Predicting outcome after aneurysmal subarachnoid hemorrhage by exploitation of signal complexity: a prospective two-center cohort study.

BACKGROUND: Signal complexity (i.e. entropy) describes the level of order within a system. Low physiological signal complexity predicts unfavorable outcome in a variety of diseases and is assumed to reflect increased rigidity of the cardio/cerebrovascular system leading to (or reflecting) autoregulation failure. Aneurysmal subarachnoid hemorrhage (aSAH) is followed by a cascade of complex systemic and cerebral sequelae. In aSAH, the value of entropy has not been established yet. METHODS: aSAH patients from 2 prospective cohorts (Zurich-derivation cohort, Aachen-validation cohort) were included. Multiscale Entropy (MSE) was estimated for arterial blood pressure, intracranial pressure, heart rate, and their derivatives, and compared to dichotomized (1-4 vs. 5-8) or ordinal outcome (GOSE-extended Glasgow Outcome Scale) at 12 months using uni- and multivariable (adjusted for age, World Federation of Neurological Surgeons grade, modified Fisher (mFisher) grade, delayed cerebral infarction), and ordinal methods (proportional odds logistic regression/sliding dichotomy). The multivariable logistic regression models were validated internally using bootstrapping and externally by assessing the calibration and discrimination. RESULTS: A total of 330 (derivation: 241, validation: 89) aSAH patients were analyzed. Decreasing MSE was associated with a higher likelihood of unfavorable outcome independent of covariates and analysis method. The multivariable adjusted logistic regression models were well calibrated and only showed a slight decrease in discrimination when assessed in the validation cohort. The ordinal analysis revealed its effect to be linear. MSE remained valid when adjusting the outcome definition against the initial severity. CONCLUSIONS: MSE metrics and thereby complexity of physiological signals are independent, internally and externally valid predictors of 12-month outcome. Incorporating high-frequency physiological data as part of clinical outcome prediction may enable precise, individualized outcome prediction. The results of this study warrant further investigation into the cause of the resulting complexity as well as its association to important and potentially preventable complications including vasospasm and delayed cerebral ischemia.

MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53.

The MDM2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that MDM2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, MDM2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the MDM2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. MDM2 physically associated with EZH2 on chromatin, enhancing the trimethylation of histone 3 at lysine 27 and the ubiquitination of histone 2A at lysine 119 (H2AK119) at its target genes. Removing MDM2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, MDM2 supports the Polycomb-mediated repression of lineage-specific genes, independent of p53.

Nociceptive and Transcriptomic Responses in a Swine Diabetic Wound Model Treated With a Topical Angiotensin 1 Receptor Antagonist.

BACKGROUND: Painful, treatment-resistant wounds are prevalent among diabetic patients and significantly affect health-related quality of life (HRQOL). Topical treatments may help alleviate pain without risk of dependence or side effects. However, there is a lack of topical wound compounds targeting pain-specific receptors. One possible target is proinflammatory angiotensin 1 receptor (AT1R), which is upregulated in diabetic skin and has been implicated in nociception. OBJECTIVES: We investigated the effects of topical valsartan, an AT1R antagonist, on pain (nociceptive thresholds) and gene expression changes (transcriptomics) in a swine model of diabetic wounds. METHODS: Eight wounds were surgically induced in diabetic, hyperglycemic Yucatan miniature swine ( n = 4). Topical AT1R antagonist was applied to wounds on one side and vehicle on the other side. Nocifensive testing was conducted at baseline and then weekly, beginning 7 days after wound induction. Mechanical and thermal stimuli were applied to the wound margins until a nocifensive reaction was elicited or a predetermined cutoff was reached. After 7 weeks of testing, tissue from the dorsal horn, dorsal root ganglion, and wounds were sequenced and analyzed with DESeq2. Unbiased pathway analyses using Metascape were conducted on differentially expressed genes. RESULTS: There was no significant difference in mechanical tolerance threshold between AT1R antagonist-treated and vehicle-treated wounds ( p = .106). Thermal tolerance was significantly higher in AT1R antagonist-treated wounds compared to vehicle-treated ( p = .015). Analysis of differentially expressed genes revealed enriched pathways of interest: interleukin-18 signaling in dorsal horn laminae IV-V and sensory perception of mechanical stimulus in wound tissue. DISCUSSION: In this study, wounds modeling diabetic ulcers were created in hyperglycemic swine and treated with a topical AT1R antagonist. AT1R-antagonist-treated wounds had a higher tolerance threshold than vehicle-treated wounds for thermal hyperalgesia, but not mechanical allodynia. Pathway analyses of differentially expressed genes revealed several pathways of interest for future pain research. Although further studies are needed to confirm the findings, this study can improve nursing care by providing information about a potential future treatment that may be used to decrease pain and improve HRQOL in patients with diabetic wounds.

