Early Metabolic Disruption and Predictive Biomarkers of Delayed-Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) is a major cause of complications and death. Here, we set out to identify high-performance predictive biomarkers of DCI and its underlying metabolic disruptions using metabolomics and lipidomics approaches. This single-center prospective observational study enrolled 61 consecutive patients with severe aSAH; among them, 22 experienced a DCI. Nine patients without aSAH were included as validation controls. Blood and cerebrospinal fluid (CSF) were sampled within the first 24 h after admission. We identified a panel of 20 metabolites that, together, showed high predictive performance for DCI. This panel of metabolites included lactate, cotinine, salicylate, 6 phosphatidylcholines, and 4 sphingomyelins. The interplay of the metabolome and the lipidome found between CSF and plasma in our patients underscores that aSAH and its associated DCI complications can extend beyond cerebral implications, with a peripheral dimension as well. As an illustration, early biological disruptions that might explain the subsequent DCI found systemic hypoxia driven mainly by higher blood lactate, arginine, and proline metabolism likely associated with vascular NO and disrupted ceramide/sphingolipid metabolism. We conclude that targeting early peripheral hypoxia preceding DCI could provide an interesting strategy for the prevention of vascular dysfunction.

Comparison of scales for the evaluation of aneurysmal subarachnoid haemorrhage: a retrospective cohort study.

BACKGROUND/OBJECTIVES: Aneurysmal subarachnoid haemorrhage (aSAH) is a life-threatening event with major complications. Delayed cerebral infarct (DCI) occurs most frequently 7 days after aSAH and can last for a prolonged period. To determine the most predictive radiological scales in grading subarachnoid or ventricular haemorrhage or both for functional outcome at 3 months in a large aSAH population, we conducted a single-centre retrospective study. METHODS: A 3-year single-centre retrospective cohort study of 230 patients hospitalised for aSAH was analysed. Initial computed tomography (CT) scans in patients hospitalised for aSAH were blindly assessed using eight grading systems: the Fisher grade, modified Fisher grade, Barrow Neurological Institute scale, Hijdra scale, Intraventricular Haemorrhage (IVH) score, Graeb score and LeRoux score. RESULTS: Of 200 patients with aSAH who survived to day 7 and were included for DCI analysis, 39% of cases were complicated with DCI. The Hijdra scale was the best predictor for DCI, with a receiver operating characteristic area under the curve (ROCAUC) of 0.80 (95% confidence interval (CI), 0.74-0.85). The IVH score was the most effective grading system for predicting acute hydrocephalus, with a ROCAUC of 0.85 (95% CI, 0.79-0.89). In multivariate analysis, the Hijdra scale was the best predictor of the occurrence of DCI (hazard ratio, 1.18; 95% CI, 1.10-1.25). CONCLUSIONS: Although these results have yet to be prospectively confirmed, our findings suggest that the Hijdra scale may be a good predictor of DCI and could be useful in daily clinical practice. CLINICAL RELEVANCE STATEMENT: Better assessment of subarachnoid haemorrhage patients would allow for better prognostication and management of expectations, as well as referral for appropriate services and helping to appropriate use limited critical care resources. KEY POINTS: Aneurysmal subarachnoid haemorrhage is a life-threatening event that causes severe disability and leads to major complications such as delayed cerebral infarction. Accurate assessment of the amount of blood in the subarachnoid spaces on computed tomography with the Hijdra scale can better predict the risk of delayed cerebral infarct. The Hijdra scale could be a good triage tool for subarachnoid haemorrhage patients.

Predictive Modeling of COVID-19 Intensive Care Unit Patient Flows and Nursing Complexity: A Monte Carlo Simulation Study.

