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Introduction: Acute ischaemic stroke is associated with important mortality, morbidity, and healthcare-related costs. Age, pre-stroke functionality and stroke severity are important contributors to functional outcome. Stroke patients also risk developing infections during hospitalization. We sought to explore possible predictors of post-stroke infections and the relationship of post-stroke infection with healthcare-related costs and functional outcome., Methods: This single-centre retrospective study included 530 patients treated for ischaemic stroke between January 2017 and February 2019. Antibiotics' administration was used as a proxy for post-stroke infection. Functional outcome at 90 days was assessed by the modified Rankin Scale (mRS). Total healthcare-related costs were recorded for the index hospital stay. Multivariable analysis for post-stroke infection was done with the independent factors sex, age, pre-stroke mRS, National Institutes of Health Stroke Scale (NIHSS) and diabetes mellitus., Results: Twenty percent of patients had a post-stroke infection. NIHSS (OR 1.10, 95%CI 1.06-1.13, p < 0.0001) and diabetes mellitus (OR 2.18, 95%CI 1.28-3.71, p = 0.0042) were independent predictors for post-stroke infection. Mean total healthcare-related costs were 15,374 euro (SD 19,968; IQR 3,380-18,165), with a mean of 31,061 euro (SD 29,995; IQR 12,584-42,843) in patients with infection, compared to 11,406 euro (SD 13,987; IQR 3,083-12,726) in patients without (p < 0.0001). Median 90-days mRS was 5 (IQR 3-6) in patients with infection versus 1 (IQR 0-3.5) in patients without (p < 0.0001)., Conclusions: In patients, admitted for acute ischaemic stroke, stroke severity and diabetes mellitus were identified as the main predictors for post-stroke infection. Hospital-acquired infections were associated with increased costs and worse functional outcome., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Various vaccines were developed to reduce the spread of the Severe Acute Respiratory Syndrome Cov-2 (SARS-CoV-2) virus. Quickly after the start of vaccination, reports emerged that anti-SARS-CoV-2 vaccines, including ChAdOx1-S, could be associated with an increased risk of thrombosis. We investigated the hemostatic changes after ChAdOx1-S vaccination in 631 health care workers. Blood samples were collected 32 days on average after the second ChAdOx1-S vaccination, to evaluate hemostatic markers such as D-dimer, fibrinogen, α2-macroglobulin, FVIII and thrombin generation. Endothelial function was assessed by measuring Von Willebrand Factor (VWF) and active VWF. IL-6 and IL-10 were measured to study the activation of the immune system. Additionally, SARS-CoV-2 anti-nucleoside and anti-spike protein antibody titers were determined. Prothrombin and fibrinogen levels were significantly reduced after vaccination (-7.5% and -16.9%, p < 0.0001). Significantly more vaccinated subjects were outside the normal range compared to controls for prothrombin (42.1% vs. 26.4%, p = 0.026) and antithrombin (23.9% vs. 3.6%, p = 0.0010). Thrombin generation indicated a more procoagulant profile, characterized by a significantly shortened lag time (-11.3%, p < 0.0001) and time-to-peak (-13.0% and p < 0.0001) and an increased peak height (32.6%, p = 0.0015) in vaccinated subjects compared to unvaccinated controls. Increased VWF (+39.5%, p < 0.0001) and active VWF levels (+24.1 %, p < 0.0001) pointed toward endothelial activation, and IL-10 levels were significantly increased (9.29 pg/mL vs. 2.43 pg/mL, p = 0.032). The persistent increase of IL-10 indicates that the immune system remains active after ChAdOx1-S vaccination. This could trigger a pathophysiological mechanism causing an increased thrombin generation profile and vascular endothelial activation, which could subsequently result in and increased risk of thrombotic events., Competing Interests: BL, RdL-K, MR, DH, and MN are employees of Synapse Research Institute, part of Diagnostica Stago. HC received funding for research from Bayer and Pfizer; compensation fees for consultancy and advisory boards from Daaichi, Pfizer, Leo, Bayer, Galapagos, Anthos, Alexion, and Alveron; shareholder from Coagulation profile; all benefits were transferred to the CARIM institute to support investigator-initiated research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 de Laat, Stragier, de Laat-Kremers, Ninivaggi, Mesotten, Thiessen, Van Pelt, Roest, Penders, Vanelderen, Huskens, De Jongh, Laenen, Fivez, ten Cate, Heylen, Heylen and Steensels.)

