Cognitive, Mental Health, Functional, and Quality of Life Outcomes 1 Year After Spontaneous Subarachnoid Hemorrhage: A Prospective Observational Study.

BACKGROUND: Patients with spontaneous subarachnoid hemorrhage (SAH) frequently encounter cognitive dysfunction and mental health issues with negative effects on health-related quality of life (HR-QoL). Here, we aimed to describe the prevalence of cognitive deficits, mental health problems, and HR-QoL impairments 1 year after SAH. METHODS: In this prospective observational study, 177 patients with SAH admitted to our neurointensive care unit over a time span of ten years followed the invitation for an in-person 1-year follow-up, including a standardized neuropsychological test battery. Mental health issues (anxiety and depression) and HR-QoL were evaluated using questionnaires (Hospital Anxiety and Depression Scale; 36-item Short Form questionnaire). Functional outcome was assessed with the modified Rankin Scale (mRS) score. RESULTS: Patients were 54 years of age (interquartile range 47-62 years) and presented with a median Hunt and Hess score of 2 (interquartile range 1-3) at admission. Most patients (93%) achieved good functional 1-year outcomes (mRS score 0-2). Seventy-one percent of patients had deficits in at least one cognitive domain, with memory deficits being the most prevalent (51%), followed by deficits in executive functions (36%), visuoconstruction (34%), and attention (21%). Even patients with perimesencephalic SAH (18%) or with full functional recovery (mRS score = 0, 46%) had a comparable prevalence of cognitive deficits (61% and 60%, respectively). Symptoms of depression and anxiety were reported by 16% and 33% of patients, respectively. HR-QoL was impaired in 37% (55 of 147). Patients with cognitive deficits (p = 0.001) or mental health issues (p < 0.001) more frequently reported impaired HR-QoL. CONCLUSIONS: Most patients with SAH have cognitive deficits and mental health issues 1 year after SAH. These deficits impair patients' quality of life.

Blood Pressure Changes in Association with Nimodipine Therapy in Patients with Spontaneous Subarachnoid Hemorrhage.

BACKGROUND: Nimodipine is recommended to prevent delayed cerebral ischemia in patients with spontaneous subarachnoid hemorrhage (SAH). Here, we studied hemodynamic side effects of different nimodipine formulations (per os [PO] and intravenous [IV]) in patients with SAH undergoing continuous blood pressure monitoring. METHODS: This observational cohort study includes consecutive patients with SAH (271 included in the IV group, 49 in the PO group) admitted to a tertiary care center between 2010 and 2021. All patients received prophylactic IV or PO nimodipine. Hemodynamic responses were evaluated based on median values within the first hour after continuous IV nimodipine initiation or PO nimodipine application (601 intakes within 15 days). Significant changes were defined as > 10% drop in systolic blood pressure (SBP) or diastolic blood pressure from baseline (median values 30 min before nimodipine application). With the use of multivariable logistic regression, risk factors associated with SBP drops were identified. RESULTS: Patients were admitted with a median Hunt & Hess score of 3 (2-5; IV 3 [2-5], PO 1 [1-2], p < 0.001) and were 58 (49-69) years of age. Initiation of IV nimodipine was associated with a > 10% SBP drop in 30% (81/271) of patients, with a maximum effect after 15 min. A start or increase in noradrenaline was necessary in 136/271 (50%) patients, and colloids were administered in 25/271 (9%) patients within 1 h after IV nimodipine initiation. SBP drops > 10% occurred after 53/601 (9%) PO nimodipine intakes, with a maximum effect after 30-45 min in 28/49 (57%) patients. Noradrenaline application was uncommon (3% before and 4% after nimodipine PO intake). Hypotensive episodes to an SBP < 90 mm Hg were not observed after IV or PO nimodipine application. In multivariable analysis, only a higher SBP at baseline was associated with a > 10% drop in SBP after IV (p < 0.001) or PO (p = 0.001) nimodipine application, after adjusting for the Hunt & Hess score on admission, age, sex, mechanical ventilation, days after intensive care unit admission, and delayed cerebral ischemia. CONCLUSIONS: Significant drops in SBP occur in one third of patients after the start of IV nimodipine and after every tenth PO intake. Early recognition and counteracting with vasopressors or fluids seems necessary to prevent hypotensive episodes.

Brain microdialysate tau dynamics predict functional and neurocognitive recovery after poor-grade subarachnoid haemorrhage.