Optimal Cerebral Perfusion Pressure and Brain Tissue Oxygen in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Targeting a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) has been gaining more attention to prevent secondary damage after acute neurological injury. Brain tissue oxygenation (PbtO2) can identify insufficient cerebral blood flow and secondary brain injury. Defining the relationship between CPPopt and PbtO2 after aneurysmal subarachnoid hemorrhage may result in (1) mechanistic insights into whether and how CPPopt-based strategies might be beneficial and (2) establishing support for the use of PbtO2 as an adjunctive monitor for adequate or optimal local perfusion. METHODS: We performed a retrospective analysis of a prospectively collected 2-center dataset of patients with aneurysmal subarachnoid hemorrhage with or without later diagnosis of delayed cerebral ischemia (DCI). CPPopt was calculated as the cerebral perfusion pressure (CPP) value corresponding to the lowest pressure reactivity index (moving correlation coefficient of mean arterial and intracranial pressure). The relationship of (hourly) deltaCPP (CPP-CPPopt) and PbtO2 was investigated using natural spline regression analysis. Data after DCI diagnosis were excluded. Brain tissue hypoxia was defined as PbtO2 <20 mmHg. RESULTS: One hundred thirty-one patients were included with a median of 44.0 (interquartile range, 20.8-78.3) hourly CPPopt/PbtO2 datapoints. The regression plot revealed a nonlinear relationship between PbtO2 and deltaCPP (P<0.001) with PbtO2 decrease with deltaCPP <0 mmHg and stable PbtO2 with deltaCPP ≥0mmHg, although there was substantial individual variation. Brain tissue hypoxia (34.6% of all measurements) was more frequent with deltaCPP <0 mmHg. These dynamics were similar in patients with or without DCI. CONCLUSIONS: We found a nonlinear relationship between PbtO2 and deviation of patients' CPP from CPPopt in aneurysmal subarachnoid hemorrhage patients in the pre-DCI period. CPP values below calculated CPPopt were associated with lower PbtO2. Nevertheless, the nature of PbtO2 measurements is complex, and the variability is high. Combined multimodality monitoring with CPP/CPPopt and PbtO2 should be recommended to redefine individual pressure targets (CPP/CPPopt) and retain the option to detect local perfusion deficits during DCI (PbtO2), which cannot be fulfilled by both measurements interchangeably.

The oxygen reactivity index indicates disturbed local perfusion regulation after aneurysmal subarachnoid hemorrhage: an observational cohort study.

BACKGROUND: Cerebral autoregulation (CA) can be impaired in patients with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). The Pressure Reactivity Index (PRx, correlation of blood pressure and intracranial pressure) and Oxygen Reactivity Index (ORx, correlation of cerebral perfusion pressure and brain tissue oxygenation, PbtO2) are both believed to estimate CA. We hypothesized that CA could be poorer in hypoperfused territories during DCI and that ORx and PRx may not be equally effective in detecting such local variances. METHODS: ORx and PRx were compared daily in 76 patients with aSAH with or without DCI until the time of DCI diagnosis. The ICP/PbtO2-probes of DCI patients were retrospectively stratified by being in or outside areas of hypoperfusion via CT perfusion image, resulting in three groups: DCI + /probe + (DCI patients, probe located inside the hypoperfused area), DCI + /probe- (probe outside the hypoperfused area), DCI- (no DCI). RESULTS: PRx and ORx were not correlated (r = - 0.01, p = 0.56). Mean ORx but not PRx was highest when the probe was located in a hypoperfused area (ORx DCI + /probe + 0.28 ± 0.13 vs. DCI + /probe- 0.18 ± 0.15, p < 0.05; PRx DCI + /probe + 0.12 ± 0.17 vs. DCI + /probe- 0.06 ± 0.20, p = 0.35). PRx detected poorer autoregulation during the early phase with relatively higher ICP (days 1-3 after hemorrhage) but did not differentiate the three groups on the following days when ICP was lower on average. ORx was higher in the DCI + /probe + group than in the other two groups from day 3 onward. ORx and PRx did not differ between patients with DCI, whose probe was located elsewhere, and patients without DCI (ORx DCI + /probe- 0.18 ± 0.15 vs. DCI- 0.20 ± 0.14; p = 0.50; PRx DCI + /probe- 0.06 ± 0.20 vs. DCI- 0.08 ± 0.17, p = 0.35). CONCLUSIONS: PRx and ORx are not interchangeable measures of autoregulation, as they likely measure different homeostatic mechanisms. PRx represents the classical cerebrovascular reactivity and might be better suited to detect disturbed autoregulation during phases with moderately elevated ICP. Autoregulation may be poorer in territories affected by DCI. These local perfusion disturbances leading up to DCI may be more readily detected by ORx than PRx. Further research should investigate their robustness to detect DCI and to serve as a basis for autoregulation-targeted treatment after aSAH.

