Saccular  Systemic SBP  113.8 ± 15.0 mm Hg  P < .001  Systemic DBP  57.3 ± 10.4 mm Hg  P < .001  Systemic PP  56.6 ± 13.7 mm Hg  P < .001  Systemic MAP  76.0 ± 10.1 mm Hg  P = .02  Heart rate  63.6 ± 14.8    Aneurysm SBP  95.1 ± 18.1 mm Hg    Aneurysm DBP  79.9 ± 16.3 mm Hg    Aneurysm PP  15.2 ± 13.8 mm Hg    Aneurysm MAP  82.5 ± 21.2 mm Hg    Rupture status  28 ruptured, 40 unruptured  Ruptured vs Non-ruptured  Diameter (ruptured)  6.1 ± 3.3 mm  P = .90  Neck (ruptured)  2.9 ± 0.9 mm  P = .77  Systolic BP (ruptured)  110.8 ± 16.1 mm Hg  P = .82  Diastolic BP (ruptured)  58.8 ± 12.6 mm Hg  P = .87  Heart rate (ruptured)  73.3 ± 15.8  P = .33  Systemic PP (ruptured)  52.0 ± 11.9 mm Hg  P = .69  MAP (ruptured)  76.1 ± 12.7 mm Hg  P = .87  Diameter (unruptured)  6.8 ± 4.5 mm    Neck (unruptured)  3.6 ± 1.9 mm    Systolic BP (unruptured)  115.8 ± 14.0 mm Hg    Diastolic BP (unruptured)  56.3 ± 8.6 mm Hg    Heart rate (unruptured)  56.6 ± 9.1    Systemic PP (unruptured)  59.8 ± 14.2 mm Hg    MAP (unruptured)  76.5 ± 8.1 mm Hg    Saturation (%)  99.1 ± 1.8    ICP (from external ventricular drain)  17.1 ± 11.9 mm Hg      Unruptured (n = 40)  Ruptured (n = 28)  P value  Age  59 ± 13 yr  58 ± 11 yr  .74  Sex  85% female  71% female    Race  80% Caucasian  86% Caucasian    Location  68% anterior circulation  82% anterior circulation    Aneurysm size (mm)  7.0 ± 4.8 mm  5.6 ± 3.3 mm  .19  Family History  15%  3.6%    Diabetes  15%  3.6%    Hypertension  62.5%  60.7%    EGFR  95.3 ± 24.1  109.8 ± 43.4  .08  Smoking  32.5%  71%    BMI  30 ± 5.7  28 ± 4.9  .14  ASA class  2.6 ± 0.5  3.5 ± 0.8  .0001  Phenylephrine  5.5 ± 5.7 mcg/kg/min  5.0 ± 4.5 mcg/kg/min  .70  Ephedrine  7.0 ± 11.8 mg  4.8 ± 10.4 mg  .43  Ventriculostomy  0  22    SBP—Systolic blood pressure, DBP—Diastolic blood pressure, PP—Pulse pressure, MAP—Mean arterial pressure, ICP—Intracranial pressure, EGFR—Estimated glomerular filtration rate, BMI—Body mass index, ASA—American Society of Anesthesiology severity scale. The middle column indicates average values with associated standard deviation (Avg ± SD). P values given on the right, a P value of <.05 was considered significant. View Large TABLE 1. Patient Demographics and Aneurysm Characteristics Age  58.4 ± 12.3    Sex  14 male, 53 female    Aneurysm Location  29.4% ACOM, 22.0% posterior circulation    Diameter  6.5 ± 4.1 mm    Neck  3.3 ± 1.6 mm  Systemic vs Intra Saccular  Systemic SBP  113.8 ± 15.0 mm Hg  P < .001  Systemic DBP  57.3 ± 10.4 mm Hg  P < .001  Systemic PP  56.6 ± 13.7 mm Hg  P < .001  Systemic MAP  76.0 ± 10.1 mm Hg  P = .02  Heart rate  63.6 ± 14.8    Aneurysm SBP  95.1 ± 18.1 mm Hg    Aneurysm DBP  79.9 ± 16.3 mm Hg    Aneurysm PP  15.2 ± 13.8 mm Hg    Aneurysm MAP  82.5 ± 21.2 mm Hg    Rupture status  28 ruptured, 40 unruptured  Ruptured vs Non-ruptured  Diameter (ruptured)  6.1 ± 3.3 mm  P = .90  Neck (ruptured)  2.9 ± 0.9 mm  P = .77  Systolic BP (ruptured)  110.8 ± 16.1 mm Hg  P = .82  Diastolic BP (ruptured)  58.8 ± 12.6 mm Hg  P = .87  Heart rate (ruptured)  73.3 ± 15.8  P = .33  Systemic PP (ruptured)  52.0 ± 11.9 mm Hg  P = .69  MAP (ruptured)  76.1 ± 12.7 mm Hg  P = .87  Diameter (unruptured)  6.8 ± 4.5 mm    Neck (unruptured)  3.6 ± 1.9 mm    Systolic BP (unruptured)  115.8 ± 14.0 mm Hg    Diastolic BP (unruptured)  56.3 ± 8.6 mm Hg    Heart rate (unruptured)  56.6 ± 9.1    Systemic PP (unruptured)  59.8 ± 14.2 mm Hg    MAP (unruptured)  76.5 ± 8.1 mm Hg    Saturation (%)  99.1 ± 1.8    ICP (from external ventricular drain)  17.1 ± 11.9 mm Hg      Unruptured (n = 40)  Ruptured (n = 28)  P value  Age  59 ± 13 yr  58 ± 11 yr  .74  Sex  85% female  71% female    Race  80% Caucasian  86% Caucasian    Location  68% anterior circulation  82% anterior circulation    Aneurysm size (mm)  7.0 ± 4.8 mm  5.6 ± 3.3 mm  .19  Family History  15%  3.6%    Diabetes  15%  3.6%    Hypertension  62.5%  60.7%    EGFR  95.3 ± 24.1  109.8 ± 43.4  .08  Smoking  32.5%  71%    BMI  30 ± 5.7  28 ± 4.9  .14  ASA class  2.6 ± 0.5  3.5 ± 0.8  .0001  Phenylephrine  5.5 ± 5.7 mcg/kg/min  5.0 ± 4.5 mcg/kg/min  .70  Ephedrine  7.0 ± 11.8 mg  