Risk factors and outcomes after interruption of sedation in subarachnoid hemorrhage (ROUTINE-SAH)-a retrospective cohort study.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) often necessitates prolonged sedation to manage elevated intracranial pressure (ICP) and to prevent secondary brain injury. Optimal timing and biomarkers for predicting adverse events (AEs) during interruption of sedation (IS) after prolonged sedation are not well established. To guide sedation management in aSAH, we aimed to explore the frequency, risk factors, and outcomes of IS in aSAH. Methods: In a retrospective cohort study, a total of 148 patients with aSAH from January 2015 to April 2020 were screened. In total, 30 patients accounting for 42 IS were included in the analysis. Adverse events (AEs) during IS were used as core outcome measures and were categorized into neurological and non-neurological AEs. Baseline characteristics, clinical parameters before IS, AEs, and functional outcomes were collected using health records. Statistical analysis used generalized linear mixed-effects models with regularization to identify candidate predictors with subsequent bootstrapping to test model stability. As an exploratory analysis, multivariate linear and logistic regression was used to analyze the association between IS and intensive care unit length of stay, duration of mechanical ventilation, and functional outcomes. Results: The mean age was 56.9 (SD 14.8) years, and a majority of the patients presented with poor-grade SAH (16/30, 53.3%). Neurological and non-neurological AEs occurred in 60.0% (18/30) of the patients. Timing, number of IS attempts, ICP burden, craniectomy status, level of consciousness, heart rate, cerebral perfusion pressure, oxygen saturation, fraction of inspired oxygen, and temperature were selected as candidate predictors. Through bootstrapping, elapsed time since disease onset (OR 0.85, 95% confidence interval (95% CI) 0.75-0.97), ICP burden (OR 1.24, 95% CI 1.02-1.52), craniectomy (OR 0.68, 95% CI 0.48-0.69), and oxygen saturation (OR, 0.80 0.72-0.89) were revealed as relevant biomarkers for neurological AEs, while none of the pre-selected predictors was robustly associated with non-neurological AEs. Conclusion: In aSAH, complications during the definite withdrawal of sedation are frequent but can potentially be predicted using clinical parameters available at the bedside. Prospective multicenter studies are essential to validate these results and further investigate the impact of IS complications.

Survey on Nutrition in Neurological Intensive Care Units (SONNIC)-A Cross-Sectional Survey among German-Speaking Neurointensivists on Medical Nutritional Therapy.

Medical nutritional therapy (MNT) in neurointensive care units (NICUs) is both particularly relevant and challenging due to prolonged analgosedation, immobilization, disorders of consciousness, and the high prevalence of dysphagia. Moreover, current guideline recommendations predominantly address the general intensive care unit (ICU) population, overlooking specific characteristics of neurological patients. We, therefore, conducted a web-based, cross-sectional survey for German-speaking neurointensivists mapping the clinical practices of MNT on NICUs to identify research gaps and common grounds for future clinical trials. A total of 25.9% (56/216) NICU representatives responded to our questionnaire. A total of 78.2% (43/55) were neurologist and 63% (34/54) held a leadership role. Overall, 80.4% (41/51) had established a standard operating procedure (SOP), largely based on the DGEM-Guideline (53.7%; 22/41), followed by the ESPEN-Guideline (14.6%; 6/41). Upon admission, 36% (18/50) conducted a risk stratification, with 83.3% primarily relying on past medical history (15/18) and clinical gestalt (15/18). Energy expenditure (EE) was measured or calculated by 75% (36/48), with 72.2% (26/36) using pragmatic weight-based equations. Indirect calorimetry was used by 19.4% (7/36). A total of 83.3% (30/36) used the patient's serum glucose level as the primary biomarker to monitor metabolic tolerance. SOPs regarding ICU-Acquired Weakness (ICUAW) were found in 8.9% (4/45) of respondents. Overall, guideline adherence was 47%. In summary, this is, to the best of our knowledge, the first study systematically describing the currently applied concepts of MNT on NICUs. The data reveal great variations in the implementation of guideline recommendations, indicating the need for further research and tailored approaches to optimize nutritional therapy in neurointensive care settings.