Path to success: female leaders in German neurosurgery.

Despite advances in gender equality, only 6% of German neurosurgical departments are currently led by women. With regard to their pioneering work and the importance of their role model effect, we aimed at reporting on the career pathways of the present and former female chairs of neurosurgical departments in Germany. We approached current and former female chairs in German neurosurgery and gathered descriptive information on their ways into leadership positions through structured interviews. Data were obtained from 16/22 (72.7%) female neurosurgical chairs, aged between 44 and 82 years. They completed their training within 6.5 ± 0.6 years, and it took them further 14.5 ± 5.9 years between training completion and chair acquisition. Having obtained their chair positions between 1993 and 2020, six (37.5%) of them have retired or changed career tracks. Of ten (62.5%) chairs still practicing, two are directors of university departments. Twelve (75.0%) hold professorships. Nine chairs (56.3%) are married, eight (50.0%) having children. Five chairs reported having experienced gender-based discrimination. Twelve had a male mentor or role model, two had a female role model, while only one had a female mentor. This study characterizes the to date small number of female neurosurgical chairs in Germany and their paths to neurosurgical leadership positions. In future, these should become historical in order to perceive the presence of women in leadership positions as self-evident normality, reflecting our society. However, further analyses comparing paths of both female and male neurosurgical chairs are necessary to explore gender-based differences in achieving neurosurgical leadership positions.

Defining Age-related OSA Features in Robin Sequence Using Polysomnographic-based Analyses of Respiratory Arousal Responses and Gas-exchange Parameters.

INTRODUCTION: Robin sequence (RS) is a leading cause of obstructive sleep apnea (OSA) in newborns. Most studies have focused on understanding anatomic factors leading to OSA and changes in apnea-hypopnea index (AHI) on polysomnography (PSG) beyond the neonatal period. This study aims to define age-related OSA features between patients with RS, without RS and healthy controls using PSG-based analyses of respiratory arousal responses and gas-exchange parameters. DESIGN: Retrospective comparison of PSG features in a total of 48 children encompassing three groups: (a) infants with RS (n = 24, <1-year old), (b) non-RS older children (1-2 years old) with severe OSA (obstructive AHI (OAHI) of ≥10 events; n = 12), and (c) control infants and children (0-2 years old) without sleep apnea (OAHI ≤1.5/h, n = 12). We examined OSA sleep-stage specific and position-specific indexes, and the relationship between OSA severity and respiratory arousal indexes (OAHI/respiratory arousal indexes). RESULTS: OSA sleep-stage specific indexes (rapid eye movement [REM] vs non-REM[NREM]) as well as position-specific indexes (supine vs nonsupine) were similar in individuals with and without RS. Relative to the non-RS groups, infants with RS have more sustained hypoxemia (time with SpO2 < 90%) and reduced arousal responses to OSA demonstrated by higher OAHI/respiratory arousal indexes. OAHI/respiratory arousal indexes significantly correlated with the severity of hypoxemia in infants with RS. CONCLUSION: Infants with RS and OSA show reduced arousal responses to apneic events, which correlates with higher hypoxemia severity. OAHI/respiratory arousal indexes in RS may identify high-risk individuals with upper airway obstruction and reduced arousal protective responses.

Intraarterial Nimodipine Versus Induced Hypertension for Delayed Cerebral Ischemia: A Modified Treatment Protocol.