4.8 ± 10.4 mg  .43  Ventriculostomy  0  22    Age  58.4 ± 12.3    Sex  14 male, 53 female    Aneurysm Location  29.4% ACOM, 22.0% posterior circulation    Diameter  6.5 ± 4.1 mm    Neck  3.3 ± 1.6 mm  Systemic vs Intra Saccular  Systemic SBP  113.8 ± 15.0 mm Hg  P < .001  Systemic DBP  57.3 ± 10.4 mm Hg  P < .001  Systemic PP  56.6 ± 13.7 mm Hg  P < .001  Systemic MAP  76.0 ± 10.1 mm Hg  P = .02  Heart rate  63.6 ± 14.8    Aneurysm SBP  95.1 ± 18.1 mm Hg    Aneurysm DBP  79.9 ± 16.3 mm Hg    Aneurysm PP  15.2 ± 13.8 mm Hg    Aneurysm MAP  82.5 ± 21.2 mm Hg    Rupture status  28 ruptured, 40 unruptured  Ruptured vs Non-ruptured  Diameter (ruptured)  6.1 ± 3.3 mm  P = .90  Neck (ruptured)  2.9 ± 0.9 mm  P = .77  Systolic BP (ruptured)  110.8 ± 16.1 mm Hg  P = .82  Diastolic BP (ruptured)  58.8 ± 12.6 mm Hg  P = .87  Heart rate (ruptured)  73.3 ± 15.8  P = .33  Systemic PP (ruptured)  52.0 ± 11.9 mm Hg  P = .69  MAP (ruptured)  76.1 ± 12.7 mm Hg  P = .87  Diameter (unruptured)  6.8 ± 4.5 mm    Neck (unruptured)  3.6 ± 1.9 mm    Systolic BP (unruptured)  115.8 ± 14.0 mm Hg    Diastolic BP (unruptured)  56.3 ± 8.6 mm Hg    Heart rate (unruptured)  56.6 ± 9.1    Systemic PP (unruptured)  59.8 ± 14.2 mm Hg    MAP (unruptured)  76.5 ± 8.1 mm Hg    Saturation (%)  99.1 ± 1.8    ICP (from external ventricular drain)  17.1 ± 11.9 mm Hg      Unruptured (n = 40)  Ruptured (n = 28)  P value  Age  59 ± 13 yr  58 ± 11 yr  .74  Sex  85% female  71% female    Race  80% Caucasian  86% Caucasian    Location  68% anterior circulation  82% anterior circulation    Aneurysm size (mm)  7.0 ± 4.8 mm  5.6 ± 3.3 mm  .19  Family History  15%  3.6%    Diabetes  15%  3.6%    Hypertension  62.5%  60.7%    EGFR  95.3 ± 24.1  109.8 ± 43.4  .08  Smoking  32.5%  71%    BMI  30 ± 5.7  28 ± 4.9  .14  ASA class  2.6 ± 0.5  3.5 ± 0.8  .0001  Phenylephrine  5.5 ± 5.7 mcg/kg/min  5.0 ± 4.5 mcg/kg/min  .70  Ephedrine  7.0 ± 11.8 mg  4.8 ± 10.4 mg  .43  Ventriculostomy  0  22    SBP—Systolic blood pressure, DBP—Diastolic blood pressure, PP—Pulse pressure, MAP—Mean arterial pressure, ICP—Intracranial pressure, EGFR—Estimated glomerular filtration rate, BMI—Body mass index, ASA—American Society of Anesthesiology severity scale. The middle column indicates average values with associated standard deviation (Avg ± SD). P values given on the right, a P value of <.05 was considered significant. View Large Patient and Aneurysm Hemodynamics A mean SBP of 113.7 mm Hg over a diastolic blood pressure (DBP) of 57.3 mm Hg with a PP of 56.6 mm Hg and an mean arterial blood pressure (MAP) of 76 mm Hg was obtained. The average heart rate was 63.5 beats per minute with a saturation of 99.1%. In patients presenting with a ventriculostomy, the average ICP during treatment was 17.1 mm Hg. In all cases, ISP was recorded using a standard 1.8-Fr 200 m length microcatheter attached to a transducer. A mean SBP of 95.1 mm Hg over a DBP of 79.9 mm Hg with a PP of 15.2 mm Hg and an MAP of 82.5 mm Hg was obtained. Intrasaccular systolic and PP were consistently lower than systemic recordings and higher diastolic and MAPs were observed compared to systemic recordings. This is a characteristic finding with measurements obtained from a long microcatheter due to increased impedance and destructive interference along the catheter length. There was no significant difference in baseline systemic or aneurysm hemodynamic parameters between ruptured and nonruptured groups (Table 1). Intrasaccular hemodynamic parameters are outlined in Table 2 comparing ruptured with nonruptured aneurysms. Hemodynamic variables were also matched to systemic values in order to account for potential variations in systemic parameters that may affect intrasaccular recordings. This ratio accounts for absolute as well as relative differences between groups and has been independently validated.14 Independent sample 2 tailed t-tests were used to compare differences in continuous variables between ruptured and nonruptured groups. TABLE 2. Aneurysm Intrasaccular Hemodynamics Parameter  Unruptured  Ruptured  P value  SBP    102 ± 16.4  84.8 ± 15.6  P < .001    % Sys  88 ± 13  76 ± 11  P < .001  DBP    81 ± 16  78.3 ± 16.9  P = .25    % Sys  145 ± 31  132 ± 23  P = .06  Pulse pressure    21 ± 15  6.58 ± 3.92  P < .001    % Sys  36 ± 24  13 ± 7  P < .001  MAP    88 ± 14  80.5 ± 16.4  P = .05    % Sys  115 ± 18  104 ± 16  P = .01  Parameter  Unruptured  Ruptured  P value  SBP    102 ± 16.4  84.8 ± 15.6  P < .001    % Sys  88 ± 13  76 ± 11  P < .001  DBP    81 ± 16  78.3 ± 16.9  P = .25    % Sys  145 ± 31  132 ± 23  P = .06  Pulse pressure    21 ± 15  6.58 ± 3.92  P < .001    % Sys  36 ± 24  13 ± 7  P < .001  MAP    88 ± 14  80.5 ± 16.4  P = .05    % Sys  115 ± 18  104 ± 16  P = .01  Average hemodynamic parameters between ruptured and unruptured aneurysm were analyzed using two-tailed T-test. P value of <.05 was considered significant. (% Sys—Percent of systemic values). View Large TABLE 2. Aneurysm Intrasaccular Hemodynamics Parameter  Unruptured  Ruptured  P value  SBP    102 ± 16.4  84.8 ± 15.6  P < .001    % Sys  88 ± 13  76 ± 11  P < .001  DBP    81 ± 16  78.3 ± 16.9  P = .25    % Sys  145 ± 31  132 ± 23  P = .06  Pulse pressure    21 ± 15  6.58 ± 3.92  P < .001    % Sys  36 ± 24  13 ± 7  P < .001  MAP    88 ± 14  80.5 ± 16.4  P = .05    % Sys  115 ± 18  104 ± 16  P = .01  Parameter  Unruptured  Ruptured  P value  SBP    102 ± 16.4  84.8 ± 15.6  P < .001    % Sys  88 ± 13  76 ± 11  P < .001  DBP    81 ± 16  78.3 ± 16.9  P = .25    % Sys  145 ± 31  132 ± 23  P = .06  Pulse pressure    21 ± 15  6.58 ± 3.92  P < .001    % Sys  36 ± 24  13 ± 7  P < .001  MAP    88 ± 14  80.5 ± 16.4  P = .05    % Sys  115 ± 18  104 ± 16  P = .01  Average hemodynamic parameters between ruptured and unruptured aneurysm were analyzed using two-tailed T-test. P value of <.05 was considered significant. (% Sys—Percent of systemic values). View Large We observed that RIAs have a lower SBP and MAP within the dome compared to NRIAs (P < .001 and P = .05, respectively). Additionally, the PP within the dome of RIAs were significantly narrower than that of NRIAs (P < .001). These findings suggest that there may be an inherent difference in hemodynamics between RIA and NRIAs. DISCUSSION NRIA have an estimated prevalence of 3% to 5% in the general population with up to 30% of these patients harboring multiple aneurysms.2,15 Current treatment paradigms are guided by estimated rupture risk, patient age, and associated comorbidity. Patients with larger aneurysms, family history, or personal history of ruptured IAs are felt to be at higher risk, while patients with smaller (less than 10 mm) aneurysms without significant associated risk factors have low risk of rupture and can be followed conservatively.9,10 Conflicting data exist however, as the majority of RIAs are small with a median size of 7 mm. Therefore, the optimal management strategy of small NRIAs is controversial.16 As NRIAs are being increasingly detected due to the improvement and increased utilization of cerebrovascular imaging, there is increased “pressure” to explore new methods of improving risk stratification of NRIAs. In attempts to further individualize rupture risk, CH has been extensively evaluated using a combination of invasive and noninvasive modalities both in vivo and ex vivo. Various authors have found significant associations between CH and aneurysm rupture risk that may prove vital in clinical decision making and facilitate our understanding and discrimination between RIAs and NRIAs.11,12 CH studies suggest that aneurysms form as a result of chronic exposure to high wall shear stress (WSS) that is often seen at the branch-point of vessels or along a lateral outward curve. This theory explains why aneurysms are commonly found at their bifurcations or branching points. Chronically high WSS results in elastin degradation, disruption of the internal elastic lamina, and apoptosis of the vascular smooth muscle.17,18 Compensatory responses to repeated microtrauma from high WSS result in vessel wall outpouching, remodeling, and ultimately dilation and aneurysm formation. Enlargement and rupture appears to incorporate the same physics combined with inflammation