Association of Fluid Balance and Hemoglobin Decline With Neurological Outcome After Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVES: To explore the relationship between fluid balance and hemoglobin decline with secondary infarctions and neurologic outcome in aneurysmal subarachnoid hemorrhage (aSAH) patients. DESIGN: Secondary analysis of the Earlydrain trial, a prospective randomized controlled study investigating prophylactic lumbar drain use in aSAH patients. SETTING: Patients with aSAH treated in ICUs at 19 tertiary hospitals in Germany, Switzerland, and Canada. PATIENTS: From January 2011 to January 2016, 287 patients were enrolled in the Earlydrain trial. Only files with complete information on both daily hemoglobin and balance values were used, leaving 237 patients for analysis. INTERVENTIONS: Investigation of fluid balance management and hemoglobin levels during the initial 8 days post-aSAH to establish thresholds for unfavorable outcomes and assess their impact on secondary infarctions and 6-month neurologic outcome on the modified Rankin Scale (mRS). MEASUREMENTS AND MAIN RESULTS: Patients with unfavorable outcome after 6 months (mRS > 2) showed greater hemoglobin decline and increased cumulative fluid balance. A significant inverse relationship existed between fluid balance and hemoglobin decline. Thresholds for unfavorable outcome were 10.4 g/dL hemoglobin and 4894 mL cumulative fluid balance in the first 8 days. In multivariable analysis, fluid balance, but not fluid intake, remained significantly associated with unfavorable outcome, while the influence of hemoglobin lessened. Fluid balance but not hemoglobin related to secondary infarctions, with the effect being significant after inverse probability of treatment weighting. Transfusion was associated with unfavorable outcomes. CONCLUSIONS: Increased fluid balance influences hemoglobin decline through hemodilution. Fluid overload, rather than a slight decrease in hemoglobin levels, appears to be the primary factor contributing to poor outcomes in aSAH patients. The results suggest aiming for euvolemia and that a modest hemoglobin decline may be tolerated. It may be advisable to adopt a restrictive approach to transfusions, as they can potentially have a negative effect on outcome.

Decompressive craniectomy plus best medical treatment versus best medical treatment alone for spontaneous severe deep supratentorial intracerebral haemorrhage: a randomised controlled clinical trial.

BACKGROUND: It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. METHODS: In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. FINDINGS: SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. INTERPRETATION: SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.

Analysis of Cerebral Spinal Fluid Drainage and Intracranial Pressure Peaks in Patients with Subarachnoid Hemorrhage.

BACKGROUND: After aneurysmal subarachnoid hemorrhage (aSAH), elevated intracranial pressure (ICP) due to disrupted cerebrospinal fluid (CSF) dynamics is a critical concern. An external ventricular drainage (EVD) is commonly employed for management; however, optimal strategies remain debated. The randomized controlled Earlydrain trial showed that an additional prophylactic lumbar drainage (LD) after aneurysm treatment improves neurological outcome. We performed a post hoc investigation on the impact of drainage volumes and critical ICP values on patient outcomes after aSAH. METHODS: Using raw patient data from Earlydrain, we analyzed CSF drainage amounts and ICP measurements in the first 8 days after aSAH. Outcomes were the occurrence of secondary infarctions and the score on the modified Rankin scale after 6 months, dichotomized in values of 0-2 as favorable and 3-6 as unfavorable. Repeated measurements were considered with generalized estimation equations. RESULTS: Earlydrain recruited 287 patients, of whom 221 received an EVD and 140 received an LD. Higher EVD volumes showed a trend to more secondary infarctions (p = 0.09), whereas higher LD volumes were associated with less secondary infarctions (p = 0.009). The mean total CSF drainage was 1052 ± 659 mL and did not differ concerning infarction and neurological outcome. Maximum ICP values were higher in patients with poor outcomes but not related to drainage volumes via EVD. After adjustment for aSAH severity and total CSF drainage, higher LD volume was linked to favorable outcome (per 100 mL: odds ratio 0.61 (95% confidence interval 0.39-0.95), p = 0.03), whereas higher EVD amounts were associated with unfavorable outcome (per 100 mL: odds ratio 1.63 (95% confidence interval 1.05-2.54), p = 0.03). CONCLUSIONS: Findings indicate that effects of CSF drainage via EVD and LD differ. Higher amounts and higher proportions of LD volumes were associated with better outcomes, suggesting a potential quantity-dependent protective effect. Optimizing LD volume and mitigating ICP spikes may be a strategy to improve patient outcomes after aSAH. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01258257.