BACKGROUND: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IANonly) treatment protocol for refractory DCI in an observational study. METHODS: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IANonly). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4-5). RESULTS: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IANonly 0.26±0.20 µg/kg per minute, P<0.0001) and minor complications (15.0% versus 48.3%, unadjusted odds ratio, 0.19 [95% CI, 0.05-0.79]; P<0.05) with comparable rates of major complications (20.0% versus 20.7%, odds ratio, 0.96 [0.23-3.95]; P=0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37-3.66]; P=0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55-6.39]; P=0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P<0.01). CONCLUSIONS: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

Optimal Cerebral Perfusion Pressure During Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: The recommendation of induced hypertension for delayed cerebral ischemia treatment after aneurysmal subarachnoid hemorrhage has been challenged recently and ideal pressure targets are missing. A new concept advocates an individual cerebral perfusion pressure where cerebral autoregulation functions best to ensure optimal global perfusion. We characterized optimal cerebral perfusion pressure at time of delayed cerebral ischemia and tested the conformity of induced hypertension with this target value. DESIGN: Retrospective analysis of prospectively collected data. SETTING: University hospital neurocritical care unit. PATIENTS: Thirty-nine aneurysmal subarachnoid hemorrhage patients with invasive neuromonitoring (20 with delayed cerebral ischemia, 19 without delayed cerebral ischemia). INTERVENTIONS: Induced hypertension greater than 180 mm Hg systolic blood pressure. MEASUREMENTS AND MAIN RESULTS: Changepoint analysis was used to calculate significant changes in cerebral perfusion pressure, optimal cerebral perfusion pressure, and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure 48 hours before delayed cerebral ischemia diagnosis. Optimal cerebral perfusion pressure increased 30 hours before the onset of delayed cerebral ischemia from 82.8 ± 12.5 to 86.3 ± 11.4 mm Hg (p < 0.05). Three hours before delayed cerebral ischemia, a changepoint was also found in the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure (decrease from -0.2 ± 11.2 to -7.7 ± 7.6 mm Hg; p < 0.05) with a corresponding increase in pressure reactivity index (0.09 ± 0.33 to 0.19 ± 0.37; p < 0.05). Cerebral perfusion pressure at time of delayed cerebral ischemia was lower than in patients without delayed cerebral ischemia in a comparable time frame (cerebral perfusion pressure delayed cerebral ischemia 81.4 ± 8.3 mm Hg, no delayed cerebral ischemia 90.4 ± 10.5 mm Hg; p < 0.05). Inducing hypertension resulted in a cerebral perfusion pressure above optimal cerebral perfusion pressure (+12.4 ± 8.3 mm Hg; p < 0.0001). Treatment response (improvement of delayed cerebral ischemia: induced hypertension+ [n = 15] or progression of delayed cerebral ischemia: induced hypertension- [n = 5]) did not correlate to either absolute values of cerebral perfusion pressure or optimal cerebral perfusion pressure, nor the resulting difference (cerebral perfusion pressure [p = 0.69]; optimal cerebral perfusion pressure [p = 0.97]; and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure [p = 0.51]). CONCLUSIONS: At the time of delayed cerebral ischemia occurrence, there is a significant discrepancy between cerebral perfusion pressure and optimal cerebral perfusion pressure with worsening of autoregulation, implying inadequate but identifiable individual perfusion. Standardized induction of hypertension resulted in cerebral perfusion pressures that exceeded individual optimal cerebral perfusion pressure in delayed cerebral ischemia patients. The potential benefit of individual blood pressure management guided by autoregulation-based optimal cerebral perfusion pressure should be explored in future intervention studies.

Individualized cerebral perfusion pressure in acute neurological injury: are we ready for clinical use?

PURPOSE OF REVIEW: Individualizing cerebral perfusion pressure based on cerebrovascular autoregulation assessment is a promising concept for neurological injuries where autoregulation is typically impaired. The purpose of this review is to describe the status quo of autoregulation-guided protocols and discuss steps towards clinical use. RECENT FINDINGS: Retrospective studies have indicated an association of impaired autoregulation and poor clinical outcome in traumatic brain injury (TBI), hypoxic-ischemic brain injury (HIBI) and aneurysmal subarachnoid hemorrhage (aSAH). The feasibility and safety to target a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) after TBI was recently assessed by the COGITATE trial. Similarly, the feasibility to calculate a MAP target (MAPopt) based on near-infrared spectroscopy was demonstrated for HIBI. Failure to meet CPPopt is associated with the occurrence of delayed cerebral ischemia in aSAH but interventional trials in this population are lacking. No level I evidence is available on potential effects of autoregulation-guided protocols on clinical outcomes. SUMMARY: The effect of autoregulation-guided management on patient outcomes must still be demonstrated in prospective, randomized, controlled trials. Selection of disease-specific protocols and endpoints may serve to evaluate the overall benefit from such approaches.

Baseline characteristics and outcome for aneurysmal versus non-aneurysmal subarachnoid hemorrhage: a prospective cohort study.