of the vessel wall. Aneurysm rupture occurs at areas of focal endothelial weakening in the dome that develops secondary to chronic exposure to low WSS; however, this has been an area of controversy.17,19–21 WSS is a vector whose scale and direction are driven by the pulsatility and flow of blood while the circumferential stress on blood vessels is determined by the variations of blood pressure and blood flow during the cardiac cycle. Therefore, the parameters affecting local WSS include SBP, DBP, and the velocity and angle of the blood flow vector.22,23 Recently, bifurcation/inflow angle, bottle-neck-ratio, neck-deviation, and other morphometric parameters have been studied to help distinguish between RIA and NRIAs.24-27 These studies highlight the need for improved patient-specific parameters to differentiate between high- and low-risk aneurysms but also further emphasize WSS and CH as an important influencer of aneurysm growth and rupture. Much of our understanding of WSS and CH has been based largely on animal or computational aneurysm models. Recordings of hemodynamic parameters within human aneurysm sacs have been predominantly limited to ex vivo imaging with very few studies citing human invasive in vivo measurements. To the best of our knowledge no such invasive investigation has been performed on RIAs. We prospectively evaluated the ISPs within RIA and NRIAs in a cross-sectional cohort of patients undergoing endovascular surgery. We observed a significant decrease in SBP, MAP, and PP within the domes of RIAs compared to their nonruptured cohorts. When hemodynamic variables were matched to systemic values to account for absolute as well as relative differences between groups and to account for potential variations in systemic parameters that may affect intrasaccular recordings, statistical significance was maintained. These data suggest that there may be an inherent difference in hemodynamics between ruptured and nonruptured aneurysms (Table 2). Our findings were initially counterintuitive, as one would predict a higher SBP and MAP within the dome of an aneurysm would increase the rate of rupture, just as a higher pressure would contribute to the expansion and ultimate rupture of a plastic balloon. On the contrary, our findings demonstrated a lower MAP and SBP within the domes of ruptured aneurysms. This apparent paradox could be explained by the consequence of vascular remodeling changing the composition of the vessel wall leading to enlargement of the aneurysm sac via secondary inflammation. As the radius of the aneurysmal sac increases, the overall pressure distributed against the wall of the aneurysm decreases as an offsetting mechanism to prevent further endothelial vessel wall injury also known as “stress-relaxation”.28 This mechanism may be akin to the process of developing poststenotic dilatations commonly seen within the aorta and proximal internal carotid artery secondary to flow disturbances and abnormal WSS produced by atherosclerosis and arteriosclerosis.29-31 “Stress-relaxation” is due to a decrease in the vessel wall thickness that results in increased compliance and loss of pressure variability seen as a narrow PP. As described by LaPlace's law, as a vessel wall thins out or diameter expands, there is an increase in wall tension needed to withstand a given internal pressure thereby elucidating the mechanism of increased risk of subsequent aneurysm rupture. As a vessel wall remodels secondary to turbulent flow, changes in regional hemodynamics ensue with the development of local stasis within the aneurysm dome that increases local inflammation and subsequent rupture. It may be a decrease in local ISP that corresponds to the stasis seen in remodeling and higher risk aneurysms. Intrasaccular WSS is a dynamic process supported by decreases seen in WSS at the site of secondary bleb formation along the aneurysm dome.32,33 Local WSS is typically lowest at the apex of an aneurysm dome compared to its neck.25,34,35 Low WSS induces stagnation of blood that precipitates thrombus formation and secondary inflammation via macrophage