Fit for Service: Preparing Residents for Neurointensive Care with Entrustable Professional Activities: A Delphi Study.

BACKGROUND: Although the relevance of neurointensive medicine and high-quality training of corresponding physicians is increasingly recognized, there is high heterogeneity in the nature, duration, and quality of neurointensive care curricula around the world. Thus, we aimed to identify, define, and establish validity evidence for entrustable professional activities (EPAs) for postgraduate training in neurointensive care to determine trainees' readiness for being on-call. METHODS: After defining EPAs through an iterative process by an expert group, we used a modified Delphi approach with a single-center development process followed by a national consensus and a single-center validation step. EPAs were evaluated by using the EQual rubric (Queen's EPA Quality Rubric). Interrater reliability was measured with Krippendorff's α. RESULTS: The expert group defined seven preliminary EPAs for neurointensive care. In two consecutive Delphi rounds, EPAs were adapted, and consensus was reached for level of entrustment and time of expiration. Ultimately, EPAs reached a high EQual score of 4.5 of 5 and above. Interrater reliability for the EQual scoring was 0.8. CONCLUSIONS: Using a multistep Delphi process, we defined and established validity evidence for seven EPAs for neurointensive medicine with a high degree of consensus to objectively describe readiness for on-call duty in neurointensive care. This operationalization of pivotal clinical tasks may help to better train clinical residents in neurointensive care across sites and health care systems and has the potential to serve as a blueprint for training in general intensive care medicine. It also represents a starting point for further research and development of medical curricula.

Intrahospital Transport of Critically Ill Patients with Subarachnoid Hemorrhage-Frequency, Timing, Complications, and Clinical Consequences.

BACKGROUND: Patients with subarachnoid hemorrhage (SAH) often necessitate intra-hospital transport (IHT) during intensive care treatment. These transfers to facilities outside of the neurointensive care unit (NICU) pose challenges due to the inherent instability of the hemodynamic, respiratory, and neurological parameters that are typical in these patients. METHODS: In this retrospective, single-center cohort study, a total of 108 IHTs were analyzed for demographics, transport rationale, clinical outcomes, and pre/post-IHT monitoring parameters. After establishing clinical thresholds, the frequency of complications was calculated, and predictors of thresholds violations were determined. RESULTS: The mean age was 55.7 (+/-15.3) years, with 68.0% showing severe SAH (World Federation of Neurosurgical Societies Scale 5). IHTs with an emergency indication made up 30.8% of all transports. Direct therapeutic consequences from IHT were observed in 38.5%. On average, the first IHT occurred 1.5 (+/-2.0) days post-admission and patients were transported 4.3 (+/-1.8) times during their stay in the NICU. Significant parameter changes from pre- to post-IHT included mean arterial pressure, systolic blood pressure, oxygen saturation, blood glucose levels, temperature, dosages of propofol and ketamine, tidal volume, inspired oxygen concentration, Horovitz index, glucose, pH, intracranial pressure, and cerebral perfusion pressure. Relevant hemodynamic thresholds were violated in 31.5% of cases, while respiratory complications occurred in 63.9%, and neurological complications in 20.4%. For hemodynamic complications, a low heart rate with a threshold of 61/min (OR 0.96, 95% CI 0.93-0.99, p = 0.0165) and low doses of midazolam with a threshold of 17.5 mg/h (OR 0.97, 95% CI 0.95-1.00, p = 0.0232) significantly predicted adverse events. However, the model did not identify significant predictors for respiratory and neurological outcomes. CONCLUSIONS: Conclusively, IHTs in SAH patients are associated with relevant changes in hemodynamic, respiratory, and neurological monitoring parameters, with direct therapeutic consequences in 4/10 IHTs. These findings underscore the importance of further studies on the clinical impact of IHTs.

Phenobarbital in super-refractory status epilepticus (PIRATE): A retrospective, multicenter analysis.

