Subphenotypes in patients with acute respiratory distress syndrome treated with high-flow oxygen.

BACKGROUND: Acute respiratory distress syndrome (ARDS) subphenotypes differ in outcomes and treatment responses. Subphenotypes in high-flow nasal oxygen (HFNO)-treated ARDS patients have not been investigated. OBJECTIVES: To identify biological subphenotypes in HFNO-treated ARDS patients. METHODS: Secondary analysis of a prospective multicenter observational study including ARDS patients supported with HFNO. Plasma inflammation markers (interleukin [IL]-6, IL-8, and IL-33 and soluble suppression of tumorigenicity-2 [sST2]) and lung epithelial (receptor for advanced glycation end products [RAGE] and surfactant protein D [SP-D]) and endothelial (angiopoietin-2 [Ang-2]) injury were measured. These biomarkers and bicarbonate were used in K-means cluster analysis to identify subphenotypes. Logistic regression was performed on biomarker combinations to predict clustering. We chose the model with the best AUROC and the lowest number of variables. This model was used to describe the HAIS (High-flow ARDS Inflammatory Subphenotype) score. RESULTS: Among 41 HFNO patients, two subphenotypes were identified. Hyperinflammatory subphenotype (n = 17) showed higher biomarker levels than hypoinflammatory (n = 24). Despite similar baseline characteristics, the hyperinflammatory subphenotype had higher 60-day mortality (47 vs 8.3% p = 0.014) and longer ICU length of stay (22.0 days [18.0-30.0] vs 39.5 [25.5-60.0], p = 0.034). The HAIS score, based on IL-8 and sST2, accurately distinguished subphenotypes (AUROC 0.96 [95%CI: 0.90-1.00]). A HAIS score ≥ 7.45 was predictor of hyperinflammatory subphenotype. CONCLUSION: ARDS patients treated with HFNO exhibit two biological subphenotypes that have similar clinical characteristics, but hyperinflammatory patients have worse outcomes. The HAIS score may identify patients with hyperinflammatory subphenotype and might be used for enrichment strategies in future clinical trials.

Repurposing electroencephalogram monitoring of general anaesthesia for building biomarkers of brain ageing: an exploratory study.

Background: Electroencephalography (EEG) is increasingly used for monitoring the depth of general anaesthesia, but EEG data from general anaesthesia monitoring are rarely reused for research. Here, we explored repurposing EEG monitoring from general anaesthesia for brain-age modelling using machine learning. We hypothesised that brain age estimated from EEG during general anaesthesia is associated with perioperative risk. Methods: We reanalysed four-electrode EEGs of 323 patients under stable propofol or sevoflurane anaesthesia to study four EEG signatures (95% of EEG power <8-13 Hz) for age prediction: total power, alpha-band power (8-13 Hz), power spectrum, and spatial patterns in frequency bands. We constructed age-prediction models from EEGs of a healthy reference group (ASA 1 or 2) during propofol anaesthesia. Although all signatures were informative, state-of-the-art age-prediction performance was unlocked by parsing spatial patterns across electrodes along the entire power spectrum (mean absolute error=8.2 yr; R2=0.65). Results: Clinical exploration in ASA 1 or 2 patients revealed that brain age was positively correlated with intraoperative burst suppression, a risk factor for general anaesthesia complications. Surprisingly, brain age was negatively correlated with burst suppression in patients with higher ASA scores, suggesting hidden confounders. Secondary analyses revealed that age-related EEG signatures were specific to propofol anaesthesia, reflected by limited model generalisation to anaesthesia maintained with sevoflurane. Conclusions: Although EEG from general anaesthesia may enable state-of-the-art age prediction, differences between anaesthetic drugs can impact the effectiveness and validity of brain-age models. To unleash the dormant potential of EEG monitoring for clinical research, larger datasets from heterogeneous populations with precisely documented drug dosage will be essential.

Association of sleep and anaesthesia EEG biomarkers with preoperative MoCA score: A pilot study.