Subarachnoid haemorrhage is a devastating disease that results in neurocognitive deficits and a poor functional outcome in a considerable proportion of patients. In this study, we investigated the prognostic value of microtubule-associated tau protein measured in the cerebral microdialysate for long-term functional and neuropsychological outcomes in poor-grade subarachnoid haemorrhage patients. We recruited 55 consecutive non-traumatic subarachnoid haemorrhage patients who underwent multimodal neuromonitoring, including cerebral microdialysis. Mitochondrial dysfunction was defined as lactate-to-pyruvate ratio >30 together with pyruvate >70 mmol/L and metabolic distress as lactate-to-pyruvate ratio >40. The multidimensional 12-month outcome was assessed by means of the modified Rankin scale (poor outcome: modified Rankin scale ≥4) and a standardized neuropsychological test battery. We used multivariable generalized estimating equation models to assess associations between total microdialysate-tau levels of the first 10 days after admission and hospital complications and outcomes. Patients were 56 ± 12 years old and presented with a median Hunt & Hess score of 5 (interquartile range: 3-5). Overall mean total microdialysate-tau concentrations were highest within the first 24 h (5585 ± 6291 pg/mL), decreased to a minimum of 2347 ± 4175 pg/mL on Day 4 (P < 0.001) and remained stable thereafter (P = 0.613). Higher total microdialysate-tau levels were associated with the occurrence of delayed cerebral ischaemia (P = 0.001), episodes of metabolic distress (P = 0.002) and mitochondrial dysfunction (P = 0.034). Patients with higher tau levels had higher odds for a poor 12-month functional outcome (adjusted odds ratio: 2.61; 95% confidence interval: 1.32-5.17; P = 0.006) and impaired results in the trail making test-B (adjusted odds ratio: 3.35; 95% confidence interval: 1.16-9.68; P = 0.026) indicative of cognitive flexibility. Total microdialysate-tau levels significantly decreased over the first 10 days (P < 0.05) in patients without delayed cerebral ischaemia or good functional outcomes and remained high in those with delayed cerebral ischaemia and poor 12-month outcomes, respectively. Dynamic changes of total tau in the cerebral microdialysate may be a useful biomarker for axonal damage associated with functional and neurocognitive recovery in poor-grade subarachnoid haemorrhage patients. In contrast, ongoing axonal damage beyond Day 3 after bleeding indicates a higher risk for delayed cerebral ischaemia as well as a poor functional outcome.

The location of intraparenchymal bleeding determines functional outcome after spontaneous subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Non-traumatic subarachnoid hemorrhage (SAH) is a devastating disease associated with high morbidity and mortality. A higher blood burden and the presence of intraparenchymal extension of the bleeding (intracerebral hemorrhage [ICH]) are well known predictors of poor outcome. Only few studies have addressed the role of hematoma location on patient's functional outcome. The main aims were to compare clinical and radiographic characteristics between SAH patients with and without ICH and to compare different ICH localizations in relation to long-term functional outcome. METHODS: We prospectively collected data on 280 consecutive SAH patients (aneurysmal and non-aneurysmal) admitted to a tertiary care hospital between 2010 and 2017 and assessed the initial computed tomography scans of the brain acquired after intensive care unit admission. Poor functional outcome was defined as a modified Rankin Scale score >2, 3 months after SAH. We used multivariable logistic linear regression to investigate associations between ICH location and clinical variables as well as functional outcome. RESULTS: Intraparenchymal extension of the hemorrhage was observed in 59/280 patients (21%). The median (interquartile range) ICH volume was 11.3 (4.9-16.2) ml and the location was supratentorial in 55/59 patients (93%). Most parenchymal hemorrhages were located in the frontal (n = 24.41%) and temporal lobes (n = 12.21%), followed by insular ICH (n = 7.12%), corpus callosum (n = 6.10%), parietal (n = 2.3%) and occipital locations (n = 2.3%). Among SAH patients with ICH, those with lesions located in the corpus callosum (n = 6/59) had a significantly higher risk of 3-month poor functional outcome in comparison to all other ICH locations, even after adjusting for Hunt and Hess grade and age (adjusted odds ratio [adjOR] 50.5, 95% confidence interval [CI] 1.3-2004.2, p = 0.034). These results remained robust when comparing the whole SAH cohort (adjOR 21.7, 95% CI 1.4-347.8, p = 0.030).  CONCLUSIONS: Intraparenchymal bleeding in patients with non-traumatic SAH, in particular that involving the corpus callosum, strongly predicts functional outcome.

Long-Term Clinical Trajectory of Patients with Subarachnoid Hemorrhage: Linking Acute Care and Neurorehabilitation.

BACKGROUND: Despite improvements in the critical care management of subarachnoid hemorrhage (SAH), a substantial number of patients still suffer from disabilities. In most areas of the world, longitudinal follow-up is not routinely performed, and the patient's trajectory remains unknown. METHODS: We prospectively collected data of 298 consecutive patients with spontaneous SAH and evaluated clinical trajectories at discharge, 3 months, and 1 year after SAH. In a subgroup of patients transferred to a local neurorehabilitation center (Rehab-Hochzirl), we studied the effects of rehabilitation intensity on clinical trajectories. Any decrease in the modified Rankin Scale (mRS) was defined as an improvement, with mRS ≤ 2 indicating good outcome. We used multivariate generalized linear models to investigate associations with clinical trajectories. RESULTS: Out of the 250 surviving patients, 35% were transferred directly to Rehab-Hochzirl (n = 87 of 250; mRS at discharge = 4), 11% were transferred to another rehabilitation center (n = 27 of 250; mRS = 1), 1% were transferred to a nursing home (n = 3 of 250; mRS = 5), 21% were transferred to their country of origin (n = 52 of 250; mRS = 4), and 32% (n = 79 of 250; mRS = 1) were discharged home. Functional outcome improved in 57% (n = 122 of 215) of patients during the first 3 months, with an additional 16% (35 of 215) improving between 3 and 12 months, resulting in an overall improvement in 73% (n = 157 of 215) of survivors. After 1 year, 60% (n = 179 of 250) of patients were functionally independent. A lower Hunt and Hess scale score at intensive care unit admission, younger age, a lower mRS at intensive care unit discharge, fewer days on mechanical ventilation, and male sex were independently associated with better functional recovery. Although the subgroup of patients transferred to Rehab-Hochzirl were more severely affected, 60% (52 of 87) improved during inpatient neurorehabilitation. CONCLUSIONS: Our results indicate ongoing functional improvement in a substantial number of patients with SAH throughout a follow-up period of 12 months. This effect was also observed in patients with severe disability receiving inpatient neurorehabilitation.