Background: Acute kidney injury (AKI) has been reported as a frequent complication of critical COVID-19. We aimed to evaluate the occurrence of AKI and use of kidney replacement therapy (KRT) in critical COVID-19, to assess patient and kidney outcomes and risk factors for AKI and differences in outcome when the diagnosis of AKI is based on urine output (UO) or on serum creatinine (sCr)., Methods: Multicenter, retrospective cohort analysis of patients with critical COVID-19 in seven large hospitals in Belgium. AKI was defined according to KDIGO within 21 days after ICU admission. Multivariable logistic regression analysis was used to explore the risk factors for developing AKI and to assess the association between AKI and ICU mortality., Results: Of 1286 patients, 85.1% had AKI, and KRT was used in 9.8%. Older age, obesity, a higher APACHE II score and use of mechanical ventilation at day 1 of ICU stay were associated with an increased risk for AKI. After multivariable adjustment, all AKI stages were associated with ICU mortality. AKI was based on sCr in 40.1% and UO in 81.5% of patients. All AKI stages based on sCr and AKI stage 3 based on UO were associated with ICU mortality. Persistent AKI was present in 88.6% and acute kidney disease (AKD) in 87.6%. Rapid reversal of AKI yielded a better prognosis compared to persistent AKI and AKD. Kidney recovery was observed in 47.4% of surviving AKI patients., Conclusions: Over 80% of critically ill COVID-19 patients had AKI. This was driven by the high occurrence rate of AKI defined by UO criteria. All AKI stages were associated with mortality (NCT04997915)., (© 2022. The Author(s).)

Background: Local anesthetics are often selected or mixed to accomplish faster onset of anesthesia. However, with ultrasound guidance, local anesthetics are delivered with greater precision, which may shorten the onset time with all classes of local anesthetics. In this study, we compared onset time and duration of ultrasound-guided wrist blocks with a fast onset versus a longer lasting local anesthetic administered via single or dual (spatially separate) injections at the level of the midforearm., Methods: In this randomized clinical trial, 36 subjects scheduled for carpal tunnel release were randomly assigned to receive ultrasound-guided median and ulnar nerve blocks with lidocaine 2% or bupivacaine 0.5% via single or dual injections (n = 9 in each group). Subjects fulfilled the study requirements. The main outcome variables were onset and duration of sensory blockade, which were tested separately in 2 (drug) × 2 (injection) analysis of variances (ANOVAs) with interaction terms., Results: Sensory block onset time did not differ significantly between subjects given lidocaine 2% (9.2 ± 3.4 minutes) or bupivacaine 0.5% (9.5 ± 3.1 minutes) (P = .76; mean difference, -0.3 ± 1.1 minutes [95% confidence interval {CI}, -2.5 to 1.9]) or between the single- (9.6 ± 2.8 minutes) and dual- (9.1 ± 3.6 minutes) injection groups (P = .69; mean difference, -0.4 ± 1.1 minutes [95% CI, -1.8 to 2.6]). Sensory duration was longer for subjects in the bupivacaine 0.5% group (27.3 ± 11.6 hours) than for subjects in the lidocaine 2% group (8.4 ± 4.1 hours) (P < .001; 95% CI, 12.7-25.1). However, sensory duration in the single- (15.7 ± 12.5 hours) and dual- (19.4 ± 13.1 hours) injection groups did not differ significantly (P = .28; mean difference, -3.7 ± 4.3 hours [95% CI, -12.6 to 5.1])., Conclusions: No significant effect was found for onset time between lidocaine 2% and bupivacaine 0.5% used in ultrasound-guided wrist blocks. Dual injections did not shorten onset time. Since mean nerve block duration was longer with bupivacaine 0.5%, our results suggest that the selection of local anesthetic for the median and ulnar nerves at the level of the midforearm should be based on the desired duration of the block and not on its speed of onset., Competing Interests: Conflicts of Interest: See Disclosures at the end of the article., (Copyright © 2022 International Anesthesia Research Society.)