A supervised, externally validated machine learning model for artifact and drainage detection in high-resolution intracranial pressure monitoring data.

OBJECTIVE: In neurocritical care, data from multiple biosensors are continuously measured, but only sporadically acknowledged by the attending physicians. In contrast, machine learning (ML) tools can analyze large amounts of data continuously, taking advantage of underlying information. However, the performance of such ML-based solutions is limited by different factors, for example, by patient motion, manipulation, or, as in the case of external ventricular drains (EVDs), the drainage of CSF to control intracranial pressure (ICP). The authors aimed to develop an ML-based algorithm that automatically classifies normal signals, artifacts, and drainages in high-resolution ICP monitoring data from EVDs, making the data suitable for real-time artifact removal and for future ML applications. METHODS: In their 2-center retrospective cohort study, the authors used labeled ICP data from 40 patients in the first neurocritical care unit (University Hospital Zurich) for model development. The authors created 94 descriptive features that were used to train the model. They compared histogram-based gradient boosting with extremely randomized trees after building pipelines with principal component analysis, hyperparameter optimization via grid search, and sequential feature selection. Performance was measured with nested 5-fold cross-validation and multiclass area under the receiver operating characteristic curve (AUROC). Data from 20 patients in a second, independent neurocritical care unit (Charité - Universitätsmedizin Berlin) were used for external validation with bootstrapping technique and AUROC. RESULTS: In cross-validation, the best-performing model achieved a mean AUROC of 0.945 (95% CI 0.92-0.969) on the development dataset. On the external validation dataset, the model performed with a mean AUROC of 0.928 (95% CI 0.908-0.946) in 100 bootstrapping validation cycles to classify normal signals, artifacts, and drainages. CONCLUSIONS: Here, the authors developed a well-performing supervised model with external validation that can detect normal signals, artifacts, and drainages in ICP signals from patients in neurocritical care units. For future analyses, this is a powerful tool to discard artifacts or to detect drainage events in ICP monitoring signals.

Intraparenchymal near-infrared spectroscopy for detection of delayed cerebral ischemia in poor-grade aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Detection of delayed cerebral ischemia (DCI) is challenging in comatose patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH). Brain tissue oxygen pressure (PbtO2) monitoring may allow early detection of its occurrence. Recently, a probe for combined measurement of intracranial pressure (ICP) and intraparenchymal near-infrared spectroscopy (NIRS) has become available. In this pilot study, the parameters PbtO2, Hboxy, Hbdeoxy, Hbtotal and rSO2 were measured in parallel and evaluated for their potential to detect perfusion deficits or cerebral infarction. METHODS: In patients undergoing multimodal neuromonitoring due to poor neurological condition after aSAH, Clark oxygen probes, microdialysis and NIRS-ICP probes were applied. DCI was suspected when the measured parameters in neuromonitoring deteriorated. Thus, perfusion CT scan was performed as follow up, and DCI was confirmed as perfusion deficit. Median values for PbtO2, Hboxy, Hbdeoxy, Hbtotal and rSO2 in patients with perfusion deficit (Tmax > 6 s in at least 1 vascular territory) and/or already demarked infarcts were compared in 24- and 48-hour time frames before imaging. RESULTS: Data from 19 patients (14 University Hospital Zurich, 5 Charité Universitätsmedizin Berlin) were prospectively collected and analyzed. In patients with perfusion deficits, the median values for Hbtotal and Hboxy in both time frames were significantly lower. With perfusion deficits, the median values for Hboxy and Hbtotal in the 24 h time frame were 46,3 [39.6, 51.8] µmol/l (no perfusion deficits 53 [45.9, 55.4] µmol/l, p = 0.019) and 69,3 [61.9, 73.6] µmol/l (no perfusion deficits 74,6 [70.1, 79.6] µmol/l, p = 0.010), in the 48 h time frame 45,9 [39.4, 51.5] µmol/l (no perfusion deficits 52,9 [48.1, 55.1] µmol/l, p = 0.011) and 69,5 [62.4, 74.3] µmol/l (no perfusion deficits 75 [70,80] µmol/l, p = 0.008), respectively. In patients with perfusion deficits, PbtO2 showed no differences in both time frames. PbtO2 was significantly lower in patients with infarctions in both time frames. The median PbtO2 was 17,3 [8,25] mmHg (with no infarctions 29 [22.5, 36] mmHg, p = 0.006) in the 24 h time frame and 21,6 [11.1, 26.4] mmHg (with no infarctions 31 [22,35] mmHg, p = 0.042) in the 48 h time frame. In patients with infarctions, the median values of parameters measured by NIRS showed no significant differences. CONCLUSIONS: The combined NIRS-ICP probe may be useful for early detection of cerebral perfusion deficits and impending DCI. Validation in larger patient collectives is needed.