Neurological outcomes 1 year after COVID-19 diagnosis: A prospective longitudinal cohort study.

BACKGROUND AND PURPOSE: Neurological sequelae from coronavirus disease 2019 (COVID-19) may persist after recovery from acute infection. Here, the aim was to describe the natural history of neurological manifestations over 1 year after COVID-19. METHODS: A prospective, multicentre, longitudinal cohort study in COVID-19 survivors was performed. At a 3-month and 1-year follow-up, patients were assessed for neurological impairments by a neurological examination and a standardized test battery including the assessment of hyposmia (16-item Sniffin' Sticks test), cognitive deficits (Montreal Cognitive Assessment < 26) and mental health (Hospital Anxiety and Depression Scale and Post-traumatic Stress Disorder Checklist 5). RESULTS: Eighty-one patients were evaluated 1 year after COVID-19, out of which 76 (94%) patients completed a 3-month and 1-year follow-up. Patients were 54 (47-64) years old and 59% were male. New and persistent neurological disorders were found in 15% (3 months) and 12% (10/81; 1 year). Symptoms at 1-year follow-up were reported by 48/81 (59%) patients, including fatigue (38%), concentration difficulties (25%), forgetfulness (25%), sleep disturbances (22%), myalgia (17%), limb weakness (17%), headache (16%), impaired sensation (16%) and hyposmia (15%). Neurological examination revealed findings in 52/81 (64%) patients without improvement over time (3 months, 61%, p = 0.230) including objective hyposmia (Sniffin' Sticks test <13; 51%). Cognitive deficits were apparent in 18%, whereas signs of depression, anxiety and post-traumatic stress disorders were found in 6%, 29% and 10% respectively 1 year after infection. These mental and cognitive disorders had not improved after the 3-month follow-up (all p > 0.05). CONCLUSION: Our data indicate that a significant patient number still suffer from neurological sequelae including neuropsychiatric symptoms 1 year after COVID-19 calling for interdisciplinary management of these patients.

Factors associated with impaired quality of life three months after being diagnosed with COVID-19.

PURPOSE: To assess patient characteristics associated with health-related quality of life (HR-QoL) and its mental and physical subcategories 3 months after diagnosis with COVID-19. METHODS: In this prospective multicentre cohort study, HR-QoL was assessed in 90 patients using the SF-36 questionnaire (36-item Short Form Health Survey), which consists of 8 health domains that can be divided into a mental and physical health component. Mental health symptoms including anxiety, depression, and post-traumatic stress disorders were evaluated using the Hospital Anxiety and Depression Scale (HADS) and Post-traumatic Stress Disorder Checklist-5 (PCL-5) 3 months after COVID-19. Using descriptive statistics and multivariable regression analysis, we identified factors associated with impaired HR-QoL 3 months after COVID-19 diagnosis. RESULTS: Patients were 55 years of age (IQR, 49-63; 39% women) and were classified as severe (23%), moderate (57%), or mild (20%) according to acute disease severity. HR-QoL was impaired in 28/90 patients (31%). Younger age [per year, adjOR (95%CI) 0.94 (0.88-1.00), p = 0.049], longer hospitalization [per day, adjOR (95%CI) 1.07 (1.01-1.13), p = 0.015], impaired sleep [adjOR (95%CI) 5.54 (1.2-25.61), p = 0.028], and anxiety [adjOR (95%CI) 15.67 (3.03-80.99), p = 0.001) were independently associated with impaired HR-QoL. Twenty-nine percent (n = 26) scored below the normal range on the mental health component of the SF-36 and independent associations emerged for anxiety, depression, and self-reported numbness. Impairments in the physical health component of the SF-36 were reported by 12 (13%) patients and linked to hypogeusia and fatigue. CONCLUSION: Every third patient reported a reduction in HR-QoL 3 months after COVID-19 diagnosis and impairments were more prominent in mental than physical well-being.

Factors Associated With Prolonged Mechanical Ventilation in Patients With Subarachnoid Hemorrhage-The RAISE Score.