This study aimed to develop a Monte Carlo simulation model to forecast the number of ICU beds needed for COVID-19 patients and the subsequent nursing complexity in a French teaching hospital during the first and second pandemic outbreaks. The model used patient data from March 2020 to September 2021, including age, sex, ICU length of stay, and number of patients on mechanical ventilation or extracorporeal membrane oxygenation. Nursing complexity was assessed using a simple scale with three levels based on patient status. The simulation was performed 1000 times to generate a scenario, and the mean outcome was compared with the observed outcome. The model also allowed for a 7-day forecast of ICU occupancy. The simulation output had a good fit with the actual data, with an R2 of 0.998 and a root mean square error of 0.22. The study demonstrated the usefulness of the Monte Carlo simulation model for predicting the demand for ICU beds and could help optimize resource allocation during a pandemic. The model's extrinsic validity was confirmed using open data from the French Public Health Authority. This study provides a valuable tool for healthcare systems to anticipate and manage surges in ICU demand during pandemics.

Impact of piperacillin unbound fraction variability on dosing recommendations in critically ill patients.

A common approach to assess the efficacy of piperacillin is to first measure the total concentration and afterwards apply a theoretical unbound fraction of 70% to obtain the unbound concentration. However, hypoalbuminemia is a common phenomenon in critically ill patients, resulting in variations in unbound fraction, therefore we aimed to simulate the impact of piperacillin unbound fraction fluctuations on the predictive performance of a population pharmacokinetic model and on the dosing recommendations of piperacillin. Unbound factors of 70%, 75%, 80% and 85% were applied to total concentrations of piperacillin administered by continuous infusion from an external dataset. A validated model was used for assessment of predictive performance and to estimate patient clearance. Dosing simulations were performed to evaluate target attainment. Variation in unbound fractions caused minimal impact on piperacillin clearance and target attainment but seemed to influence model validity.

Deep Brain Stimulation-Withdrawal Syndrome in Parkinson's Disease: Risk Factors and Pathophysiological Hypotheses of a Life-Threatening Emergency.

BACKGROUND AND OBJECTIVES: Subthalamic nucleus deep brain stimulation (DBS) is the most common therapeutic surgical procedure for patients with Parkinson's disease with motor fluctuations, dyskinesia, or tremor. Routine follow-up of patients allows clinicians to anticipate replacement of the DBS battery reaching the end of its life. Patients who experience a sudden stop of the DBS battery experience a rapid worsening of symptoms unresponsive to high dose of levodopa, in a life-threatening phenomenon called "DBS-withdrawal syndrome." In the current context of the COVID-19 pandemic, in which many surgeries are being deprogrammed, it is of utmost importance to determine to what extent DBS battery replacement surgeries should be considered an emergency. In this study, we attempt to identify risk factors of DBS-withdrawal syndrome and provide new insights about pathophysiological hypotheses. We then elaborate on the optimal approach to avoid and manage such a situation. MATERIALS AND METHODS: We conducted a systematic review of the literature on the subject and reported the cases of 20 patients (including five from our experience) with DBS-withdrawal syndrome, comparing them with 15 undisturbed patients (including three from our experience), all having undergone neurostimulation discontinuation. RESULTS: A long disease duration at battery removal and many years of DBS therapy are the main potential identified risk factors (p < 0.005). In addition, a trend for older age at the event and higher Unified Parkinson's Disease Rating Scale motor score before initial DBS implantation (evaluated in OFF-drug condition) was found (p < 0.05). We discuss several hypotheses that might explain this phenomenon, including discontinued functioning of the thalamic-basal ganglia loop due to DBS-stimulation cessation in a context in which cortical-basal ganglia loop had lost its cortical input, and possible onset of a severe bradykinesia through the simultaneous occurrence of an alpha and high-beta synchronized state. CONCLUSIONS: The patients' clinical condition may deteriorate rapidly, be unresponsive to high dose of levodopa, and become life-threatening. Hospitalization is suggested for clinical monitoring. In the context of the current COVID-19 pandemic, it is important to widely communicate the replacement of DBS batteries reaching the end of their life. More importantly, in cases in which the battery has stopped, there should be no delay in performing replacement as an emergent surgery.

Avdoralimab (Anti-C5aR1 mAb) Versus Placebo in Patients With Severe COVID-19: Results From a Randomized Controlled Trial (FOR COVID Elimination [FORCE]).

OBJECTIVES: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19. DESIGN: FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study. SETTING: Twelve clinical sites in France (ICU and general hospitals). PATIENTS: Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3. INTERVENTIONS: Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2. MEASUREMENTS AND MAIN RESULTS: We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified. CONCLUSIONS: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367).