Red Blood Cells in the Cerebrospinal Fluid Compartment After Subarachnoid Haemorrhage: Significance and Emerging Therapeutic Strategies.

Subarachnoid haemorrhage (SAH) is a subtype of stroke that predominantly impacts younger individuals. It is associated with high mortality rates and can cause long-term disabilities. This review examines the contribution of the initial blood load and the dynamics of clot clearance to the pathophysiology of SAH and the risk of adverse outcomes. These outcomes include hydrocephalus and delayed cerebral ischaemia (DCI), with a particular focus on the impact of blood located in the cisternal spaces, as opposed to ventricular blood, in the development of DCI. The literature described underscores the prognostic value of haematoma characteristics, such as volume, density, and anatomical location. The limitations of traditional radiographic grading systems are discussed, compared with the more accurate volumetric quantification techniques for predicting patient prognosis. Further, the significance of red blood cells (RBCs) and their breakdown products in secondary brain injury after SAH is explored. The review presents novel interventions designed to accelerate clot clearance or mitigate the effects of toxic byproducts released from erythrolysis in the cerebrospinal fluid following SAH. In conclusion, this review offers deeper insights into the complex dynamics of SAH and discusses the potential pathways available for advancing its management.

Similarities in the Electrographic Patterns of Delayed Cerebral Infarction and Brain Death After Aneurysmal and Traumatic Subarachnoid Hemorrhage.

While subarachnoid hemorrhage is the second most common hemorrhagic stroke in epidemiologic studies, the recent DISCHARGE-1 trial has shown that in reality, three-quarters of focal brain damage after subarachnoid hemorrhage is ischemic. Two-fifths of these ischemic infarctions occur early and three-fifths are delayed. The vast majority are cortical infarcts whose pathomorphology corresponds to anemic infarcts. Therefore, we propose in this review that subarachnoid hemorrhage as an ischemic-hemorrhagic stroke is rather a third, separate entity in addition to purely ischemic or hemorrhagic strokes. Cumulative focal brain damage, determined by neuroimaging after the first 2 weeks, is the strongest known predictor of patient outcome half a year after the initial hemorrhage. Because of the unique ability to implant neuromonitoring probes at the brain surface before stroke onset and to perform longitudinal MRI scans before and after stroke, delayed cerebral ischemia is currently the stroke variant in humans whose pathophysiological details are by far the best characterized. Optoelectrodes located directly over newly developing delayed infarcts have shown that, as mechanistic correlates of infarct development, spreading depolarizations trigger (1) spreading ischemia, (2) severe hypoxia, (3) persistent activity depression, and (4) transition from clustered spreading depolarizations to a negative ultraslow potential. Furthermore, traumatic brain injury and subarachnoid hemorrhage are the second and third most common etiologies of brain death during continued systemic circulation. Here, we use examples to illustrate that although the pathophysiological cascades associated with brain death are global, they closely resemble the local cascades associated with the development of delayed cerebral infarcts.