INTRODUCTION: Preoperative cognitive impairments increase the risk of postoperative complications. The electroencephalogram (EEG) could provide information on cognitive vulnerability. The feasibility and clinical relevance of sleep EEG (EEGsleep ) compared to intraoperative EEG (EEGintraop ) in cognitive risk stratification remains to be explored. We investigated similarities between EEGsleep and EEGintraop vis-a-vis preoperative cognitive impairments. METHODS: Pilot study including 27 patients (63 year old [53.5, 70.0]) to whom Montreal cognitive assessment (MoCA) and EEGsleep were administered 1 day before a propofol-based general anaesthesia, in addition to EEGintraop acquisition from depth-of-anaesthesia monitors. Sleep spindles on EEGsleep and intraoperative alpha-band power on EEGintraop were particularly explored. RESULTS: In total, 11 (41%) patients had a MoCA <25 points. These patients had a significantly lower sleep spindle power on EEGsleep (25 vs. 40 µv2 /Hz, p = .035) and had a weaker intraoperative alpha-band power on EEGintraop (85 vs. 150 µv2 /Hz, p = .001) compared to patients with normal MoCA. Correlation between sleep spindle and intraoperative alpha-band power was positive and significant (r = 0.544, p = .003). CONCLUSION: Preoperative cognitive impairment appears to be detectable by both EEGsleep and EEGintraop . Preoperative sleep EEG to assess perioperative cognitive risk is feasible but more data are needed to demonstrate its benefit compared to intraoperative EEG.

Management strategies in clival and craniovertebral junction chordomas: a 29-year experience.

OBJECTIVE: Chordomas represent one of the most challenging subsets of skull base and craniovertebral junction (CVJ) tumors to treat. Despite extensive resection followed by proton-beam radiation therapy, the recurrence rate remains high, highlighting the importance of developing efficient treatment strategies. In this study, the authors present their experience in treating clival and CVJ chordomas over a 29-year period. METHODS: The authors conducted a retrospective study of clival and CVJ chordomas that were surgically treated at their institution from 1991 to 2020. This study focuses on three aspects of the management of these tumors: the factors influencing the extent of resection (EOR), the predictors of survival, and the outcomes of the endoscopic endonasal approaches (EEAs) compared with open approaches (OAs). RESULTS: A total of 265 surgical procedures were performed in 210 patients, including 123 OAs (46.4%) and 142 EEAs (53.6%). Tumors that had an intradural extension (p = 0.03), brainstem contact (p = 0.005), cavernous sinus extension (p = 0.004), major artery encasement (p = 0.01), petrous apex extension (p = 0.003), or high volume (p = 0.0003) were significantly associated with a lower EOR. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 52.1% and 75.1%, respectively. Gross-total resection and Ki-67 labeling index < 6% were considered to be independent prognostic factors of longer PFS (p = 0.0005 and p = 0.003, respectively) and OS (p = 0.02 and p = 0.03, respectively). Postoperative radiation therapy correlated independently with a longer PFS (p = 0.006). Previous surgical treatment was associated with a lower EOR (p = 0.01) and a higher rate of CSF leakage after EEAs (p = 0.02) but did not have significantly lower PFS and OS compared with primary surgery. Previously radiation therapy correlated with a worse outcome, with lower PFS and OS (p = 0.001 and p = 0.007, respectively). EEAs were more frequently used in patients with upper and middle clival tumors (p = 0.002 and p < 0.0001, respectively), had a better rate of EOR (p = 0.003), and had a lower risk of de novo neurological deficit (p < 0.0001) compared with OAs. The overall rate of postoperative CSF leakage after EEAs was 14.8%. CONCLUSIONS: This large study showed that gross-total resection should be attempted in a multidisciplinary skull base center before providing radiation therapy. EEAs should be considered as the gold-standard approach for upper/middle clival lesions based on the satisfactory surgical outcome, but OAs remain important tools for large complex chordomas.

proANP Metabolism Provides New Insights Into Sacubitril/Valsartan Mode of Action.