infiltration, degradation of elastin, and apoptosis of vascular smooth muscle.32,36–38 Low WSS has been associated with known points of rupture further confirmed by studies where hemodynamic parameters were obtained auspiciously just prior to the event of rupture.39–44 A narrow intrasaccular PP observed within the dome of ruptured aneurysms also corroborates LaPlace's law and the “stress-relaxation” theory of an enlarging or fragile aneurysm. Decreasing aneurysm wall thickness induces increased compliance and loss of pressure variability that is manifested as a narrow PP. Measuring intrasaccular PPs may therefore raise suspicion to growing or fragile aneurysms. A narrow PP seen in RIAs also supports the hypothesis that areas of low WSS and resultant stasis can precipitate inflammation and secondary aneurysm rupture. Decreased PP can facilitate decreased outflow and local pooling of blood that may be observed on diagnostic angiography as contrast stasis within a secondary bleb. Low ISPs and narrow PPs may therefore serve as a potential surrogate marker for low WSS and assist in predicting aneurysm risk. Morphological parameters associated with RIA have been investigated. Meaningful parameters associated with higher risk of SAH include higher size ratio, height-width ratio, undulation index, nonsphericity index, ellipticity index, aneurysm, and parent vessel angles.45,46 Unfortunately, CH studies are not widely available and to date this technique and the use of morphological parameters have had little application in clinical practice.13 In contrast, measurement of ISP is extremely commonplace within neuroendovascular surgery and has been used as an adjunct during venography for diagnosing pseudotumor cerebri and balloon test occlusion. Measuring ISPs may have diagnostic utility and may serve as a surrogate for detecting low WSS. As previously discussed, parameters that affect local WSS include blood pressure and velocity, which are directly influenced by the SBP and DBP locally within the aneurysm dome. Such recordings obtained during angiography could potentially become a widely applied technique to augment risk stratification of NRIAs. In our cohort of RIA, only 3 of 28 cases were found to have a PP of greater than 10 mm Hg, whereas in the NRIA cohort 9 of 40 aneurysms had a PP below 10 mm Hg. In Table 3, we present the patient characteristics of those NRIA with narrow PP. In this group, 7 of 8 patients had strong family history, history of previous aneurysm rupture, multiple IAs, or developed a new cranial neuropathy likely from enlargement of the aneurysm. Only one patient did not have a high-risk factor for rupture. This is in contrast to the remaining NRIA cohort with high PPs, where 17 of 32 patients did not have high-risk factors. TABLE 3. Demographic and Angiographic Characteristics of Patients With NRIAs With Low Pulse Pressure Age  Sex  Location  Morphology  Neck  Size  A-SBP  A-DBP  PP  High-risk features  79  F  MCA  Saccular  2 mm  2.5 × 2.5 × 3 mm  106  100  6  Has 6 aneurysms and strong family history of rupture  57  F  P2  Saccular  2 mm  2 × 2 × 2.5 mm  105  101  4  Previous ruptured MCA  44  F  Paraclinoid  Multilobulated  3 mm  9 × 6 × 6 mm  91  84  7  Developed new cranial neuropathy, suspect enlarging aneurysm  51  F  Paraclinoid  Saccular  2.5 mm  3.5 × 3 × 2.5 mm  90  82  8  None  35  F  ACOM  Dysplastic with recurrent bleb  2 mm  2 × 2.5 × 2 mm  84  81  3  Previous rupture s/p coiling and new recurrence adjacent to previous neck  46  F  Paraclinoid  Multilobulated  3 mm  8 × 6 × 6 mm  90  84  6  Has multiple intracranial aneurysms  58  F  ACOM  Multilobulated  5 mm  8 × 12 × 6 mm  98  94  4  Strong family history of rupture  63  F  PCOM  Multilobulated  3 mm  3 × 2 × 6 mm  87  78  9  Has multiple intracranial aneurysms and strong family history of aneurysm rupture  Age  Sex  Location  Morphology  Neck  Size  A-SBP  A-DBP  PP  High-risk features  79  F  MCA  Saccular  2 mm  2.5 × 2.5 × 3 mm  106  100  6  Has 6 aneurysms and strong family history of rupture  57  F  P2  Saccular  2 mm  2 × 2 × 2.5 mm  105  101  4  