Early Complications and Outcome After Treatment of Ruptured Aneurysms in Patients with Subarachnoid Hemorrhage-A Post Hoc Analysis of the EARLYDRAIN Trial.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) from a ruptured intracranial aneurysm is a severe, life-threatening condition, with high morbidity and mortality. The current treatment often involves surgical clipping or endovascular treatment within the first 24-48 hours. Although there is ample evidence of complications in treating unruptured aneurysms, similar data in patients with acutely ruptured aneurysms are limited. The recently completed EARLYDRAIN trial showed improved neurologic results from lumbar drainage after aneurysm treatment in patients with aSAH. Using this data set, we aim to study the frequency and effects of complications and identify associated risk factors. METHODS: A substudy was carried out of the prospective multicenter randomized controlled EARLYDRAIN trial. We analyzed treatment-associated complications (bleeding and/or infarctions) detected on computed tomography on day 1 after aneurysm occlusion. Outcomes were the occurrence of postprocedural complications, secondary infarctions in the acute phase, and the modified Rankin Scale score after 6 months. RESULTS: The EARLYDRAIN trial recruited 287 patients in 19 centers. Of these patients, 56 (19.5%) experienced a treatment complication. Twenty-five patients (8.7%) experienced postprocedural intracranial hemorrhage and 34 patients (11.8%) experienced a treatment-associated infarction. Patients with a complication showed more secondary infarctions (P = 0.049) and worse neurologic outcomes after 180 days (P = 0.025) compared with patients with no complication. Aneurysm location, rebleeding before the treatment, number of patients recruited per center, and the day of the treatment were independent risk factors for the occurrence of complications. CONCLUSIONS: The present study shows that patients with aSAH frequently experience intervention-associated complications associated with aneurysm occlusion required to prevent recurrent hemorrhage. Consequently, patients with aSAH with treatment-related complications more often experience a worse clinical course and poor outcome.

A randomized, single ascending dose safety, tolerability and pharmacokinetics study of NicaPlant® in aneurysmal subarachnoid hemorrhage patients undergoing clipping.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Post-hemorrhagic vasospasm with neurological deterioration is a major concern in this context. NicaPlant®, a modified release formulation of the calcium channel blocker nicardipine, has shown vasodilator efficacy preclinically and a similar formulation known as NPRI has shown anti-vasospasm activity in aSAH patients under compassionate use. Research question: The study aimed to assess pharmacokinetics and pharmacodynamics of NicaPlant® pellets to prevent vasospasm after clip ligation in aSAH. Material and methods: In this multicenter, controlled, randomized, dose escalation trial we assessed the safety and tolerability of NicaPlant®. aSAH patients treated by clipping were randomized to receive up to 13 NicaPlant® implants, similarly to the dose of NPRIs previous used, or standard of care treatment. Results: Ten patients across four dose groups were treated with NicaPlant® (3-13 implants) while four patients received standard of care. 45 non-serious and 13 serious adverse events were reported, 4 non-serious adverse events and 5 serious adverse events assessed a probable or possible causal relationship to the investigational medical product. Across the NicaPlant® groups there was 1 case of moderate vasospasm, while in the standard of care group there were 2 cases of severe vasospasm. Discussion and conclusion: The placement of NicaPlant® during clip ligation of a ruptured cerebral aneurysm raised no safety concern. The dose of 10 NicaPlant® implants was selected for further clinical studies.

Involvement of the Macrophage Migration Inhibitory Factor (MIF) in Lipedema.