OBJECTIVE: Super-refractory status epilepticus (SRSE) is an enduring or recurring SE after 24 h or more of general anesthesia. This study aimed to evaluate the efficacy and safety of phenobarbital (PB) for the treatment of SRSE. METHODS: This retrospective, multicenter study included neurointensive care unit (NICU) patients with SRSE treated with PB between September 2015 and September 2020 from six participating centers of the Initiative of German NeuroIntensive Trial Engagement (IGNITE) to evaluate the efficacy and safety of PB treatment for SRSE. The primary outcome measure was seizure termination. In addition, we evaluated maximum reached serum levels, treatment duration, and clinical complications using a multivariate generalized linear model. RESULTS: Ninety-one patients were included (45.1% female). Seizure termination was achieved in 54 patients (59.3%). Increasing serum levels of PB were associated with successful seizure control (per µg/mL: adjusted odds ratio [adj.OR] = 1.1, 95% confidence interval [CI] 1.0-1.2, p < .01). The median length of treatment in the NICU was 33.7 [23.2-56.6] days across groups. Clinical complications occurred in 89% (n = 81) of patients and included ICU-acquired infections, hypotension requiring catecholamine therapy, and anaphylactic shock. There was no association between clinical complications and treatment outcome or in-hospital mortality. The overall average modified Rankin scale (mRS) at discharge from the NICU was 5 ± 1. Six patients (6.6%) reached mRS ≤3, of whom five were successfully treated with PB. In-hospital mortality was significantly higher in patients in whom seizure control could not be achieved. SIGNIFICANCE: We observed a high rate in attainment of seizure control in patients treated with PB. Success of treatment correlated with higher dosing and serum levels. However, as one would expect in a cohort of critically ill patients with prolonged NICU treatment, the rate of favorable clinical outcome at discharge from the NICU remained extremely low. Further prospective studies evaluating long-term clinical outcome of PB treatment as well as an earlier use of PB at higher doses would be of value.

Sedation protocols in non-traumatic SAH (SPRINT-SAH): A cross-sectional survey among German-speaking neurointensivists.

Background: In subarachnoid hemorrhage (SAH), titrating sedation to find a balance between wakefulness with the ability to perform valid clinical examinations on the one hand, and deep sedation to minimize secondary brain damage, on the other hand, is challenging. However, data on this topic are scarce, and current guidelines do not provide recommendations for sedation protocols in SAH. Methods: We designed a web-based, cross-sectional survey for German-speaking neurointensivists to map current standards for the indication and monitoring of sedation, duration of prolonged sedation, and biomarkers for the withdrawal of sedation. Results: Overall, 17.4% (37/213) of neurointensivists answered the questionnaire. Most of the participants were neurologists (54.1%, 20/37) and exhibited a long-standing experience in intensive care medicine (14.9 years, SD 8.3). Among indications for prolonged sedation in SAH, the control of intracranial pressure (ICP) (94.6%) and status epilepticus (91.9%) were most significant. With regard to further complications in the course of the disease, therapy refractory ICP (45.9%, 17/37) and radiographic surrogates of elevated ICP, such as parenchymal swelling (35.1%, 13/37), were the most relevant topics for experts. Regular awakening trials were performed by 62.2% of neurointensivists (23/37). All participants used clinical examination for the therapeutic monitoring of sedation depth. A total of 83.8% of neurointensivists (31/37) used methods based on electroencephalography. As a mean duration of sedation before attempting an awakening trial in patients with unfavorable biomarkers, neurointensivists suggested 4.5 days (SD 1.8) for good-grade SAH and 5.6 days (SD 2.8) for poor-grade SAH, respectively. Many experts performed cranial imaging before the definite withdrawal of sedation [84.6% (22/26)], and 63.6% (14/22) of the participants required an absence of herniation, space-occupying lesions, or global cerebral edema. The values of ICP tolerated for definite withdrawal were smaller compared to that of awakening trials (17.3 mmHg vs. 22.1 mmHg), and patients were required to stay below the threshold value for several hours (21.3 h, SD 10.7). Conclusion: Despite the paucity of clear recommendations for sedation management in SAH in the pre-existing literature, we found some level of agreement indicating clinical efficacy for certain clinical practices. By mapping the current standard, this survey may help to identify controversial aspects in the clinical care of SAH and thereby streamline future research.