OBJECTIVES: Patients suffering from spontaneous subarachnoid hemorrhage frequently require mechanical ventilation. Here, we aimed to identify factors associated with prolonged mechanical ventilation in subarachnoid hemorrhage patients and to create a new predictive score for prolonged mechanical ventilation. DESIGN: Prospective cohort study with retrospective data analysis. SETTING: Neurocritical care unit at a tertiary academic medical center. PATIENTS: Two hundred ninety-seven consecutive nontraumatic adult subarachnoid hemorrhage patients. METHODS: In patients with mechanical ventilation, we identified factors associated with mechanical ventilation greater than 48 hours, greater than 7 days, and greater than 14 days compared with mechanical ventilation less than or equal to 48 hours, less than or equal to 7 days, or less than or equal to 14 days in multivariable generalized linear models. Ventilated patients who died before 48 hours, 7 days, or 14 days and those never ventilated were excluded from the respective analysis. We incorporated those factors into a new prognostic score (the RAISE score) to predict prolonged mechanical ventilation greater than 7 days. The calculation was based on a random dataset of 60% of subarachnoid hemorrhage patients and was internally validated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were 57 years old (interquartile range, 47-68 yr) and presented with a median Hunt and Hess grade of 3 (1-5). Two hundred forty-two patients (82%) required mechanical ventilation for 9 days (2-20 d). In multivariable analysis, a higher Acute Physiology Score was associated with mechanical ventilation greater than 48 hours, greater than 7 days, and greater than 14 days, a higher Hunt and Hess grade with greater than 7 days and greater than 14 days. Early neuroimaging findings were associated with mechanical ventilation greater than 48 hours (hydrocephalus; high-grade Subarachnoid Hemorrhage Early Brain Edema Score), greater than 7 days (high-grade Subarachnoid Hemorrhage Early Brain Edema Score, co-occurrence of intracerebral bleeding) but not with prolonged mechanical ventilation greater than 14 days. The RAISE score, including age, Acute Physiology Score, Hunt and Hess grade, Subarachnoid Hemorrhage Early Brain Edema Score, and the co-occurrence of intracerebral hemorrhage accurately stratified patients by prolonged mechanical ventilation greater than 7 days (C-statistic 0.932). A RAISE score of 12 predicted 60% likelihood of mechanical ventilation greater than 7 days. CONCLUSIONS: Initial disease severity and neuroimaging findings detected within 24 hours after ICU admission were associated with the need for prolonged mechanical ventilation in patients with subarachnoid hemorrhage. These results may be helpful for patient families and caregivers to better anticipate the course of therapy.

The effect of the volemic and cardiac status on brain oxygenation in patients with subarachnoid hemorrhage: a bi-center cohort study.

BACKGROUND: Fluid management in patients after subarachnoid hemorrhage (SAH) aims at the optimization of cerebral blood flow and brain oxygenation. In this study, we investigated the effects of hemodynamic management on brain oxygenation by integrating advanced hemodynamic and invasive neuromonitoring. METHODS: This observational cohort bi-center study included data of consecutive poor-grade SAH patients who underwent pulse contour cardiac output (PiCCO) monitoring and invasive neuromonitoring. Fluid management was guided by the transpulmonary thermodilution system and aimed at euvolemia (cardiac index, CI ≥ 3.0 L/min/m2; global end-diastolic index, GEDI 680-800 mL/m2; stroke volume variation, SVV < 10%). Patients were managed using a brain tissue oxygenation (PbtO2) targeted protocol to prevent brain tissue hypoxia (BTH, PbtO2 < 20 mmHg). To assess the association between CI and PbtO2 and the effect of fluid challenges on CI and PbtO2, we used generalized estimating equations to account for repeated measurements. RESULTS: Among a total of 60 included patients (median age 56 [IQRs 47-65] years), BTH occurred in 23% of  the monitoring time during the first 10 days since admission. Overall, mean CI was within normal ranges (ranging from 3.1 ± 1.3 on day 0 to 4.1 ± 1.1 L/min/m2 on day 4). Higher CI levels were associated with higher PbtO2 levels (Wald = 14.2; p < 0.001). Neither daily fluid input nor fluid balance was associated with absolute PbtO2 levels (p = 0.94 and p = 0.85, respectively) or the occurrence of BTH (p = 0.68 and p = 0.71, respectively). PbtO2 levels were not significantly different in preload dependent patients compared to episodes of euvolemia. PbtO2 increased as a response to fluid boluses only if BTH was present at baseline (from 13 ± 6 to 16 ± 11 mmHg, OR = 13.3 [95% CI 2.6-67.4], p = 0.002), but not when all boluses were considered (p = 0.154). CONCLUSIONS: In this study a moderate association between increased cardiac output and brain oxygenation was observed. Fluid challenges may improve PbtO2 only in the presence of baseline BTH. Individualized hemodynamic management requires advanced cardiac and brain monitoring in critically ill SAH patients.

Individualized blood pressure targets in the postoperative care of patients with intracerebral hemorrhage.