BACKGROUND: Sacubitril/valsartan (S/V) treatment is beneficial in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase in ANP (atrial natriuretic peptide). METHODS: Combining mass spectrometry and enzymatic assay in the plasma of 73 HFrEF patients treated with S/V and controls, we deciphered proANP processing that converts proANP into 4 vasoactive peptides. RESULTS: We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p, hence increasing levels of proANP-derived bioactive peptides. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, and possibly hypotension. Furthermore, proANP glycosylation interferes with the midregional proANP assay -a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. The analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects. CONCLUSIONS: These findings offer mechanistic evidence to the natriuretic peptide -defective state in HFrEF, which is improved by S/V. These data also strongly suggests that S/V increases plasma ANP by multiple mechanisms that involve 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.

The ICEBERG: A score and visual representation to track the severity of traumatic brain injury: Design principles and preliminary results.

BACKGROUND: Establishing neurological prognoses in traumatic brain injury (TBI) patients remains challenging. To help physicians in the early management of severe TBI, we have designed a visual score (ICEBERG score) including multimodal monitoring and treatment-related criteria. We evaluated the ICEBERG scores among patients with severe TBI to predict the 28-day mortality and long-term disability (Extended Glasgow Outcome Scale score at 3 years). In addition, we made a preliminary assessment of the nurses and doctors on the uptake and reception to the use of the ICEBERG visual tool. METHODS: This study was part of a larger prospective cohort study of 207 patients with severe TBI in the Parisian region (PariS-TBI study). The ICEBERG score included six variables from multimodal monitoring and treatment-related criteria: cerebral perfusion pressure, intracranial pressure, body temperature, sedation depth, arterial partial pressure of CO 2 , and blood osmolarity. The primary outcome measures included the ICEBERG score and its relationship with hospital mortality and Extended Glasgow Outcome Score. RESULTS: The hospital mortality was 21% (45/207). The ICEBERG score baseline value and changes during the 72nd first hours were more strongly associated with TBI prognosis than the ICEBERG parameters measured individually. Interestingly, when the clinical and computed tomography parameters at admission were combined with the ICEBERG score at 48 hours using a multimodal approach, the predictive value was significantly increased (area under the curve = 0.92). Furthermore, comparing the ICEBERG visual representation with the traditional numerical readout revealed that changes in patient vitals were more promptly detected using ICEBERG representation ( p < 0.05). CONCLUSION: The ICEBERG score could represent a simple and effective method to describe severity in TBI patients, where a high score is associated with increased mortality and disability. In addition, ICEBERG representation could enhance the recognition of unmet therapeutic goals and dynamic evolution of the patient's condition. These preliminary results must be confirmed in a prospective manner. LEVEL OF EVIDENCE: Diagnostic Tests or Criteria; Level III.

Impact of impaired cerebral blood flow autoregulation on electroencephalogram signals in adults undergoing propofol anaesthesia: a pilot study.

Background: Cerebral autoregulation actively maintains cerebral blood flow over a range of MAPs. During general anaesthesia, this mechanism may not compensate for reductions in MAP leading to brain hypoperfusion. Cerebral autoregulation can be assessed using the mean flow index derived from Doppler measurements of average blood velocity in the middle cerebral artery, but this is impractical for routine monitoring within the operating room. Here, we investigate the possibility of using the EEG as a proxy measure for a loss of cerebral autoregulation, determined by the mean flow index. Methods: Thirty-six patients (57.5 [44.25; 66.5] yr; 38.9% women, non-emergency neuroradiology surgery) anaesthetised using propofol were prospectively studied. Continuous recordings of MAP, average blood velocity in the middle cerebral artery, EEG, and regional cerebral oxygen saturation were made. Poor cerebral autoregulation was defined as a mean flow index greater than 0.3. Results: Eighteen patients had preserved cerebral autoregulation, and 18 had altered cerebral autoregulation. The two groups had similar ages, MAPs, and average blood velocities in the middle cerebral artery. Patients with altered cerebral autoregulation exhibited a significantly slower alpha peak frequency (9.4 [9.0, 9.9] Hz vs 10.5 [10.1, 10.9] Hz, P<0.001), which persisted after adjusting for age, norepinephrine infusion rate, and ASA class (odds ratio=0.038 [confidence interval, 0.004, 0.409]; P=0.007). Conclusion: In this pilot study, we found that loss of cerebral autoregulation was associated with a slower alpha peak frequency, independent of age. This work suggests that impaired cerebral autoregulation could be monitored in the operating room using the existing EEG setup. Clinical trial registration: NCT03769142.