Lipedema is a chronic disorder that mainly affects women. It is often misdiagnosed, and its etiology remains unknown. Recent research indicates an accumulation of macrophages and a shift in macrophage polarization in lipedema. One known protein superfamily that contributes to macrophage accumulation and polarization is the macrophage migration inhibitory factor (MIF) family. MIF-1 and MIF-2 are ubiquitously expressed and also regulate inflammatory processes in adipose tissue. In this study, the expression of MIF-1, MIF-2 and CD74-a common receptor for both cytokines-was analyzed in tissue samples of 11 lipedema and 11 BMI-matched, age-matched and anatomically matched control patients using qPCR and immunohistochemistry (IHC). The mRNA expression of MIF-1 (mean 1.256; SD 0.303; p = 0.0485) and CD74 (mean 1.514; SD 0.397; p = 0.0097) were significantly elevated in lipedema patients, while MIF-2 expression was unaffected (mean 1.004; SD 0.358; p = 0.9718). The IHC analysis corroborated the results for CD74 expression on a cellular level. In conclusion, our results provide first evidence for a potential involvement of the MIF family, presumably via the MIF-1-CD74 axis, in lipedema.

Enhancing the prediction for shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage using a machine learning approach.

Early and reliable prediction of shunt-dependent hydrocephalus (SDHC) after aneurysmal subarachnoid hemorrhage (aSAH) may decrease the duration of in-hospital stay and reduce the risk of catheter-associated meningitis. Machine learning (ML) may improve predictions of SDHC in comparison to traditional non-ML methods. ML models were trained for CHESS and SDASH and two combined individual feature sets with clinical, radiographic, and laboratory variables. Seven different algorithms were used including three types of generalized linear models (GLM) as well as a tree boosting (CatBoost) algorithm, a Naive Bayes (NB) classifier, and a multilayer perceptron (MLP) artificial neural net. The discrimination of the area under the curve (AUC) was classified (0.7 ≤ AUC < 0.8, acceptable; 0.8 ≤ AUC < 0.9, excellent; AUC ≥ 0.9, outstanding). Of the 292 patients included with aSAH, 28.8% (n = 84) developed SDHC. Non-ML-based prediction of SDHC produced an acceptable performance with AUC values of 0.77 (CHESS) and 0.78 (SDASH). Using combined feature sets with more complex variables included than those incorporated in the scores, the ML models NB and MLP reached excellent performances, with an AUC of 0.80, respectively. After adding the amount of CSF drained within the first 14 days as a late feature to ML-based prediction, excellent performances were reached in the MLP (AUC 0.81), NB (AUC 0.80), and tree boosting model (AUC 0.81). ML models may enable clinicians to reliably predict the risk of SDHC after aSAH based exclusively on admission data. Future ML models may help optimize the management of SDHC in aSAH by avoiding delays in clinical decision-making.

Interdisciplinary perspectives on computed tomography in sepsis: survey among medical doctors at a large university medical center.

OBJECTIVES: This study aims to describe physicians' perspectives on the use of computed tomography (CT) in patients with sepsis. METHODS: In January 2022, physicians of a large European university medical center were surveyed using a web-based questionnaire asking about their views on the role of CT in sepsis. A total of 371 questionnaires met the inclusion criteria and were analyzed using work experience, workplace, and medical specialty of physicians as variables. Chi-square tests were performed. RESULTS: Physicians considered the ability to detect an unknown focus as the greatest benefit of CT scans in sepsis (70.9%, n = 263/371). Two clinical criteria - "signs of decreased vigilance" (89.2%, n = 331/371) and "increased catecholamine demand" (84.7%, n = 314/371) - were considered highly relevant for a CT request. Elevated procalcitonin (82.7%, n = 307/371) and lactate levels (83.6%, n = 310/371) were consistently found to be critical laboratory values to request a CT. As long as there is evidence of infection in one organ region, most physicians (42.6%, n = 158/371) would order a CT scan based on clinical assessment. Combined examination of the chest, abdomen, and pelvis was favored (34.8%, n = 129/371) in cases without clinical clues of an infection source. A time window of ≥ 1-6 h was preferred for both CT examinations (53.9%, n = 200/371) and CT-guided interventions (59.3%, n = 220/371) in patients with sepsis. CONCLUSION: Despite much consensus, there are significant differences in attitudes towards the use of CT in septic patients among physicians from different workplaces and medical specialties. Knowledge of these perspectives may improve patient management and interprofessional communication. KEY POINTS: Despite interdisciplinary consensus on the use of CT in sepsis, statistically significant differences in the responses are apparent among physicians from different workplaces and medical specialties. The detection of a previously unknown source of infection and the ability to plan interventions and/or surgery based on CT findings are considered key advantages of CT in septic patients. Timing of CT reflects the requirements of specific disciplines.