OBJECTIVE: Recent guidelines recommend targeting a systolic blood pressure (SBP) < 140 mm Hg in the early management of patients with spontaneous intracerebral hemorrhage (ICH). The optimal SBP targets for ICH patients after hematoma evacuation (HE) remain unclear. Here, the authors aimed to define the optimal SBP range based on multimodal neuromonitoring data. METHODS: Forty poor-grade ICH patients who had undergone HE and then monitoring of intracerebral pressure, brain tissue oxygen tension (PbtO2), and cerebral metabolism (via cerebral microdialysis [CMD]) were prospectively included. Episodes of brain tissue hypoxia (BTH) (1-hour averaged PbtO2 < 20 mm Hg) and metabolic distress (CMD-lactate/pyruvate ratio [LPR] ≥ 40) were identified and linked to corresponding parameters of hemodynamic monitoring (SBP and cerebral perfusion pressure [CPP]). Multivariable regression analysis was performed using generalized estimating equations to identify associations between SBP levels, PbtO2, and brain metabolism. RESULTS: The mean patient age was 60 (range 51-66) years and the median [IQR] initial ICH volume was 47 [29-60] ml. In multivariable models adjusted for Glasgow Coma Scale score, probe location, ICH volume, and age, lower SBP was independently associated with a higher risk of BTH (≤ 120 mm Hg: adjusted OR 2.9, p = 0.007; 120-130 mm Hg: adj OR 2.4, p = 0.002; 130-140 mm Hg: adj OR 1.6, p = 0.017) compared to a reference range of 140-150 mm Hg at the level of the foramen interventriculare Monroi, which corresponded to a CPP of 70-80 mm Hg and SBP levels between 150 and 160 mm Hg at the heart level. After exclusion of episodes with mitochondrial dysfunction, SBP targets < 140 mm Hg were associated with higher odds of cerebral metabolic distress (≤ 130 mm Hg: OR 2.5, p = 0.041; 130-140 mm Hg: OR 2.3, p = 0.033). Patients with a modified Rankin Scale score ≥ 5 at neurological ICU discharge more often exhibited BTH than patients with better outcomes (51% vs 10%, p = 0.003). CONCLUSIONS: These data suggest that lower SPB and CPP levels are associated with a higher risk for BTH. Further studies are needed to evaluate whether a higher SPB target may prevent BTH and improve outcomes.

Hyperactive delirium in patients after non-traumatic subarachnoid hemorrhage.

PURPOSE: Hyperactive delirium is common after subarachnoid hemorrhage (SAH). We aimed to identify risk factors for delirium and to evaluate its impact on outcome. METHODS: We collected daily Richmond Agitation Sedation Scale (RASS) and Intensive Care Delirium Screening Checklist (ICDSC) scores in 276 SAH patients. Hyperactive delirium was defined as ICDSC ≥4 when RASS was >0. We investigated risk factors for delirium and its association with 3-month functional outcome using generalized linear models. RESULTS: Patients were 56 (IQR 47-67) years old and had a Hunt&Hess (H&H) grade of 3 (IQR 1-5). Sixty-five patients (24%) developed hyperactive delirium 6 (IQR 3-16) days after SAH. In multivariable analysis, mechanical ventilation>48 h (adjOR = 4.46; 95%-CI = 1.89-10.56; p = 0.001), the detection of an aneurysm (adjOR = 4.38; 95%-CI = 1.48-12.97; p = 0.008), a lower H&H grade (adjOR = 0.63; 95%-CI = 0.48-0.83; p = 0.001) and a pre-treated psychiatric disorder (adjOR = 3.17; 95%-CI = 1.14-8.83; p = 0.027) were associated with the development of delirium. Overall, delirium was not associated with worse outcome (p = 0.119). Interestingly, patients with delirium more often had a modified Rankin Scale Score (mRS) of 1-3 (77%) compared to an mRS of 0 (14%) or 4-6 (9%). CONCLUSION: Our data indicate that hyperactive delirium is common after SAH patients and requires a certain degree of brain connectivity based ono the highest prevalence found in SAH patients with intermediate outcomes.

The Importance of PbtO2 Probe Location for Data Interpretation in Patients with Intracerebral Hemorrhage.

BACKGROUND/OBJECTIVE: Monitoring of brain tissue oxygen tension (PbtO2) provides insight into brain pathophysiology after intracerebral hemorrhage (ICH). Integration of probe location is recommended to optimize data interpretation. So far, little is known about the importance of PbtO2 catheter location in ICH patients. METHODS: We prospectively included 40 ICH patients after hematoma evacuation (HE) who required PbtO2-monitoring. PbtO2-probe location was evaluated in all head computed tomography (CT) scans within the first 6 days after HE and defined as location in the healthy brain tissue or perilesional when the catheter tip was located within 1 cm of a focal lesion (hypodense or hyperdense). Generalized estimating equations were used to investigate levels of PbtO2 in relation to different probe locations. RESULTS: Patients were 60 [51-66] years old and had a median ICH-volume of 47 [29-60] mL. Neuromonitoring probes remained for a median of 6 [2-11] days. PbtO2-probes were located in healthy brain tissue in 18/40 (45%) patients and in perilesional brain tissue in 22/40 (55%) patients. In the acute phase after HE (0-72 h), PbtO2 levels were significantly lower (21 ± 12 mmHg vs. 29 ± 10 mmHg, p = 0.010) and brain tissue hypoxia (BTH) was more common in the perilesional area as compared to healthy brain tissue (46% vs. 19%, adjOR 4.0, 95% CI 1.54-10.58, p = 0.005). Episodes of BTH significantly decreased over time in patients with probes in perilesional location (p = 0.001) but remained stable in normal appearing area (p = 0.485). A significant association between BTH and poor functional outcome was only found when probes were located in the perilesional brain tissue (adjOR 6.6, 95% CI 1.3-33.8, p = 0.023). CONCLUSIONS: In the acute phase, BTH was more common in the perilesional area compared to healthy brain tissue. The improvement of BTH in the perilesional area over time may be the result of targeted treatment interventions and tissue regeneration. Due to the localized measurement of invasive neuromonitoring devices, integration of probe location in the clinical management of ICH patients and in research protocols seems mandatory.