Diagnostic Utility of Temporal Muscle Thickness as a Monitoring Tool for Muscle Wasting in Neurocritical Care.

Temporalis muscle (TM) atrophy has emerged as a potential biomarker for muscle wasting. However, its diagnostic utility as a monitoring tool in intensive care remains uncertain. Hence, the objective of this study was to evaluate the diagnostic value of sequential ultrasound- and computed tomography (CT)-based measurements of TM thickness (TMT). With a prospective observational design, we included 40 patients without preexisting sarcopenia admitted to a neurointensive care unit. TMT measurements, performed upon admission and serially every 3−4 days, were correlated with rectus femoris muscle thickness (RFT) ultrasound measurements. Interrater reliability was assessed by Bland Altmann plots and intraclass correlation coefficient (ICC). Analysis of variance was performed in subgroups to evaluate differences in the standard error of measurement (SEM). RFT decline was paralleled by ultrasound- as well as CT-based TMT measurements (TMT to RFT: r = 0.746, p < 0.001; CT-based TMT to ultrasound-based RFT: r = 0.609, p < 0.001). ICC was 0.80 [95% CI 0.74, 0.84] for ultrasound-based assessment and 0.90 [95% CI 0.88, 0.92] for CT-based TMT measurements. Analysis of variance for BMI, Heckmatt score, fluid balance, and agitation showed no evidence of measurement errors in these subgroups. This study demonstrates the clinical feasibility and utility of ultrasound- and CT-based TMT measurements for the assessment of muscle wasting.

Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC.

BACKGROUND: Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients. METHODS: In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome. RESULTS: Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5-14.9, p < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9-8.2, p < 0.001) were the strongest predictors of poor outcome among the included patients. CONCLUSIONS: Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.

COVID-19 and Intracranial Hemorrhage: A Multicenter Case Series, Systematic Review and Pooled Analysis.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). RESULTS: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. CONCLUSION: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future.

Bispecific Antibodies Enable Synthetic Agonistic Receptor-Transduced T Cells for Tumor Immunotherapy.

PURPOSE: Genetically engineered T cells are powerful anticancer treatments but are limited by safety and specificity issues. We herein describe an MHC-unrestricted modular platform combining autologous T cells, transduced with a targetable synthetic agonistic receptor (SAR), with bispecific antibodies (BiAb) that specifically recruit and activate T cells for tumor killing. EXPERIMENTAL DESIGN: BiAbs of different formats were generated by recombinant expression. T cells were retrovirally transduced with SARs. T-cell activation, proliferation, differentiation, and T-cell-induced lysis were characterized in three murine and human tumor models in vitro and in vivo. RESULTS: Murine T cells transduced with SAR composed of an extracellular domain EGFRvIII fused to CD28 and CD3ζ signaling domains could be specifically recruited toward murine tumor cells expressing EpCAM by anti-EGFRvIII × anti-EpCAM BiAb. BiAb induced selective antigen-dependent activation, proliferation of SAR T cells, and redirected tumor cell lysis. Selectivity was dependent on the monovalency of the antibody for EGFRvIII. We identified FAS ligand as a major mediator of killing utilized by the T cells. Similarly, human SAR T cells could be specifically redirected toward mesothelin-expressing human pancreatic cancer cells. In vivo, treatment with SAR T cells and BiAb mediated antitumoral activity in three human pancreatic cancer cell xenograft models. Importantly, SAR activity, unlike CAR activity, was reversible in vitro and in vivo. CONCLUSIONS: We describe a novel ACT platform with antitumor activity in murine and human tumor models with a distinct mode of action that combines adoptive T-cell therapy with bispecific antibodies.