Synergistic Role of Quantitative Diffusion Magnetic Resonance Imaging and Structural Magnetic Resonance Imaging in Predicting Outcomes After Traumatic Brain Injury.

OBJECTIVE: This study aimed to assess if quantitative diffusion magnetic resonance imaging analysis would improve prognostication of individual patients with severe traumatic brain injury. METHODS: We analyzed images of 30 healthy controls to extract normal fractional anisotropy ranges along 18 white-matter tracts. Then, we analyzed images of 33 patients, compared their fractional anisotropy values with normal ranges extracted from controls, and computed severity of injury to white-matter tracts. We also asked 2 neuroradiologists to rate severity of injury to different brain regions on fluid-attenuated inversion recovery and susceptibility-weighted imaging. Finally, we built 3 models: (1) fed with neuroradiologists' ratings, (2) fed with white-matter injury measures, and (3) fed with both input types. RESULTS: The 3 models respectively predicted survival at 1 year with accuracies of 70%, 73%, and 88%. The accuracy with both input types was significantly better (P < 0.05). CONCLUSIONS: Quantifying severity of injury to white-matter tracts complements qualitative imaging findings and improves outcome prediction in severe traumatic brain injury.

Early Left-Planum Temporale Asymmetry in newborn monkeys (Papio anubis): A longitudinal structural MRI study at two stages of development.

The "language-ready" brain theory suggests that the infant brain is pre-wired for language acquisition prior to language exposure. As a potential brain marker of such a language readiness, a leftward structural brain asymmetry was found in human infants for the Planum Temporale (PT), which overlaps with Wernicke's area. In the present longitudinal in vivo MRI study conducted in 35 newborn monkeys (Papio anubis), we found a similar leftward PT surface asymmetry. Follow-up rescanning sessions on 29 juvenile baboons at 7-10 months showed that such an asymmetry increases across the two ages classes. These original findings in non-linguistic primate infants strongly question the idea that the early PT asymmetry constitutes a human infant-specific marker for language development. Such a shared early perisylvian organization provides additional support that PT asymmetry might be related to a lateralized system inherited from our last common ancestor with Old-World monkeys at least 25-35 million years ago.

CSF concentration of cefotaxime in adult patients with pneumococcal meningitis: a multicentre retrospective study.

BACKGROUND AND OBJECTIVES: Pneumococcal meningitis is a devastating disease that requires adequate meningeal antibiotic penetration to limit the mortality. Despite a large usage in this indication, data about CSF concentration of cefotaxime during pneumococcal meningitis in adults are scarce. Therefore, we aimed to describe the CSF concentration obtained after high-dose cefotaxime administration in adult patients treated for Streptococcus pneumoniae meningitis. PATIENTS AND METHODS: In this multicentre, observational, retrospective study, cases of adult patients with S. pneumoniae meningitis hospitalized between January 2013 and October 2019 for whom cefotaxime concentration was measured in CSF were reviewed. RESULTS: Cefotaxime concentration was analysed in 44 CSF samples collected among 31 patients. Median (IQR) age was 61 years (52-69). Dexamethasone was administered in 27 subjects. Median (IQR) cefotaxime daily dosage was 15 g (12-19), corresponding to 200 mg/kg (150-280). CSF samples were collected approximately 5 days after cefotaxime initiation. Median (IQR, range) cefotaxime CSF concentration was 10.3 mg/L (4.8-19.3, 1.2-43.4). Median (range) MIC for Streptococcus pneumoniae was 0.25 mg/L (0.008-1) (n = 22). The median (IQR, range) CSF/MIC ratio was 38 (12-146, 4-1844). Twenty-five CSF concentrations (81%) were above 10 times the MIC. Cefotaxime was discontinued in two patients for toxicity. In-hospital mortality rate was 29%. CONCLUSIONS: Adult patients with pneumococcal meningitis treated with a high dose of cefotaxime (200 mg/kg/day) had elevated CSF concentrations with satisfying pharmacokinetics/pharmacodynamics parameters and tolerability profile. This study brings reassuring pharmacological data regarding the use of high-dose cefotaxime monotherapy for treating pneumococcal meningitis with susceptible strains to cefotaxime.