Simplified frontal EEG in adults under veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: EEG-based prognostication studies in intensive care units often rely on a standard 21-electrode montage (stdEEG) requiring substantial human, technical, and financial resources. We here evaluate whether a simplified 4-frontal electrode montage (4-frontEEG) can detect EEG patterns associated with poor outcomes in adult patients under veno-arterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: We conducted a reanalysis of EEG data from a prospective cohort on 118 adult patients under VA-ECMO, in whom EEG was performed on admission to intensive care. EEG patterns of interest included background rhythm, discontinuity, reactivity, and the Synek's score. They were all reassessed by an intensivist on a 4-frontEEG montage, whose analysis was then compared to an expert's interpretation made on stdEEG recordings. The main outcome measure was the degree of correlation between 4-frontEEG and stdEEG montages to identify EEG patterns of interest. The performance of the Synek scores calculated on 4-frontEEG and stdEEG montage to predict outcomes (i.e., 28-day mortality and 90-day Rankin score [Formula: see text]) was investigated in a secondary exploratory analysis. RESULTS: The detection of EEG patterns using 4-frontEEG was statistically similar to that of stdEEG for background rhythm (Spearman rank test, ρ = 0.66, p < 0.001), discontinuity (Cohen's kappa, [Formula: see text] = 0.955), reactivity ([Formula: see text] = 0.739) and the Synek's score (ρ = 0.794, p < 0.001). Using the Synek classification, we found similar performances between 4-frontEEG and stdEEG montages in predicting 28-day mortality (AUC 4-frontEEG 0.71, AUC stdEEG 0.68) and for 90-day poor neurologic outcome (AUC 4-frontEEG 0.71, AUC stdEEG 0.66). An exploratory analysis confirmed that the Synek scores determined by 4 or 21 electrodes were independently associated with 28-day mortality and poor 90-day functional outcome. CONCLUSION: In adult patients under VA-ECMO, a simplified 4-frontal electrode EEG montage interpreted by an intensivist, detected common EEG patterns associated with poor outcomes, with a performance similar to that of a standard EEG montage interpreted by expert neurophysiologists. This simplified montage could be implemented as part of a multimodal evaluation for bedside prognostication.

Tumor Growth Rate as a New Predictor of Progression-Free Survival After Chordoma Surgery.

BACKGROUND: Currently, different postoperative predictors of chordoma recurrence have been identified. Tumor growth rate (TGR) is an image-based calculation that provides quantitative information of tumor's volume changing over time and has been shown to predict progression-free survival (PFS) in other tumor types. OBJECTIVE: To explore the usefulness of TGR as a new preoperative radiological marker for chordoma recurrence. METHODS: A retrospective single-institution study was carried out including patients reflecting these criteria: confirmed diagnosis of chordoma on pathological analysis, no history of previous radiation, and at least 2 preoperative thin-slice magnetic resonance images available to measure TGR. TGR was calculated for all patients, showing the percentage change in tumor size over 1 mo. RESULTS: A total of 32 patients were retained for analysis. Patients with a TGR ≥ 10.12%/m had a statistically significantly lower mean PFS (P < .0001). TGR ≥ 10.12%/m (odds ratio = 26, P = .001) was observed more frequently in recurrent chordoma. In a subgroup analysis, we found that the association of Ki-67 labeling index ≥ 6% and TGR ≥ 10.12%/m was correlated with recurrence (P = .0008). CONCLUSION: TGR may be considered as a preoperative radiological indicator of tumor proliferation and seems to preoperatively identify more aggressive tumors with a higher tendency to recur. Our findings suggest that the therapeutic strategy and clinical-radiological follow-up of patients with chordoma can be adapted also according to this new parameter.

Propofol Requirement and EEG Alpha Band Power During General Anesthesia Provide Complementary Views on Preoperative Cognitive Decline.