The Effect of Temperature Increases on Brain Tissue Oxygen Tension in Patients with Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Substudy.

Fever may aggravate secondary brain injury after traumatic brain injury (TBI). The aim of this study was to identify episodes of temperature increases through visual plot analysis and algorithm supported detection, and to describe associated patterns of changes in on brain tissue oxygen tension (PbtO2). Data derive from the high-resolution cohort of the multicenter prospective Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. Temperature increases (≥0.5°C) were visually identified in 33 patients within the first 11 days of monitoring. Generalized estimating equations were used to detect significant changes of systemic and neuromonitoring parameters from baseline to the highest temperature. Patients were median 50 (interquartile range [IQR], 35-62) years old, and presented with a Glasgow Coma Scale (GCS) of 8 (IQR, 4-10). In 202 episodes of temperature increases, mean temperature rose by 1.0°C ± 0.5°C within 4 hours. Overall, PbtO2 slightly increased (ΔPbtO2 = 0.9 ± 6.1 mmHg, p = 0.022) during temperature increases. PbtO2 increased in 35% (p < 0.001), was stable in 49% (p = 0.852), and decreased in 16% (p < 0.001) of episodes. During episodes of temperature increases and simultaneous drops in PbtO2, cerebral perfusion pressure (CPP) decreased (ΔCPP -6.3 ± 11.5 mmHg; p < 0.001). Brain tissue hypoxia (PbtO2 <20 mmHg) developed during 27/164 (17%) episodes of effervescences, in the remaining 38/202 episodes baseline PbtO2 was already <20 mmHg. Comparable results were found when using algorithm-supported detection of temperature increases. In conclusion, during effervescences, PbtO2 was mostly stable or slightly increased. A decrease of PbtO2 was observed in every sixth episode, where it was associated with a decrease in CPP. Our data highlight the need for special attention to CPP monitoring and maintenance during episodes of fever.

Early alterations in heart rate are associated with poor outcome in patients with intracerebral hemorrhage.

PURPOSE: Cardiac complications are common after spontaneous intracerebral hemorrhage (ICH). In this study we intended to investigate factors associated with higher alterations in heart rate and their impact on outcome. METHODS: Eighty-eight ICH patients were included. A simplified approach to calculate heart rate variability (HRSD) in analogy to systolic blood pressure variability (SBPSD) with daily standard deviations of HR in the acute (first 24 h) and subacute phase (day1-day7) was used. Using multivariable regression, factors associated with higher HRSD and the association between higher HRSD and poor 3-month outcome (modified Rankin Scale > 3) were analyzed. All models were adjusted for age, atrial fibrillation, mechanical ventilation, vasopressor administration, and mean HR. RESULTS: Patients were 71 (IQR = 60-79) years old and presented with an admission ICH-Score of 2 (IQR = 1-3). In multivariable analysis, intraventricular hemorrhage (adjOR = 8.66, 95%-CI = 1.89-39.60, p = 0.005), a QRS complex >120 ms (adjOR = 19.02; 95%-CI = 2.08-175.05, p = 0.009) and female sex (adjOR = 4.24; 95%-CI = 1.08-16.64, p = 0.038) were associated with higher HRSD in the acute phase. A higher HRSD (adjOR = 1.29, 95%-CI = 1.01-1.66, p = 0.045) in the acute but not in the subacute phase (p = 0.764) was associated with poor 3-month outcome. CONCLUSION: The study suggests that a higher variation in heart rate in the early phase after ICH may discriminate patients with poor outcome.

Hemodynamic response during endotracheal suctioning predicts awakening and functional outcome in subarachnoid hemorrhage patients.

BACKGROUND: Endotracheal suctioning (ES) provokes a cumulative hemodynamic response by activation of sympathetic and parasympathetic circuits in the central nervous system. In this proof-of-concept study, we aimed to analyze hemodynamic changes during ES in ventilated subarachnoid hemorrhage (SAH) patients and investigated whether the associated hemodynamic changes relate to the time to arousal and functional outcome. METHODS: For the current observational study, 191 SAH patients admitted to the neurological intensive care unit of a tertiary hospital requiring mechanical ventilation were included. One thousand eighty ES episodes during the first 72 h of admission were analyzed. Baseline median heart rate (HR) and mean arterial pressure (MAP) were compared to peak HR and MAP during ES based on 5-min averaged data (ΔHR and ΔMAP). Multivariable analysis to assess associations between ΔHR and ΔMAP and time to arousal (time to Richmond Agitation Sedation Scale ≥ 0, RASS) and poor functional outcome (modified Rankin Scale Score > 2, mRS) was performed using generalized estimating equations. RESULTS: Patients were 59 (IQR, 50-70) years old and presented with a median admission H&H grade of 4 (IQR, 3-5). In-hospital mortality was 22% (25% at 3 months) and median time to arousal was 13 (IQR, 4-21) days. HR increased by 2.3 ± 7.1 beats per minute (bpm) from 75.1 ± 14.8 bpm at baseline. MAP increased by 3.2 ± 7.8 mmHg from baseline 80.9 ± 9.8 mmHg. In multivariable analysis, ΔHR (p < 0.001) was significantly lower in patients who regained consciousness at a later time point and a lower ΔHR was associated with poor functional 3-month outcome independent of RASS (adjOR = 0.95; 95% CI = 0.93-0.98) or midazolam dose (adjOR = 0.96; 95% CI = 0.94-0.98). ΔMAP was neither associated with the time to regain consciousness (p = 0.087) nor with functional outcome (p = 0.263). CONCLUSION: Augmentation in heart rate may quantify the hemodynamic response during endotracheal suctioning in brain-injured patients. The value as a biomarker to early discriminate the time to arousal and functional outcome in acutely brain-injured patients needs prospective confirmation.