Perioperative Open-lung Approach, Regional Ventilation, and Lung Injury in Cardiac Surgery.

BACKGROUND: In the Protective Ventilation in Cardiac Surgery (PROVECS) randomized, controlled trial, an open-lung ventilation strategy did not improve postoperative respiratory outcomes after on-pump cardiac surgery. In this prespecified subanalysis, the authors aimed to assess the regional distribution of ventilation and plasma biomarkers of lung epithelial and endothelial injury produced by that strategy. METHODS: Perioperative open-lung ventilation consisted of recruitment maneuvers, positive end-expiratory pressure (PEEP) = 8 cm H2O, and low-tidal volume ventilation including during cardiopulmonary bypass. Control ventilation strategy was a low-PEEP (2 cm H2O) low-tidal volume approach. Electrical impedance tomography was used serially throughout the perioperative period (n = 56) to compute the dorsal fraction of ventilation (defined as the ratio of dorsal tidal impedance variation to global tidal impedance variation). Lung injury was assessed serially using biomarkers of epithelial (soluble form of the receptor for advanced glycation end-products, sRAGE) and endothelial (angiopoietin-2) lung injury (n = 30). RESULTS: Eighty-six patients (age = 64 ± 12 yr; EuroSCORE II = 1.65 ± 1.57%) undergoing elective on-pump cardiac surgery were studied. Induction of general anesthesia was associated with ventral redistribution of tidal volumes and higher dorsal fraction of ventilation in the open-lung than the control strategy (0.38 ± 0.07 vs. 0.30 ± 0.10; P = 0.004). No effect of the open-lung strategy on the dorsal fraction of ventilation was noted at the end of surgery after median sternotomy closure (open-lung = 0.37 ± 0.09 vs. control = 0.34 ± 0.11; P = 0.743) or in extubated patients at postoperative day 2 (open-lung = 0.63 ± 0.18 vs. control = 0.59 ± 0.11; P > 0.999). Open-lung ventilation was associated with increased intraoperative plasma sRAGE (7,677 ± 3,097 pg/ml vs. 6,125 ± 1,400 pg/ml; P = 0.037) and had no effect on angiopoietin-2 (P > 0.999). CONCLUSIONS: In cardiac surgery patients, open-lung ventilation provided larger dorsal lung ventilation early during surgery without a maintained benefit as compared with controls at the end of surgery and postoperative day 2 and was associated with higher intraoperative plasma concentration of sRAGE suggesting lung overdistension.

Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.

BACKGROUND: Acute acidaemia is frequently observed during critical illness. Sodium bicarbonate infusion for the treatment of severe metabolic acidaemia is a possible treatment option but remains controversial, as no studies to date have examined its effect on clinical outcomes. Therefore, we aimed to evaluate whether sodium bicarbonate infusion would improve these outcomes in critically ill patients. METHODS: We did a multicentre, open-label, randomised controlled, phase 3 trial. Local investigators screened eligible patients from 26 intensive care units (ICUs) in France. We included adult patients (aged ≥18 years) who were admitted within 48 h to the ICU with severe acidaemia (pH ≤7·20, PaCO2 ≤45 mm Hg, and sodium bicarbonate concentration ≤20 mmol/L) and with a total Sequential Organ Failure Assessment score of 4 or more or an arterial lactate concentration of 2 mmol/L or more. We randomly assigned patients (1:1), by stratified randomisation with minimisation via a restricted web platform, to receive either no sodium bicarbonate (control group) or 4·2% of intravenous sodium bicarbonate infusion (bicarbonate group) to maintain the arterial pH above 7·30. Our protocol recommended that the volume of each infusion should be within the range of 125-250 mL in 30 min, with a maximum of 1000 mL within 24 h after inclusion. Randomisation criteria were stratified among three prespecified strata: age, sepsis status, and the Acute Kidney Injury Network (AKIN) score. The primary outcome was a composite of death from any cause by day 28 and the presence of at least one organ failure at day 7. All analyses were done on data from the intention-to-treat population, which included all patients who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02476253. FINDINGS: Between May 5, 2015, and May 7, 2017, we enrolled 389 patients into the intention-to-treat analysis in the overall population (194 in the control group and 195 in the bicarbonate group). The primary outcome occurred in 138 (71%) of 194 patients in the control group and 128 (66%) of 195 in the bicarbonate group (absolute difference estimate -5·5%, 95% CI -15·2 to 4·2; p=0·24). The Kaplan-Meier method estimate of the probability of survival at day 28 between the control group and bicarbonate group was not significant (46% [95% CI 40-54] vs 55% [49-63]; p=0·09. In the prespecified AKIN stratum of patients with a score of 2 or 3, the Kaplan-Meier method estimate of survival by day 28 between the control group and bicarbonate group was significant (37% [95% CI 28-48] vs 54% [45-65]; p=0·0283). [corrected] Metabolic alkalosis, hypernatraemia, and hypocalcaemia were observed more frequently in the bicarbonate group than in the control group, with no life-threatening complications reported. INTERPRETATION: In patients with severe metabolic acidaemia, sodium bicarbonate had no effect on the primary composite outcome. However, sodium bicarbonate decreased the primary composite outcome and day 28 mortality in the a-priori defined stratum of patients with acute kidney injury. FUNDING: French Ministry of Health and the Société Française d'Anesthésie Réanimation.