Previous ruptured MCA  44  F  Paraclinoid  Multilobulated  3 mm  9 × 6 × 6 mm  91  84  7  Developed new cranial neuropathy, suspect enlarging aneurysm  51  F  Paraclinoid  Saccular  2.5 mm  3.5 × 3 × 2.5 mm  90  82  8  None  35  F  ACOM  Dysplastic with recurrent bleb  2 mm  2 × 2.5 × 2 mm  84  81  3  Previous rupture s/p coiling and new recurrence adjacent to previous neck  46  F  Paraclinoid  Multilobulated  3 mm  8 × 6 × 6 mm  90  84  6  Has multiple intracranial aneurysms  58  F  ACOM  Multilobulated  5 mm  8 × 12 × 6 mm  98  94  4  Strong family history of rupture  63  F  PCOM  Multilobulated  3 mm  3 × 2 × 6 mm  87  78  9  Has multiple intracranial aneurysms and strong family history of aneurysm rupture  MCA—Middle cerebral artery, P2—Segment 2 of posterior cerebral artery, ACOM—Anterior communicating artery, PCOM—Posterior communicating artery. View Large TABLE 3. Demographic and Angiographic Characteristics of Patients With NRIAs With Low Pulse Pressure Age  Sex  Location  Morphology  Neck  Size  A-SBP  A-DBP  PP  High-risk features  79  F  MCA  Saccular  2 mm  2.5 × 2.5 × 3 mm  106  100  6  Has 6 aneurysms and strong family history of rupture  57  F  P2  Saccular  2 mm  2 × 2 × 2.5 mm  105  101  4  Previous ruptured MCA  44  F  Paraclinoid  Multilobulated  3 mm  9 × 6 × 6 mm  91  84  7  Developed new cranial neuropathy, suspect enlarging aneurysm  51  F  Paraclinoid  Saccular  2.5 mm  3.5 × 3 × 2.5 mm  90  82  8  None  35  F  ACOM  Dysplastic with recurrent bleb  2 mm  2 × 2.5 × 2 mm  84  81  3  Previous rupture s/p coiling and new recurrence adjacent to previous neck  46  F  Paraclinoid  Multilobulated  3 mm  8 × 6 × 6 mm  90  84  6  Has multiple intracranial aneurysms  58  F  ACOM  Multilobulated  5 mm  8 × 12 × 6 mm  98  94  4  Strong family history of rupture  63  F  PCOM  Multilobulated  3 mm  3 × 2 × 6 mm  87  78  9  Has multiple intracranial aneurysms and strong family history of aneurysm rupture  Age  Sex  Location  Morphology  Neck  Size  A-SBP  A-DBP  PP  High-risk features  79  F  MCA  Saccular  2 mm  2.5 × 2.5 × 3 mm  106  100  6  Has 6 aneurysms and strong family history of rupture  57  F  P2  Saccular  2 mm  2 × 2 × 2.5 mm  105  101  4  Previous ruptured MCA  44  F  Paraclinoid  Multilobulated  3 mm  9 × 6 × 6 mm  91  84  7  Developed new cranial neuropathy, suspect enlarging aneurysm  51  F  Paraclinoid  Saccular  2.5 mm  3.5 × 3 × 2.5 mm  90  82  8  None  35  F  ACOM  Dysplastic with recurrent bleb  2 mm  2 × 2.5 × 2 mm  84  81  3  Previous rupture s/p coiling and new recurrence adjacent to previous neck  46  F  Paraclinoid  Multilobulated  3 mm  8 × 6 × 6 mm  90  84  6  Has multiple intracranial aneurysms  58  F  ACOM  Multilobulated  5 mm  8 × 12 × 6 mm  98  94  4  Strong family history of rupture  63  F  PCOM  Multilobulated  3 mm  3 × 2 × 6 mm  87  78  9  Has multiple intracranial aneurysms and strong family history of aneurysm rupture  MCA—Middle cerebral artery, P2—Segment 2 of posterior cerebral artery, ACOM—Anterior communicating artery, PCOM—Posterior communicating artery. View Large Could NRIAs with narrow PP represent a subgroup of NRIA that are at higher risk of future rupture? Additionally, could this information be used to help intraoperatively predict the culprit aneurysm in a case of SAH in the setting of multiple IAs? Limitations The accuracy and precision of transducing microcatheter stump pressures have been independently validated in both animal and human studies but the largest limitation of this study remains the use of a long and narrow microcatheter for the measurement of ISPs.14,47-49 Although a relatively well-established technique in endovascular surgery, pressure recordings via a microcatheter have inherent biases. There is a substantial impedance and destructive interference effect on the accuracy of measurements—a theoretical dampening effect transmitted through length of the catheter to the pressure transducer attached to the hub. As previously mentioned, we consistently observed lower ISPs, narrow PPs, and higher DBP and MAPs compared to systemic radial artery recordings. This is a