Subarachnoid Hemorrhage is Followed by Pituitary Gland Volume Loss: A Volumetric MRI Observational Study.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating disease associated with high mortality and morbidity. Besides neurological sequelae, neuropsychological deficits largely contribute to patients' long-term quality of life. Little is known about the pituitary gland volume (PGV) after SAH compared to healthy referents and the association of PGV with long-term outcome including cognitive function. METHODS: Sixty consecutive non-traumatic SAH patients admitted to the neurological intensive care unit between 2010 and 2014 were enrolled. 3-Tesla magnetic resonance imagining was performed at baseline (16 days) and 12 months after SAH to measure PGV semi-automatically using the software iPlan Net 3.5.0. PGV was compared to age and sex matched healthy referents. The difference between baseline and 1-year-PGV was classified as increase (> 20 mm3 PGV increase), stable (± 20 mm3), or decrease (> 20 mm3 PGV decrease). In addition, total intracerebral volume was calculated. Neuropsychological testing was applied in 43 SAH patients at 1-year follow up encompassing several domains (executive, attention, memory) and self-assessment (questionnaire for self-perceived deficits in attention [German: FEDA]) of distractibility in mental processes, fatigue and decrease in motivation. Multivariable regression with multivariable generalized linear models was used for comparison of PGVs and for subgroup analysis to evaluate a potential association between PGV and neuropsychological outcome. RESULTS: Patients were 53 years old (IQR = 44-63) and presented with a median Hunt&Hess grade of 2 (IQR = 1-3). SAH patients had a significantly lower PGV both at baseline (360 ± 19 mm3, p < 0.001) and 1 year (367 ± 18 mm3p < 0.001) as compared to matched referents (mean 505 ± 18 mm3). PGV decreased by 75 ± 8 mm3 in 28 patients, increased by 120 ± 22 mm3 in 22 patients and remained stable in 10 patients at 1-year follow-up. PGV in patients with PGV increase at 12 months was not different to healthy referents (p = 0.062). Low baseline PGV was associated with impaired executive functions at 1 year (adjOR = 8.81, 95%-CI = 1.46-53.10, p = 0.018) and PGV decrease within 1 year was associated with self-perceived worse motivation (FEDA; Wald-statistic = 6.6, df = 1, p = 0.010). CONCLUSIONS: Our data indicate significantly lower PGVs following SAH. The association of sustained PGV decrease with impaired neuropsychological long-term outcome warrants further investigations including neuroendocrine hormone measurements.

Fluid Intake But Not Fluid Balance Is Associated With Poor Outcome in Nontraumatic Subarachnoid Hemorrhage Patients.

OBJECTIVES: Optimal fluid management is important in patients with acute brain injury, including subarachnoid hemorrhage. We aimed to examine the relationship between daily fluid intake and fluid balance with hospital complications and functional outcome. DESIGN: Retrospective observational cohort study. SETTING: Neurocritical care unit at a tertiary academic medical center. PATIENTS: Two-hundred thirty-seven consecutive nontraumatic subarachnoid hemorrhage patients admitted to the neurologic ICU between 2010 and 2016. INTERVENTIONS: Total daily amount of fluids and fluid balance were calculated over 15 days. Using multivariate generalized estimating equation models the association of daily fluid intake and fluid balance with disease severity, hospital complications and poor functional outcome (3-mo modified Rankin Score ≥ 3) was investigated. Additionally, we described the composition of fluids given. MEASUREMENTS AND MAIN RESULTS: Patients presented with a median admission Hunt and Hess grade of 3 (interquartile range, 1-5) and were 57 years old (interquartile range, 47-67 yr old). A higher daily fluid intake was associated with higher admission Hunt and Hess grade (odds ratio, 1.61; 95% CI, 1.47-1.76; p < 0.001), increased pulmonary fluid accumulation (adjusted odds ratio, 1.11; 95% CI, 1.01-1.21; p = 0.033), prolonged mechanical ventilation (Wald statistic = 20.08; degrees of freedom = 1; p < 0.001), higher daily Subarachnoid hemorrhage Early Brain Edema Score (adjusted odds ratio, 1.11; 95% CI, 1.01-1.22; p = 0.034), occurrence of anemia (adjusted odds ratio, 1.36; 95% CI, 1.20-1.54; p < 0.001), delayed cerebral ischemia (adjusted odds ratio, 1.31; 95% CI, 1.14-1.51; p < 0.001), and poor functional outcome (adjusted odds ratio, 1.25; 95% CI, 1.10-1.41; p < 0.001). Daily fluid balance was associated with higher admission Hunt and Hess grade (odds ratio, 1.09; 95% CI, 1.05-1.13; p < 0.001) and anemia (adjusted odds ratio, 1.17; 95% CI, 1.03-1.33; p = 0.019). The main contributors to fluids were nutritional compounds (31%), IV drugs (30%), and volume substitution (17%). CONCLUSIONS: Our study demonstrates a significant association of fluid intake but not fluid balance with hospital complications and poor functional outcome in subarachnoid hemorrhage patients. A larger prospective study is needed to confirm our results.