Effectiveness of Lumbar Cerebrospinal Fluid Drain Among Patients With Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.

Importance: After aneurysmal subarachnoid hemorrhage, the use of lumbar drains has been suggested to decrease the incidence of delayed cerebral ischemia and improve long-term outcome. Objective: To determine the effectiveness of early lumbar cerebrospinal fluid drainage added to standard of care in patients after aneurysmal subarachnoid hemorrhage. Design, Setting, and Participants: The EARLYDRAIN trial was a pragmatic, multicenter, parallel-group, open-label randomized clinical trial with blinded end point evaluation conducted at 19 centers in Germany, Switzerland, and Canada. The first patient entered January 31, 2011, and the last on January 24, 2016, after 307 randomizations. Follow-up was completed July 2016. Query and retrieval of data on missing items in the case report forms was completed in September 2020. A total of 20 randomizations were invalid, the main reason being lack of informed consent. No participants meeting all inclusion and exclusion criteria were excluded from the intention-to-treat analysis. Exclusion of patients was only performed in per-protocol sensitivity analysis. A total of 287 adult patients with acute aneurysmal subarachnoid hemorrhage of all clinical grades were analyzable. Aneurysm treatment with clipping or coiling was performed within 48 hours. Intervention: A total of 144 patients were randomized to receive an additional lumbar drain after aneurysm treatment and 143 patients to standard of care only. Early lumbar drainage with 5 mL per hour was started within 72 hours of the subarachnoid hemorrhage. Main Outcomes and Measures: Primary outcome was the rate of unfavorable outcome, defined as modified Rankin Scale score of 3 to 6 (range, 0 to 6), obtained by masked assessors 6 months after hemorrhage. Results: Of 287 included patients, 197 (68.6%) were female, and the median (IQR) age was 55 (48-63) years. Lumbar drainage started at a median (IQR) of day 2 (1-2) after aneurysmal subarachnoid hemorrhage. At 6 months, 47 patients (32.6%) in the lumbar drain group and 64 patients (44.8%) in the standard of care group had an unfavorable neurological outcome (risk ratio, 0.73; 95% CI, 0.52 to 0.98; absolute risk difference, -0.12; 95% CI, -0.23 to -0.01; P = .04). Patients treated with a lumbar drain had fewer secondary infarctions at discharge (41 patients [28.5%] vs 57 patients [39.9%]; risk ratio, 0.71; 95% CI, 0.49 to 0.99; absolute risk difference, -0.11; 95% CI, -0.22 to 0; P = .04). Conclusion and Relevance: In this trial, prophylactic lumbar drainage after aneurysmal subarachnoid hemorrhage lessened the burden of secondary infarction and decreased the rate of unfavorable outcome at 6 months. These findings support the use of lumbar drains after aneurysmal subarachnoid hemorrhage. Trial Registration: ClinicalTrials.gov Identifier: NCT01258257.

A Survey on Monitoring and Management of Cerebral Vasospasm and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: The Mantra Study.

INTRODUCTION: Cerebral infarction from delayed cerebral ischemia (DCI) is a leading cause of poor neurological outcome after aneurysmal subarachnoid hemorrhage (aSAH). We performed an international clinical practice survey to identify monitoring and management strategies for cerebral vasospasm associated with DCI in aSAH patients requiring intensive care unit admission. METHODS: The survey questionnaire was available on the European Society of Intensive Care Medicine (May 2021-June 2022) and Neurocritical Care Society (April - June 2022) websites following endorsement by these societies. RESULTS: There were 292 respondents from 240 centers in 38 countries. In conscious aSAH patients or those able to tolerate an interruption of sedation, neurological examination was the most frequently used diagnostic modality to detect delayed neurological deficits related to DCI caused by cerebral vasospasm (278 respondents, 95.2%), while in unconscious patients transcranial Doppler/cerebral ultrasound was most frequently used modality (200, 68.5%). Computed tomography angiography was mostly used to confirm the presence of vasospasm as a cause of DCI. Nimodipine was administered for DCI prophylaxis by the majority of the respondents (257, 88%), mostly by an enteral route (206, 71.3%). If there was a significant reduction in arterial blood pressure after nimodipine administration, a vasopressor was added and nimodipine dosage unchanged (131, 45.6%) or reduced (122, 42.5%). Induced hypertension was used by 244 (85%) respondents as first-line management of DCI related to vasospasm; 168 (59.6%) respondents used an intra-arterial procedure as second-line therapy. CONCLUSIONS: This survey demonstrated variability in monitoring and management strategies for DCI related to vasospasm after aSAH. These findings may be helpful in promoting educational programs and future research.