characteristic finding of increased impedance and destructive interference of measuring pressures across the length of a long and narrow tube. Despite these inherent biases, the precision of measurements comparing RIAs and NRIAs should be retained. All data were accumulated using a standard 1.8-French coiling microcatheter of the same brand, length, and make except 2 cases that were of the same length and diameter but of a different manufacturer. Partial occlusion of the aneurysm neck by the microcatheter during ISP recordings may also bias the results with larger aneurysm necks having reduced effects. There was no difference in aneurysm neck diameter between the RIA and NRIA cohorts. In the index case, the same microcatheter was used in both aneurysms and produced readings that were consistent with our overall findings. Other limitation of this study include a small sample size, the location of the microcatheter placement during data collection, as well as the presence of an EVD or intravascular balloon during measurements that could have a dampening effect on ISP recordings. To the best of our ability, we centralized the microcatheter within the dome of the aneurysm during data collection. The EVD was clamped and any intravascular balloon was deflated during recording to prevent any loss of resistance. Not all RIAs had an EVD placed during data collection although the majority did (6/28 patients did not). Only 3 out of 67 patients (all ruptured cases) were treated with the assistance of an intravascular balloon. Alternatively, our findings of lower ISPs could also be an effect of aneurysm rupture rather than a cause. In the acute setting after SAH, ICP rises rapidly to reduce transmural pressure and facilitate thrombus formation at the rupture site to achieve hemostasis.50 Local thrombosis and vasospasm within the aneurysm wall may confound ISPs by reducing the inflow and compliance of the local vessel wall. Increased ICP also results in autonomic dysregulation and global hypoperfusion that may manifest lower ISPs. Subsequent to the acute stage of SAH, which typically lasts only a few minutes, elevated ICP begins to resolve and secondary injury is induced.50,51 Secondary injury that develops within 4 h after SAH produces cerebral ischemia and secondary edema.51 Cerebral edema after SAH may reduce cerebral compliance reflected as a decrease in PP. Therefore, lower and narrower ISPs may simply be a result of recent SAH. In our cohort, increased ICP after aneurysm rupture was managed medically and with the use of an external ventricular drain. ICP was maintained below 25 mm Hg in all cases with a mean of 17 mm Hg. A good waveform was demonstrated on the ICP monitor in all cases that suggests adequate cerebral compliance. Although the intricate mechanisms after SAH may confound ISP recordings, ISPs could still prove to be a useful technique in helping distinguish between RIAs and NRIAs when multiple are present. The rupture effect as a cause of lower and narrower ISPs does not explain the observation of a small subset of morphologically and clinically high-risk appearing group of NRIAs with narrow PPs. The role of PP and WSS in aneurysm formation and rupture has not been conclusively elucidated. Future studies are needed to expound upon these preliminary findings. CONCLUSION Cerebral hemodynamics is critical to the understanding of cerebral aneurysm formation, progression, and rupture. Decreased WSS may be an important predictive parameter to augment risk stratification of NRIA; however, computational fluid dynamic studies are not widely available. We present the largest prospective cross-sectional cohort of ISP recordings of RIA and NRIAs and found lower overall stump pressures and narrow PPs observed within the domes of RIAs compared to NRIAs. Future studies are needed to validate these findings but our preliminary data present new evidence that may have a critical role as a predictive parameter to stratify the natural history of NRIA and is a new avenue for future investigation. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes Oral Abstract Presentation at the Annual Congress of Neurological Surgeons Society Meeting, Boston, Massachusetts, October 10th, 2017. REFERENCES 1. Schievink WI. Intracranial aneurysms. N Engl J Med . 1997; 336( 1): 28- 40. 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Neurol Res . 2006; 28( 4): 381- 398. Google Scholar CrossRef Search ADS PubMed  51. Trojanowski T. Blood-brain barrier changes after experimental subarachnoid haemorrhage. Acta neurochir . 1982; 60( 1–2): 45- 54. Google Scholar CrossRef Search ADS PubMed  COMMENTS Since ISUIA (the The International Study of Unruptured Intracranial Aneurysms), one major deciding factor for intervening on unruptured intracranial aneurysms is the size. As our diagnostic capabilities become more sophisticated, there is an increasing demand to more safely identify high-risk features in unruptured aneurysms. In this paper, the authors elegantly, albeit invasively, measure intrasaccular pressures of both ruptured and unruptured aneurysms. They note significantly lower intrasaccular pressures and narrow pulse pressures were found in the ruptured aneurysm cohort as compared to the unruptured aneurysm cohort. Although a noninvasive test would be ideal, measuring intrasaccular pressures in an unruptured aneurysm may add more prognostic information regarding the danger posed by the aneurysm. Moving forward, the authors should be commended on their work and further data should be compiled to determine the usefulness of intrasaccular measurements. Daniel Felbaum Erol Veznedaroglu Pennington, New Jersey The discovery of modern, reliable predictors for intracranial aneurysm rupture has captivated many academic cerebrovascular neurosurgeons and neurointerventionalists, acknowledging the fact that we continue to rely on traditional markers of high rupture risk (ie, size, irregular morphology) to determine the necessity of aneurysm treatment. Fortunately, as imaging techniques and computational analyses advance, many have isolated specific cerebrovascular hemodynamic parameters as potential biomarkers in identifying high-risk aneurysm. In the current manuscript, the authors assess the differences in arterial and aneurysmal blood pressures in patients with either ruptured or unruptured intracranial aneurysms. In their retrospective review of 67 patients, the authors observed a significantly decreased systolic, mean arterial, and pulse pressures in ruptured aneurysms, compared to unruptured aneurysms undergoing elective treatment. As discussed, the authors posit that this decrease in intrasaccular pressures may be associated with aneurysmal vascular remodeling, inflammation, and higher rupture risk. Extrapolated as a potential biomarker, the use of routine intrasaccular pressure (ISP) monitoring could serve a dual purpose. First, in determination of elective aneurysm treatment, aneurysms with low ISPs might be considered for treatment, even if other high-risk features are absent. Second, in patients with subarachnoid hemorrhage and multiple aneurysms present, the culprit ruptured aneurysm may have lower ISP than the others, and thus be isolated for immediate treatment. However, 2 considerations should be made prior to incorporating routine ISP monitoring for aneurysm risk stratification. First, we must consider the added procedural time and risk of aneurysmal pressure monitoring. While it may be exceedingly low, the risk would still be non-zero, and should be further discussed with patients undergoing angiography. Second, we must acknowledge that this procedure will be obviously self-selecting for patients who are already undergoing cerebral angiography, and thus representing a pool of patients at higher than average risk. Ideally, such a biomarker would be non-invasive, such as with MR vessel wall imaging or quantitative hemodynamic analysis, in order to totally preclude the inherent procedural risks of angiography. Kurt Yaeger J Mocco New York, New York Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

NeurosurgeryOxford University Press

Published: May 8, 2018

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