This study aims to investigate the characteristics of patients with mild aneurysmal and non-aneurysmal perimesencephalic and non-perimesencephalic subarachnoid hemorrhage (aSAH, pmSAH, npmSAH) with emphasis on admission biomarkers, clinical course, and outcome. A prospective cohort of 115 patients with aSAH (Hunt and Hess 1-3) and of 35 patients without aneurysms (16 pmSAH and 19 npmSAH) admitted between January 2014 and January 2020 was included. Demographic data, blood samples on admission, complications (hydrocephalus, shunt dependency, delayed cerebral ischemia DCI, DCI-related infarction, and mortality), and outcome after 6 months were analyzed. Demographic data was comparable between all groups except for age (aSAH 55 [48-65] vs. npmSAH 60 [56-68] vs. pmSAH 52 [42-60], p = 0.032) and loss of consciousness (33% vs. 0% vs. 0%, p = 0.0004). Admission biomarkers showed poorer renal function and highest glucose levels for npmSAH patients. Complication rate in npmSAH was high and comparable to that of aSAH patients (hydrocephalus, shunt dependency, DCI, DCI-related infarction, mortality), but nearly absent in patients with pmSAH. Favorable outcome after 6 months was seen in 92.9% of pmSAH, 83.3% of npmSAH, and 62.7% of aSAH (p = 0.0264). In this prospective cohort of SAH patients, npmSAH was associated with a complicated clinical course, comparable to that of patients with aSAH. In contrast, such complications were nearly absent in pmSAH patients, suggesting fundamental differences in the pathophysiology of patients with different types of non-aneurysmal hemorrhage. Our findings underline the importance for a precise terminology according the hemorrhage etiology as a basis for more vigilant management of npmSAH patients. NCT02142166, 05/20/2014, retrospectively registered.

Decompressive hemicraniectomy after aneurysmal subarachnoid hemorrhage-justifiable in light of long-term outcome?

PURPOSE: Decompressive hemicraniectomy (DHC) is a potentially lifesaving procedure in refractory intracranial hypertension, which can prevent death from brainstem herniation but may cause survival in a disabled state. The spectrum of indications is expanding, and we present long-term results in a series of patients suffering from aneurysmal subarachnoid hemorrhage (SAH). METHODS: We performed a retrospective analysis of previously registered data including all patients treated for SAH between 2010 and 2018 in a single institution. Patients treated with decompressive hemicraniectomy due to refractory intracranial hypertension were identified. Clinical outcome was assessed by means of the Glasgow outcome scale after 12 months. RESULTS: Of all 341 SAH cases, a total of 82 (24.0%) developed intracranial hypertension. Of those, 63 (18.5%) patients progressed into refractory ICP elevation and were treated with DHC. Younger age (OR 0.959, 95% CI 0.933 to 0.984; p = 0.002), anterior aneurysm location (OR 0.253, 95% CI 0.080 to 0.799; 0.019; p = 0.019), larger aneurysm size (OR 1.106, 95% CI 1.025 to 1.194; p = 0.010), and higher Hunt and Hess grading (OR 1.944, 95% CI 1.431 to 2.641; p < 0.001) were independently associated with the need for DHC. After 1 year, 10 (15.9%) patients after DHC were categorized as favorable outcome. Only younger age was independently associated with favorable outcome (OR 0.968 95% CI 0.951 to 0.986; p = 0.001). CONCLUSIONS: Decompressive hemicraniectomy, though lifesaving, has only a limited probability of survival in a clinically favorable condition. We identified young age to be the sole independent predictor of favorable outcome after DHC in SAH.

Incremental Versus Immediate Induction of Hypertension in the Treatment of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) is a common complication of aneurysmal subarachnoid hemorrhage and contributes to unfavorable outcome. In patients with deterioration despite prophylactic nimodipine treatment, induced hypertension (iHTN) can be considered, although the safety and efficacy of induction are still a matter of debate. In this study, two iHTN treatment algorithms were compared with different approaches toward setting pressure targets. METHODS: In a cohort of 325 consecutive patients with subarachnoid hemorrhage, 139 patients were treated by induced hypertension as a first tier treatment. On diagnosing DCI, blood pressure was raised via norepinephrine infusion in 20-mm Hg increments in 37 patients (iHTNincr), whereas 102 patients were treated by immediate elevation to systolic pressure above 180 mm Hg (iHTNimm). Treatment choice was based on personal preference of the treating physician but with a gradual shift away from incremental elevation. Both groups were evaluated for DCI-caused infarction, the need of additional endovascular rescue treatment, the occurrence of pressor-treatment-related complications, and clinical outcome assessed by the extended Glasgow outcome scale after 12 months. RESULTS: The rate of refractory DCI requiring additional rescue therapy was comparable in both groups (48.9% in iHTNincr, 40.0% in iHTNimm; p = 0.332). The type of induced hypertension was not independently associated with the occurrence of DCI-related infarction in a logistic regression model (odds ratio 1.004; 95% confidence interval 0.329-3.443; p = 0.942). Similar rates of pressor-treatment-related complications were observed in both treatment groups. Favorable outcome was reached in 44 (43.1%) patients in the immediate vs. 10 (27.0%) patients in the incremental treatment group (p = 0.076). However, only Hunt and Hess grading was identified as an independent predictor variable of clinical outcome (odds ratio 0.422; 95% confidence interval 0.216-0.824; p = 0.012). CONCLUSIONS: Immediate induction of hypertension with higher pressure targets did not result in a lower rate of DCI-related infarctions but was not associated with a higher complication rate compared with an incremental approach. Future tailored blood pressure management based on patient- and time-point-specific needs will hopefully better balance the neurological advantages versus the systemic complications of induced hypertension.