A Comparative Analysis to Dissect the Histological and Molecular Differences among Lipedema, Lipohypertrophy and Secondary Lymphedema.

Lipedema, lipohypertrophy and secondary lymphedema are three conditions characterized by disproportionate subcutaneous fat accumulation affecting the extremities. Despite the apparent similarities and differences among their phenotypes, a comprehensive histological and molecular comparison does not yet exist, supporting the idea that there is an insufficient understanding of the conditions and particularly of lipohypertrophy. In our study, we performed histological and molecular analysis in anatomically-, BMI- and gender-matched samples of lipedema, lipohypertrophy and secondary lymphedema versus healthy control patients. Hereby, we found a significantly increased epidermal thickness only in patients with lipedema and secondary lymphedema, while significant adipocyte hypertrophy was identified in both lipedema and lipohypertrophy. Interestingly, the assessment of lymphatic vessel morphology showed significantly decreased total area coverage in lipohypertrophy versus the other conditions, while VEGF-D expression was significantly decreased across all conditions. The analysis of junctional genes often associated with permeability indicated a distinct and higher expression only in secondary lymphedema. Finally, the evaluation of the immune cell infiltrate verified the increased CD4+ cell and macrophage infiltration in lymphedema and lipedema respectively, without depicting a distinct immune cell profile in lipohypertrophy. Our study describes the distinct histological and molecular characteristics of lipohypertrophy, clearly distinguishing it from its two most important differential diagnoses.

Measuring and preliminary modeling of drift interception by plant species.

Currently, the concept of plant capture efficiency is not quantitatively considered in the evaluation of off-target drift for the purposes of pesticide risk assessment in the United States. For on-target pesticide applications, canopy capture efficiency is managed by optimizing formulations or tank-mixing with adjuvants to maximize retention of spray droplets. These efforts take into consideration the fact that plant species have diverse morphology and surface characteristics, and as such will retain varying levels of applied pesticides. This work aims to combine plant surface wettability potential, spray droplet characteristics, and plant morphology into describing the plant capture efficiency of drifted spray droplets. In this study, we used wind tunnel experiments and individual plants grown to 10-20 cm to show that at two downwind distances and with two distinct nozzles capture efficiency for sunflower (Helianthus annuus L.), lettuce (Lactuca sativa L.), and tomato (Solanum lycopersicum L.) is consistently higher than rice (Oryza sativa L.), peas (Pisum sativum L). and onions (Allium cepa L.), with carrots (Daucus carota L.) showing high variability and falling between the two groups. We also present a novel method for three-dimensional modeling of plants from photogrammetric scanning and use the results in the first known computational fluid dynamics simulations of drift capture efficiency on plants. The mean simulated drift capture efficiency rates were within the same order of magnitude of the mean observed rates of sunflower and lettuce, and differed by one to two orders for rice and onion. We identify simulating the effects of surface roughness on droplet behavior, and the effects of wind flow on plant movement as potential model improvements requiring further species-specific data collection.

Oscillation analysis as a supporting element toward safe and reliable lumbar catheter intracranial pressure monitoring.