Thromboxane-prostaglandin receptor antagonist, terutroban, prevents neurovascular events after subarachnoid haemorrhage: a nanoSPECT study in rats.

BACKGROUND: Several lipid metabolites in cerebrospinal fluid are correlated with poor outcomes in aneurysmal subarachnoid haemorrhage. Most of these metabolites bind to ubiquitous thromboxane-prostaglandin (TP) receptors, causing vasoconstriction and inflammation. Here, we evaluated terutroban (TBN), a specific TP receptor antagonist, for the prevention of post-haemorrhage blood-brain barrier disruption, neuronal apoptosis and delayed cerebral hypoperfusion. METHODS: The rat double subarachnoid haemorrhage model was produced by twice injecting (days 1 and 2) autologous blood into the cisterna magna. Seventy-eight male Sprague-Dawley rats were assigned to experimental groups. Rats exposed to subarachnoid haemorrhage were allocated to no treatment (SAH group) or TBN treatment by gastric gavage during the first 5 days after haemorrhage (SAH+TBN group). Control rats received artificial cerebrospinal fluid injections (CSF group). Sham-operated rats with or without TBN administration were also studied. Body weight and Garcia neurological scores were assessed on day 2 and day 5. We used nanoscale single-photon emission computed tomography (nanoSPECT) to measure brain uptake of three radiolabelled agents: 99mTechnetium-diethylenetriaminepentacetate (99mTc-DTPA), which indicated blood-brain barrier permeability on day 3, 99mTechnetium-annexin V-128 (99mTc-Anx-V128), which indicated apoptosis on day 4, and 99mTechnetium-hexamethylpropyleneamineoxime (99mTc-HMPAO), which indicated cerebral perfusion on day 5. Basilar artery narrowing was verified histologically, and cerebral TP receptor agonists were quantified. RESULTS: 99mTc-DTPA uptake unveiled blood-brain barrier disruption in the SAH group. TBN mitigated this disruption in the brainstem area. 99mTc-Anx-V128 uptake was increased in the SAH group and TBN diminished this effect in the cerebellum. 99mTc-HMPAO uptake revealed a global decreased perfusion on day 5 in the SAH group that was significantly counteracted by TBN. TBN also mitigated basilar artery vasoconstriction, neurological deficits (on day 2), body weight loss (on day 5) and cerebral production of vasoconstrictors such as Thromboxane B2 and Prostaglandin F2α. CONCLUSIONS: Based on in vivo nanoscale imaging, we demonstrated that TBN protected against blood-brain barrier disruption, exerted an anti-apoptotic effect and improved cerebral perfusion. Thus, TP receptor antagonists showed promising results in treating post-haemorrhage neurovascular events.

Early Functional Connectome Integrity and 1-Year Recovery in Comatose Survivors of Cardiac Arrest.