Revisiting the Timeline of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: Toward a Temporal Risk Profile.

BACKGROUND: Delayed cerebral ischemia (DCI) is one of the main determinants of clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). The classical description of risk for DCI over time is currently based on the outdated concept of angiographic vasospasm. The goal of this study was to assess the temporal risk profile of DCI, defined by extended clinical and radiological criteria, as well as the impact the time point of DCI onset has on clinical outcome. METHODS: All patients with aneurysmal SAH referred to a single tertiary care center between 2010 and 2018 were considered for inclusion. This study was designed as a retrospective cohort analysis and data were extracted from existing patient files. In conscious patients, DCI was diagnosed clinically, and in unconscious patients, diagnosis was based on perfusion computed tomography imaging and multimodal neuromonitoring. Extended Glasgow Outcome Scale scores were assessed after 12 months and compared between patients with early (< day 7) and late (≥ day 7) DCI onset. RESULTS: The median delay from day of the hemorrhage (day 0) until detection of the first DCI event was 7.0 days, with an interquartile range of 5 days. The probability of DCI development over time demonstrated a bimodal distribution with a peak risk on day 5 (0.084; confidence interval 0.05.5-0.122) and a second peak on day 9 (0.077; confidence interval 0.045-0.120). A total of 27 patients (15.6%) suffered dominant hemispheric or severe bilateral DCI-related infarctions, resulting in the withdrawal of technical life support. Of those, the majority (20 patients, 22.2%) presented with early DCI onset (vs. late onset: 7 patients, 8.4%; p = 0.013). CONCLUSIONS: The risk profile of DCI over time mirrors the description of angiographic vasospasm; however, it comes with an added timely delay of 1 to 2 days. Early occurrence of DCI (before day 7) is associated with a higher infarct load and DCI-related mortality. Although the exact causal relationship remains to be determined, the time point of DCI onset may serve as an independent prognostic criterion in decision-making.

Vector Angle Analysis of Multimodal Neuromonitoring Data for Continuous Prediction of Delayed Cerebral Ischemia.

BACKGROUND: Dysfunctional cerebral autoregulation often precedes delayed cerebral ischemia (DCI). Currently, there are no data-driven techniques that leverage this information to predict DCI in real time. Our hypothesis is that information using continuous updated analyses of multimodal neuromonitoring and cerebral autoregulation can be deployed to predict DCI. METHODS: Time series values of intracranial pressure, brain tissue oxygenation, cerebral perfusion pressure (CPP), optimal CPP (CPPOpt), ΔCPP (CPP - CPPOpt), mean arterial pressure, and pressure reactivity index were combined and summarized as vectors. A validated temporal signal angle measurement was modified into a classification algorithm that incorporates hourly data. The time-varying temporal signal angle measurement (TTSAM) algorithm classifies DCI at varying time points by vectorizing and computing the angle between the test and reference time signals. The patient is classified as DCI+ if the error between the time-varying test vector and DCI+ reference vector is smaller than that between the time-varying test vector and DCI- reference vector. Finally, prediction at time point t is calculated as the majority voting over all the available signals. The leave-one-patient-out cross-validation technique was used to train and report the performance of the algorithms. The TTSAM and classifier performance was determined by balanced accuracy, F1 score, true positive, true negative, false positive, and false negative over time. RESULTS: One hundred thirty-one patients with aneurysmal subarachnoid hemorrhage who underwent multimodal neuromonitoring were identified from two centers (Columbia University: 52 [39.7%], Aachen University: 79 [60.3%]) and included in the analysis. Sixty-four (48.5%) patients had DCI, and DCI was diagnosed 7.2 ± 3.3 days after hemorrhage. The TTSAM algorithm achieved a balanced accuracy of 67.3% and an F1 score of 0.68 at 165 h (6.9 days) from bleed day with a true positive of 0.83, false positive of 0.16, true negative of 0.51, and false negative of 0.49. CONCLUSIONS: A TTSAM algorithm using multimodal neuromonitoring and cerebral autoregulation calculations shows promise to classify DCI in real time.