OBJECTIVE: Lumbar drainage of cerebrospinal fluid for treatment of refractory increased intracranial pressure (ICP) is associated with the risk of infratentorial herniation, but real-time biomarkers for signaling herniation at bedside are lacking. Here, the authors tested whether an alteration of pulsatile waveform conduction across the level of the foramen magnum could serve as an indicator of insufficient hydrostatic communication and impending herniation. METHODS: This prospective observational cohort study included patients with severe acute brain injury who underwent continuous external ventricular drain monitoring of ICP and lumbar drain pressure monitoring. Continuous recordings of ICP, lumbar pressure (LP), and arterial blood pressure (ABP) were screened throughout a recording period of 4-10 days. Pressure differences between ICP and LP > 5 mm Hg for 5 minutes were defined as a Δ-event, implicating nonsufficient hydrostatic communication. During this period, oscillation analysis of the ICP, LP, and ABP waveforms was performed by determining the eigenfrequencies (EFs) and their amplitudes (AEF) via Fourier transformation scripted in Python. RESULTS: Of 142 patients, 14 exhibited a Δ-event, with a median (range) ICP of 12.2 (10.7-18.8) mm Hg and LP of 5.6 (3.3-9.8) mm Hg during 2993 hours of recording time. The AEF ratio between ICP and LP (p < 0.01) and between ABP and LP (p = 0.032) increased significantly during Δ-events compared with the baseline values determined 3 hours prior to the event. The ratio between ICP and ABP remained unaffected. CONCLUSIONS: Oscillation behavior analysis of LP and ABP waveforms during controlled lumbar drainage may serve as a personalized, simple, and effective biomarker to signal impending infratentorial herniation in real time without the need for simultaneous ICP monitoring.

BBLN triggers CAMK2D pathology in mice under cardiac pressure overload and potentially in unrepaired hearts with tetralogy of Fallot.

Tetralogy of Fallot (TOF) is one of the most prevalent congenital heart defects, with adverse cardiac remodeling and long-term cardiac complications. Here, searching for pathomechanisms, we find upregulated bublin coiled-coil protein (BBLN) in heart specimens of TOF patients with cyanosis, which positively correlates with cardiac remodeling pathways. Human BBLN, a protein with largely unknown function, promoted heart failure features, with increased mortality when overexpressed in mice, in a protein dosage-dependent manner. BBLN enhanced cardiac inflammation, fibrosis and necroptosis by calcium/calmodulin-dependent protein kinase II delta (CAMK2D) activation, whereas a BBLN mutant with impaired CAMK2D binding was inert. Downregulation of CAMK2D by an interfering RNA retarded BBLN-induced symptoms of heart failure. Endogenous BBLN was induced by hypoxia as a major TOF feature in human patients and by chronic pressure overload in mice, and its downregulation decreased CAMK2D hyperactivity, necroptosis and cardiovascular dysfunction. Thus, BBLN promotes CAMK2D-induced pathways to pathological cardiac remodeling, which are triggered by hypoxia in TOF.

Is Lymphedema a Systemic Disease? A Paired Molecular and Histological Analysis of the Affected and Unaffected Tissue in Lymphedema Patients.

Secondary lymphedema is a chronic, debilitating disease and one of the most common side effects of oncologic surgery, substantially decreasing quality of life. Despite the progress conducted in lymphedema research, the underlying pathomechanisms remain elusive. Lymphedema is considered to be a disease affecting an isolated extremity, yet imaging studies suggest systemic changes of the lymphatic system in the affected patients. To evaluate potential systemic manifestations in lymphedema, we collected matched fat and skin tissue from the edematous and non-edematous side of the same 10 lymphedema patients as well as anatomically matched probes from control patients to evaluate whether known lymphedema manifestations are present systemically and in comparison to health controls. The lymphedematous tissue displayed various known hallmarks of lymphedema compared to the healthy controls, such as increased epidermis thickness, collagen deposition in the periadipocyte space and the distinct infiltration of CD4+ cells. Furthermore, morphological changes in the lymphatic vasculature between the affected and unaffected limb in the same lymphedema patient were visible. Surprisingly, an increased collagen deposition as well as CD4 expression were also detectable in the non-lymphedematous tissue of lymphedema patients, suggesting that lymphedema may trigger systemic changes beyond the affected extremity.