Purpose To assess whether early brain functional connectivity is associated with functional recovery 1 year after cardiac arrest (CA). Materials and Methods Enrolled in this prospective multicenter cohort were 46 patients who were comatose after CA. Principal outcome was cerebral performance category at 12 months, with favorable outcome (FO) defined as cerebral performance category 1 or 2. All participants underwent multiparametric structural and functional magnetic resonance (MR) imaging less than 4 weeks after CA. Within- and between-network connectivity was measured in dorsal attention network (DAN), default-mode network (DMN), salience network (SN), and executive control network (ECN) by using seed-based analysis of resting-state functional MR imaging data. Structural changes identified with fluid-attenuated inversion recovery and diffusion-weighted imaging sequences were analyzed by using validated morphologic scales. The association between connectivity measures, structural changes, and the principal outcome was explored with multivariable modeling. Results Patients underwent MR imaging a mean 12.6 days ± 5.6 (standard deviation) after CA. At 12 months, 11 patients had an FO. Patients with FO had higher within-DMN connectivity and greater anticorrelation between SN and DMN and between SN and ECN compared with patients with unfavorable outcome, an effect that was maintained after multivariable adjustment. Anticorrelation of SN-DMN predicted outcomes with higher accuracy than fluid-attenuated inversion recovery or diffusion-weighted imaging scores (area under the receiver operating characteristic curves, respectively, 0.88, 0.74, and 0.71). Conclusion MR imaging-based measures of cerebral functional network connectivity obtained in the acute phase of CA were independently associated with FO at 1 year, warranting validation as early markers of long-term recovery potential in patients with anoxic-ischemic encephalopathy. © RSNA, 2017.

Optimizing continuous renal replacement therapy in the ICU: a team strategy.

PURPOSE OF REVIEW: The consideration of acute kidney injury, its incidence and its impact on the outcome of patients has grown continuously in recent years, leading to an increase in the use of renal replacement therapy (RRT) techniques. However, the successful conduct of RRT depends on the effectiveness of the entire team, doctors and nurses. It is therefore important to know the essential elements to be implemented in the ICU to ensure optimal RRT. RECENT FINDINGS: Recent studies show that the successful conduct of a RRT session requires a good knowledge of the principles of the technique, regular basic training, identification of experts, drafting clear and well followed protocols and good communication between the various stakeholders. In addition, the use of the latest advances, such as regional citrate anticoagulation, allows further optimization of therapy, only if, again, both physicians and nurses are properly trained and highly involved. SUMMARY: We now have a better understanding of the measures to be deployed to optimize RRT. Organization, training, evaluation and protocols are the key points of the team's efficiency for a safe and effective implementation of RRT.

Peri-operative oral caffeine does not prevent postoperative atrial fibrillation after heart valve surgery with cardiopulmonary bypass: A randomised controlled clinical trial.

BACKGROUND: Raised plasma levels of endogenous adenosine after cardiac surgery using cardiopulmonary bypass (CPB) have been related to the incidence of postoperative atrial fibrillation (POAF). OBJECTIVE: We wished to assess if caffeine, an adenosine receptor antagonist could have a beneficial effect on the incidence of POAF. DESIGN: A randomised controlled study. SETTING: Single University Hospital. PATIENTS: One hundred and ten patients scheduled for heart valve surgery with CPB. INTERVENTIONS: We randomly assigned patients to receive peri-operative oral caffeine (400 mg every 8 h for 2 days) or placebo. Adenosine plasma concentrations and caffeine pharmacokinetic profile were evaluated in a subgroup of 50 patients. MAIN OUTCOME MEASURES: The primary endpoint was the rate of atrial fibrillation during postoperative hospital stay. RESULTS: The current study was stopped for futility by the data monitoring board after an interim analysis. The incidence of atrial fibrillation was similar in the caffeine and in the placebo group during hospital stay (33 vs. 29%, P = 0.67) and the first 3 postoperative days (18 vs. 15%; P = 0.60). Basal and postoperative adenosine plasma levels were significantly associated with the primary outcome. Adenosine plasma levels were similar in the two treatment groups. Caffeine administration was associated with a higher incidence of postoperative nausea and vomiting (27 vs. 7%, P = 0.005). CONCLUSION: Oral caffeine does not prevent POAF after heart valve surgery with CPB but increased the incidence of postoperative nausea and vomiting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, no.: NCT01999829.