Invasive Multimodal Neuromonitoring in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review.

Background and Purpose: Aneurysmal subarachnoid hemorrhage is a devastating disease leaving surviving patients often severely disabled. Delayed cerebral ischemia (DCI) has been identified as one of the main contributors to poor clinical outcome after subarachnoid hemorrhage. The objective of this review is to summarize existing clinical evidence assessing the diagnostic value of invasive neuromonitoring (INM) in detecting DCI and provide an update of evidence since the 2014 consensus statement on multimodality monitoring in neurocritical care. Methods: Three invasive monitoring techniques were targeted in the data collection process: brain tissue oxygen tension (ptiO2), cerebral microdialysis, and electrocorticography. Prospective and retrospective studies as well as case series (≥10 patients) were included as long as monitoring was used to detect DCI or guide DCI treatment. Results: Forty-seven studies reporting INM in the context of DCI were included (ptiO2: N=21; cerebral microdialysis: N=22; electrocorticography: N=4). Changes in brain oxygen tension are associated with angiographic vasospasm or reduction in regional cerebral blood flow. Metabolic monitoring with trend analysis of the lactate to pyruvate ratio using cerebral microdialysis, identifies patients at risk for DCI. Clusters of cortical spreading depolarizations are associated with clinical neurological worsening and cerebral infarction in selected patients receiving electrocorticography monitoring. Conclusions: Data supports the use of INM for the detection of DCI in selected patients. Generalizability to all subarachnoid hemorrhage patients is limited by design bias of available studies and lack of randomized trials. Continuous data recording with trend analysis and the combination of INM modalities can provide tailored treatment support in patients at high risk for DCI. Future trials should test interventions triggered by INM in relation to cerebral infarctions.

Dynamic Detection of Delayed Cerebral Ischemia: A Study in 3 Centers.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage negatively impacts long-term recovery but is often detected too late to prevent damage. We aim to develop hourly risk scores using routinely collected clinical data to detect DCI. METHODS: A DCI classification model was trained using vital sign measurements (heart rate, blood pressure, respiratory rate, and oxygen saturation) and demographics routinely collected for clinical care. Twenty-two time-varying physiological measures were computed including mean, SD, and cross-correlation of heart rate time series with each of the other vitals. Classification was achieved using an ensemble approach with L2-regularized logistic regression, random forest, and support vector machines models. Classifier performance was determined by area under the receiver operating characteristic curves and confusion matrices. Hourly DCI risk scores were generated as the posterior probability at time t using the Ensemble classifier on cohorts recruited at 2 external institutions (n=38 and 40). RESULTS: Three hundred ten patients were included in the training model (median, 54 years old [interquartile range, 45-65]; 80.2% women, 28.4% Hunt and Hess scale 4-5, 38.7% Modified Fisher Scale 3-4); 101 (33%) developed DCI with a median onset day 6 (interquartile range, 5-8). Classification accuracy before DCI onset was 0.83 (interquartile range, 0.76-0.83) area under the receiver operating characteristic curve. Risk scores applied to external institution datasets correctly predicted 64% and 91% of DCI events as early as 12 hours before clinical detection, with 2.7 and 1.6 true alerts for every false alert. CONCLUSIONS: An hourly risk score for DCI derived from routine vital signs may have the potential to alert clinicians to DCI, which could reduce neurological injury.