Background: Although cognitive decline (CD) is associated with increased post-operative morbidity and mortality, routinely screening patients remains difficult. The main objective of this prospective study is to use the EEG response to a Propofol-based general anesthesia (GA) to reveal CD. Methods: 42 patients with collected EEG and Propofol target concentration infusion (TCI) during GA had a preoperative cognitive assessment using MoCA. We evaluated the performance of three variables to detect CD (MoCA < 25 points): age, Propofol requirement to induce unconsciousness (TCI at SEF95: 8-13 Hz) and the frontal alpha band power (AP at SEF95: 8-13 Hz). Results: The 17 patients (40%) with CD were significantly older (p < 0.001), had lower TCI (p < 0.001), and AP (p < 0.001). We found using logistic models that TCI and AP were the best set of variables associated with CD (AUC: 0.89) and performed better than age (p < 0.05). Propofol TCI had a greater impact on CD probability compared to AP, although both were complementary in detecting CD. Conclusion: TCI and AP contribute additively to reveal patient with preoperative cognitive decline. Further research on post-operative cognitive trajectory are necessary to confirm the interest of intra operative variables in addition or as a substitute to cognitive evaluation.

Alpha rhythm collapse predicts iso-electric suppressions during anesthesia.

Could an overly deep sedation be anticipated from ElectroEncephaloGram (EEG) patterns? We report here motifs hidden in the EEG signal that predict the appearance of Iso-Electric Suppressions (IES), observed during epileptic encephalopathies, drug intoxications, comatose, brain death or during anesthetic over-dosage that are considered to be detrimental. To show that IES occurrences can be predicted from EEG traces dynamics, we focus on transient suppression of the alpha rhythm (8-14 Hz) recorded for 80 patients, that had a Propofol target controlled infusion of 5 µg/ml during a general anesthesia. We found that the first time of appearance as well as changes in duration of these Alpha-Suppressions (αS) are two parameters that anticipate the appearance of IES. Using machine learning, we predicted IES appearance from the first 10 min of EEG (AUC of 0.93). To conclude, transient motifs in the alpha rhythm predict IES during anesthesia and can be used to identify patients, with higher risks of post-operative complications.

EEG power spectral density under Propofol and its association with burst suppression, a marker of cerebral fragility.

OBJECTIVE: Under General Anesthesia (GA), age and Burst Suppression (BS) are associated with cognitive postoperative complications, yet how these parameters are related to per-operative EEG and hypnotic doses is unclear. In this prospective study, we address this question comparing age and BS occurrences with a new score (BPTIVA) based on Propofol doses, EEG and alpha-band power spectral densities, evaluated for SEF95 = 8-13 Hz. METHODS: 59 patients (55 [34-67] yr, 67% female) undergoing neuroradiology or orthopedic surgery were included. Total IntraVenous Anesthesia was used for Propofol and analgesics infusion. Cerebral activity was monitored from a frontal electrodes montage EEG. RESULTS: BPTIVA was inversely correlated with age (Pearson r = -0.78, p < 0.001), and was significantly lower (p < 0.001) when BS occurred during the GA first minutes (induction). Additionally, the age-free BPTIVA score was better associated with BS at induction than age (AUC = 0.94 versus 0.82, p < 0.05). CONCLUSION: We designed BPTIVA score based on hypnotics and EEG. It was correlated with age yet was better associated to BS occurring during GA induction, the latter being a cerebral fragility sign. SIGNIFICANCE: This advocate for an approach based on evaluating the cerebral physiological age («brain age¼) to predict postoperative cognitive evolution.

Deconvolution of Voltage Sensor Time Series and Electro-diffusion Modeling Reveal the Role of Spine Geometry in Controlling Synaptic Strength.

Most synaptic excitatory connections are made on dendritic spines. But how the voltage in spines is modulated by its geometry remains unclear. To investigate the electrical properties of spines, we combine voltage imaging data with electro-diffusion modeling. We first present a temporal deconvolution procedure for the genetically encoded voltage sensor expressed in hippocampal cultured neurons and then use electro-diffusion theory to compute the electric field and the current-voltage conversion. We extract a range for the neck resistances of 〈R〉=100±35MΩ. When a significant current is injected in a spine, the neck resistance can be inversely proportional to its radius, but not to the radius square, as predicted by Ohm's law. We conclude that the postsynaptic voltage cannot only be modulated by changing the number of receptors, but also by the spine geometry. Thus, spine morphology could be a key component in determining synaptic transduction and plasticity.