Brain Gray Matter MRI Morphometry for Neuroprognostication After Cardiac Arrest.

OBJECTIVES: We hypothesize that the combined use of MRI cortical thickness measurement and subcortical gray matter volumetry could provide an early and accurate in vivo assessment of the structural impact of cardiac arrest and therefore could be used for long-term neuroprognostication in this setting. DESIGN: Prospective cohort study. SETTING: Five Intensive Critical Care Units affiliated to the University in Toulouse (France), Paris (France), Clermont-Ferrand (France), Liège (Belgium), and Monza (Italy). PATIENTS: High-resolution anatomical T1-weighted images were acquired in 126 anoxic coma patients ("learning" sample) 16 ± 8 days after cardiac arrest and 70 matched controls. An additional sample of 18 anoxic coma patients, recruited in Toulouse, was used to test predictive model generalization ("test" sample). All patients were followed up 1 year after cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cortical thickness was computed on the whole cortical ribbon, and deep gray matter volumetry was performed after automatic segmentation. Brain morphometric data were employed to create multivariate predictive models using learning machine techniques. Patients displayed significantly extensive cortical and subcortical brain volumes atrophy compared with controls. The accuracy of a predictive classifier, encompassing cortical and subcortical components, has a significant discriminative power (learning area under the curve = 0.87; test area under the curve = 0.96). The anatomical regions which volume changes were significantly related to patient's outcome were frontal cortex, posterior cingulate cortex, thalamus, putamen, pallidum, caudate, hippocampus, and brain stem. CONCLUSIONS: These findings are consistent with the hypothesis of pathologic disruption of a striatopallidal-thalamo-cortical mesocircuit induced by cardiac arrest and pave the way for the use of combined brain quantitative morphometry in this setting.

Reliability of standard pupillometry practice in neurocritical care: an observational, double-blinded study.

BACKGROUND: In critical care units, pupil examination is an important clinical parameter for patient monitoring. Current practice is to use a penlight to observe the pupillary light reflex. The result seems to be a subjective measurement, with low precision and reproducibility. Several quantitative pupillometer devices are now available, although their use is primarily restricted to the research setting. To assess whether adoption of these technologies would benefit the clinic, we compared automated quantitative pupillometry with the standard clinical pupillary examination currently used for brain-injured patients. METHODS: In order to determine inter-observer agreement of the device, we performed repetitive measurements in 200 healthy volunteers ranging in age from 21 to 58 years, providing a total of 400 paired (alternative right eye, left eye) measurements under a wide variety of ambient light condition with NeuroLight Algiscan pupillometer. During another period, we conducted a prospective, observational, double-blinded study in two neurocritical care units. Patients admitted to these units after an acute brain injury were included. Initially, nursing staff measured pupil size, anisocoria and pupillary light reflex. A blinded physician subsequently performed measurement using an automated pupillometer. RESULTS: In 200 healthy volunteers, intra-class correlation coefficient for maximum resting pupil size was 0.95 (IC: 0.93-0.97) and for minimum pupil size after light stimulation 0.87 (0.83-0.89). We found only 3-pupil asymmetry (≥ 1 mm) in these volunteers (1.5% of the population) with a clear pupil asymmetry during clinical inspection. The mean pupil light reactivity was 40 ± 7%. In 59 patients, 406 pupillary measurements were prospectively performed. Concordance between measurements for pupil size collected using the pupillometer, versus subjective assessment, was poor (Spearmen's rho = 0.75, IC: 0.70-0.79; P < 0.001). Nursing staff failed to diagnose half of the cases (15/30) of anisocoria detected using the pupillometer device. A global rate of discordance of 18% (72/406) was found between the two techniques when assessing the pupillary light reflex. For measurements with small pupils (diameters <2 mm) the error rate was 39% (24/61). CONCLUSION: Standard practice in pupillary monitoring yields inaccurate data. Automated quantitative pupillometry is a more reliable method with which to collect pupillary measurements at the bedside.