Body mass index and leptin levels in serum and cerebrospinal fluid in relation to delayed cerebral ischemia and outcome after aneurysmal subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is associated with a high mortality rate and may leave surviving patients severely disabled. After the initial hemorrhage, clinical outcome is further compromised by the occurrence of delayed cerebral ischemia (DCI). Overweight and obesity have previously been associated with protective effects in the post-bleeding phase. The aim of this study was to assess the effects of a patient's body mass index (BMI) and leptin levels on the occurrence of DCI, DCI-related cerebral infarction, and clinical outcome. In total, 263 SAH patients were included of which leptin levels were assessed in 24 cases. BMI was recorded along disease severity documented by the Hunt and Hess and modified Fisher scales. The occurrence of clinical or functional DCI (neuromonitoring, CT Perfusion) was assessed. Long-term clinical outcome was documented after 12 months (extended Glasgow outcome scale). A total of 136 (51.7%) patients developed DCI of which 72 (27.4%) developed DCI-related cerebral infarctions. No association between BMI and DCI occurrence (P = .410) or better clinical outcome (P = .643) was identified. Early leptin concentration in serum (P = .258) and CSF (P = .159) showed no predictive value in identifying patients at risk of unfavorable outcomes. However, a significant increase of leptin levels in CSF occurred from 326.0 pg/ml IQR 171.9 prior to DCI development to 579.2 pg/ml IQR 211.9 during ongoing DCI (P = .049). In our data, no association between obesity and clinical outcome was detected. After DCI development, leptin levels in CSF increased either by an upsurge of active transport or disruption of the blood-CSF barrier. This trial has been registered at ClinicalTrials.gov (NCT02142166) as part of a larger-scale prospective data collection. BioSAB: https://clinicaltrials.gov/ct2/show/NCT02142166.

Treatment of Delayed Cerebral Ischemia in Good-Grade Subarachnoid Hemorrhage: Any Role for Invasive Neuromonitoring?

BACKGROUND: Good-grade aneurysmal subarachnoid hemorrhage (Hunt and Hess 1-2) is generally associated with a favorable prognosis. Nonetheless, patients may still experience secondary deterioration due to delayed cerebral ischemia (DCI), contributing to poor outcome. In those patients, neurological assessment is challenging and invasive neuromonitoring (INM) may help guide DCI treatment. METHODS: An observational analysis of 135 good-grade SAH patients referred to a single tertiary care center between 2010 and 2018 was performed. In total, 54 good-grade SAH patients with secondary deterioration evading further neurological assessment, were prospectively enrolled for this analysis. The cohort was separated into two groups: before and after introduction of INM in 2014 (pre-INMSecD: n = 28; post-INMSecD: n = 26). INM included either parenchymal oxygen saturation measurement (ptiO2), cerebral microdialysis or both. Episodes of DCI (ptiO2 < 10 mmHg or lactate/pyruvate > 40) were treated via induced hypertension or in refractory cases by endovascular means. The primary outcome was defined as the extended Glasgow outcome scale after 12 months. In addition, we recorded the amount of imaging studies performed and the occurrence of silent and overall DCI-related infarction. RESULTS: Secondary deterioration, impeding neurological assessment, occurred in 54 (40.0%) of all good-grade SAH patients. In those patients, a comparable rate of favorable outcome at 12 months was observed before and after the introduction of INM (pre-INMSecD 14 (50.0%) vs. post-INMSecD 16, (61.6%); p = 0.253). A significant increase in good recovery (pre-INMSecD 6 (50.0%) vs. post-INMSecD 14, (61.6%); p = 0.014) was observed alongside a reduction in the incidence of silent infarctions (pre-INMSecD 8 (28.6%) vs. post-INMSecD 2 (7.7%); p = 0.048) and of overall DCI-related infarction (pre-INMSecD 12 (42.8%) vs. post-INMSecD 4 (23.1%); p = 0.027). The number of CT investigations performed during the DCI time frame decreased from 9.8 ± 5.2 scans in the pre-INMSecD group to 6.1 ± 4.0 (p = 0.003) in the post-INMSecD group. CONCLUSIONS: A considerable number of patients with good-grade SAH experiences secondary deterioration rendering them neurologically not assessable. In our cohort, the introduction of INM to guide DCI treatment in patients with secondary deterioration increased the rate of good recovery after 12 months. Additionally, a significant reduction of CT scans and infarction load was recorded, which may have an underestimated impact on quality of life and more subtle neuropsychological deficits common after SAH.

Targeted therapy use in adults with cancer ≥85 years of age.

PURPOSE: Assess patient- and clinical-related variables associated with targeted cancer treatments (TTs) for adults ≥85 years of age. RATIONALE: TTs have pathway-specific side effects that negatively affect QoL and medication adherence, which may reduce TT efficacy. Research has not focused on patients aged ≥85 years; therefore, the scope of TT use in this age group is not understood. METHODS: We conducted an electronic medical record review to identify individuals ≥85 years treated with TT. RESULTS: The sample (N = 295) was 53.5% male, 41% married/partnered, and 73.7% Caucasian. Common cancer types included breast (26.3%), prostate (31.3%), and leukemia (14.1%). Only one-third (n = 98) of the sample had TT side effects noted in their patient chart. CONCLUSIONS: Patients aged ≥85 years took similar TTs and experienced similar side effects as reported by research of younger patients; however, symptom experience was not well-reported.