Delayed Resolution of Cerebral Edema Is Associated With Poor Outcome After Nontraumatic Subarachnoid Hemorrhage.

Background and Purpose- Global cerebral edema occurs in up to 57% of patients with subarachnoid hemorrhage (SAH) and is associated with prolonged hospital stay and poor outcome. Recently, admission brain edema was successfully graded using a simplified computed tomography-based semiquantitative score (subarachnoid hemorrhage early brain edema score [SEBES]). Longitudinal evaluation of the SEBES grade may discriminate patients with rapid and delayed edema resolution after SAH. Here, we aimed to describe the resolution of brain edema and to study the relationship between this radiographic biomarker and hospital course and outcome after SAH. Methods- For the current observational cohort study, computed tomography scans of 283 consecutive nontraumatic SAH patients admitted to the neurological intensive care unit of a tertiary hospital were graded based on the absence of visible sulci at 2 predefined brain tissue levels in each hemisphere (SEBES ranging from 0 to 4). A score of ≥3 was defined as high-grade SEBES. Multivariable regression models using generalized linear models were used to identify associated factors with delayed edema resolution based on the median time to resolution (SEBES ≤2) in SAH survivors. Results- Patients were 57 years old (interquartile range, 48-68) and presented with a median admission Hunt and Hess grade of 3 (interquartile range, 1-5). High-grade SEBES was common (106/283, 37%) and resolved within a median of 8 days (interquartile range, 4-15) in survivors (N=80). Factors associated with delayed edema resolution were early (<72 hours) hypernatremia (>150 mmol/L; adjusted odds ratio [adjOR], 4.88; 95% CI, 1.68-14.18), leukocytosis (>15 G/L; adjOR, 3.14; 95% CI, 1.24-8.77), hyperchloremia (>121 mmol/L; adjOR, 5.24; 95% CI, 1.64-16.76), and female sex (adjOR, 3.71; 95% CI, 1.01-13.64) after adjusting for admission Hunt and Hess grade and age. Delayed brain edema resolution was an independent predictor of worse functional 3-month outcome (adjOR, 2.52; 95% CI, 1.07-5.92). Conclusions- Our data suggest that repeated quantification of the SEBES can identify SAH patients with delayed edema resolution. Based on its' prognostic value as radiographic biomarker, the SEBES may be integrated in future trials aiming to improve edema resolution after SAH.

Systemic Inflammatory Response Syndrome as Predictor of Poor Outcome in Nontraumatic Subarachnoid Hemorrhage Patients.

OBJECTIVES: Subarachnoid hemorrhage is a life-threatening disease associated with high mortality and morbidity. A substantial number of patients develop systemic inflammatory response syndrome. We aimed to identify risk factors for systemic inflammatory response syndrome development and to evaluate the role of systemic inflammatory response syndrome on patients' outcome. DESIGN: Retrospective observational cohort study of prospectively collected data. SETTING: Neurocritical care unit at a tertiary academic medical center. PATIENTS: Two-hundred and ninety-seven consecutive nontraumatic subarachnoid hemorrhage patients admitted to the neurologic ICU between 2010 and 2017. INTERVENTIONS: Systemic inflammatory response syndrome was diagnosed based on greater than or equal to two criteria (hypo-/hyperthermia, tachypnea, leukopenia/leukocytosis, tachycardia) and defined as early (≤ 3 d) and delayed (days 6-10) systemic inflammatory response syndrome burden (systemic inflammatory response syndrome positive days within the first 10 d). Using multivariate analysis, risk factors for the development of early and delayed systemic inflammatory response syndrome and the relationship of systemic inflammatory response syndrome with poor 3-month functional outcome (modified Rankin Scale score ≥ 3) were analyzed. MEASUREMENTS AND MAIN RESULTS: Seventy-eight percent of subarachnoid hemorrhage patients had early systemic inflammatory response syndrome, and 69% developed delayed systemic inflammatory response syndrome. Median systemic inflammatory response syndrome burden was 60% (interquartile range, 10-90%). Risk factors for early systemic inflammatory response syndrome were higher admission Hunt and Hess grade (odds ratio, 1.75; 95% CI, 1.09-2.83; p = 0.02), aneurysm clipping (odds ratio, 4.84; 95% CI, 1.02-23.05; p = 0.048), and higher modified Fisher Scale score (odds ratio, 1.88; 95% CI, 1.25-2.89; p = 0.003). Hunt and Hess grade and pneumonia were independently associated with delayed systemic inflammatory response syndrome development. Systemic inflammatory response syndrome burden (area under the curve, 0.84; 95% CI, 0.79-0.88) had a higher predictive value for 3-month poor outcome compared with early systemic inflammatory response syndrome (area under the curve, 0.76; 95% CI, 0.70-0.81; p < 0.001). CONCLUSIONS: Systemic inflammatory response syndrome is common after subarachnoid hemorrhage and independently contributes to poor functional outcome. Systemic inflammatory response syndrome burden more accurately predicts poor outcome than early systemic inflammatory response syndrome.