In Vivo Tumour Mapping Using Electrocorticography Alterations During Awake Brain Surgery: A Pilot Study.

During awake brain surgery for tumour resection, in situ EEG recording (ECoG) is used to identify eloquent areas surrounding the tumour. We used the ECoG setup to record the electrical activity of cortical and subcortical tumours and then performed frequency and connectivity analyses in order to identify ECoG impairments and map tumours. We selected 16 patients with cortical (8) and subcortical (8) tumours undergoing awake brain surgery. For each patient, we computed the spectral content of tumoural and healthy areas in each frequency band. We computed connectivity of each electrode using connectivity markers (linear and non-linear correlations, phase-locking and coherence). We performed comparisons between healthy and tumour electrodes. The ECoG alterations were used to implement automated classification of the electrodes using clustering or neural network algorithms. ECoG alterations were used to image cortical tumours.Cortical tumours were found to profoundly alter all frequency contents (normalized and absolute power), with an increase in the δ activity and a decreases for the other bands (P < 0.05). Cortical tumour electrodes showed high level of connectivity compared to surrounding electrodes (all markers, P < 0.05). For subcortical tumours, a relative decrease in the γ1 band and in the alpha band in absolute amplitude (P < 0.05) were the only abnormalities. The neural network algorithm classification had a good performance: 93.6 % of the electrodes were classified adequately on a test subject. We found significant spectral and connectivity ECoG changes for cortical tumours, which allowed tumour recognition. Artificial neural algorithm pattern recognition seems promising for electrode classification in awake tumour surgery.

Early matrix metalloproteinase-9 concentration in the first 48 h after aneurysmal subarachnoid haemorrhage predicts delayed cerebral ischaemia: An observational study.

BACKGROUND: Delayed cerebral ischaemia from vasospasm is an important cause of complications and death after aneurysmal subarachnoid haemorrhage. There is currently no established biomarker for identifying patients at high risk of delayed cerebral ischaemia. OBJECTIVE: Considering the important role of inflammation in the pathogenesis of delayed cerebral ischaemia, we investigated whether matrix metalloproteinase-9 (MMP-9) may be an efficient biomarker for predicting elayed cerebral ischaemia after subarachnoid haemorrhage. DESIGN: Single-centre prospective observational study. SETTING: Neuroscience Critical Care Unit of a teaching hospital. PARTICIPANTS: Thirty consecutive patients with severe subarachnoid haemorrhage requiring external ventricular drainage were enrolled during 2013 and 2014. INTERVENTIONS: Blood and cerebrospinal fluid (CSF) were sampled within the first 24 h and between 48 and 72 h after admission. We evaluated the activity and concentrations of MMP-9 and endothelin-1 with zymography and ELISA. Patients were allocated to groups with delayed cerebral ischaemia (n = 16) or without delayed cerebral ischaemia (n = 14). RESULTS: Within 24 h, median [interquartile range] MMP-9 concentrations in CSF were significantly higher in patients with delayed cerebral ischaemia (47 [21 to 102] ng ml) than in those without delayed cerebral ischaemia (4 [2 to 13] ng ml, P = 0.001). CSF MMP-9 activity and endothelin-1 concentrations were correlated (r = 0.6, P = 0.02). The areas under the receiver operating characteristic curves were 0.73 (95% confidence interval [0.53 to 0.87]) and 0.91 (95% confidence interval [0.75 to 0.98]) for MMP-9 concentrations in plasma and CSF, respectively, at 24 h to predict delayed cerebral ischaemia CSF MMP-9 concentrations more than 14.3 ng ml at 24 h predicted the occurrence of delayed cerebral ischaemia with a sensitivity and specificity of 88 and 86%, respectively. After multivariate logistic analysis, only CSF MMP-9 concentrations at 24 h predicted the occurrence of delayed cerebral ischaemia (P = 0.01). CONCLUSION: MMP-9 concentrations in both plasma and CSF, measured within 48 h after subarachnoid haemorrhage, were highly predictive of the occurrence of delayed cerebral ischaemia within the first 2 weeks. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02397759.