Aim: This paper presents the preliminary results from the ongoing REMOTE trial. It aims to explore the opportunities and hurdles of using insertable cardiac monitors (ICMs) and photoplethysmography-based mobile health (PPG-based mHealth) using a smartphone or smartwatch to detect atrial fibrillation (AF) in cryptogenic stroke and transient ischemic attack (TIA) patients., Methods and Results: Cryptogenic stroke or TIA patients ( n = 39) received an ICM to search for AF and were asked to use a blinded PPG-based mHealth application for 6 months simultaneously. They were randomized to smartphone or smartwatch monitoring. In total, 68,748 1-min recordings were performed using PPG-based mHealth. The number of mHealth recordings decreased significantly over time in both smartphone and smartwatch groups ( p < 0.001 and p = 0.002, respectively). Insufficient signal quality was more frequently observed in smartwatch (43.3%) compared to smartphone recordings (17.8%, p < 0.001). However, when looking at the labeling of the mHealth recordings on a patient level, there was no significant difference in signal quality between both groups. Moreover, the use of a smartwatch resulted in significantly more 12-h periods (91.4%) that were clinically useful compared to smartphone users (84.8%) as they had at least one recording of sufficient signal quality. Simultaneously, continuous data was collected from the ICMs, resulting in approximately 6,660,000 min of data (i.e., almost a 100-fold increase compared to mHealth). The ICM algorithm detected AF and other cardiac arrhythmias in 10 and 19 patients, respectively. However, these were only confirmed after adjudication by the remote monitoring team in 1 (10%) and 5 (26.3%) patients, respectively. The confirmed AF was also detected by PPG-based mHealth., Conclusion: Based on the preliminary observations, our paper illustrates the potential as well as the limitations of PPG-based mHealth and ICMs to detect AF in cryptogenic stroke and TIA patients in four elements: (i) mHealth was able to detect AF in a patient in which AF was confirmed on the ICM; (ii) Even state-of-the-art ICMs yielded many false-positive AF registrations; (iii) Both mHealth and ICM still require physician revision; and (iv) Blinding of the mHealth results impairs compliance and motivation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor DD declared a past collaboration with the authors HG, PV, and DVe., (Copyright © 2022 Wouters, Gruwez, Vranken, Vanhaen, Daelman, Ernon, Mesotten, Vandervoort and Verhaert.)

Objectives: To investigate healthcare system-driven variation in general characteristics, interventions, and outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU within one Western European region across three countries., Design: Multicenter observational cohort study., Setting: Seven ICUs in the Euregio Meuse-Rhine, one region across Belgium, The Netherlands, and Germany., Patients: Consecutive COVID-19 patients supported in the ICU during the first pandemic wave., Interventions: None., Measurements and Main Results: Baseline demographic and clinical characteristics, laboratory values, and outcome data were retrieved after ethical approval and data-sharing agreements. Descriptive statistics were performed to investigate country-related practice variation. From March 2, 2020, to August 12, 2020, 551 patients were admitted. Mean age was 65.4 ± 11.2 years, and 29% were female. At admission, Acute Physiology and Chronic Health Evaluation II scores were 15.0 ± 5.5, 16.8 ± 5.5, and 15.8 ± 5.3 (p = 0.002), and Sequential Organ Failure Assessment scores were 4.4 ± 2.7, 7.4 ± 2.2, and 7.7 ± 3.2 (p < 0.001) in the Belgian, Dutch, and German parts of Euregio, respectively. The ICU mortality rate was 22%, 42%, and 44%, respectively (p < 0.001). Large differences were observed in the frequency of organ support, antimicrobial/inflammatory therapy application, and ICU capacity. Mixed-multivariable logistic regression analyses showed that differences in ICU mortality were independent of age, sex, disease severity, comorbidities, support strategies, therapies, and complications., Conclusions: COVID-19 patients admitted to ICUs within one region, the Euregio Meuse-Rhine, differed significantly in general characteristics, applied interventions, and outcomes despite presumed genetic and socioeconomic background, admission diagnosis, access to international literature, and data collection are similar. Variances in healthcare systems' organization, particularly ICU capacity and admission criteria, combined with a rapidly spreading pandemic might be important drivers for the observed differences. Heterogeneity between patient groups but also healthcare systems should be presumed to interfere with outcomes in coronavirus disease 2019., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Introduction: Radiofrequency (RF) treatment of the genicular nerves is a promising treatment for chronic osteoarthritic and persistent postsurgical knee pain (PPSP), refractory to conventional medical management., Methods: The RECORGEN study is a retrospective single-center cohort study of patients treated with ultrasound-guided conventional RF of the genicular nerves for chronic knee pain in Hospital Oost-Limburg, Genk from September 2017 to June 2020. Subgroup analysis based on etiology of pain (PPSP and degenerative knee pain) was performed in addition to the total study population analysis. Outcome parameters were global perceived effect (GPE), Numeric Rating Scale for pain, consumption of strong opioids, and safety of the treatment at 6 weeks and cross-sectionally at a variable time point. Treatment success was defined as GPE≥50%., Results: Sixty-eight cases were screened of which 59 (46 diagnosed with PPSP and 13 with degenerative knee pain) were included in the study. Treatment success at 6 weeks was achieved in 19 of 59 interventions (32.2%) and was similar in both groups. Seventeen responders were evaluated at follow-up. 45.1% (8/17) continued to have a positive effect at the second time point. The mean duration of effect of the RF treatment was 8.3 months. Safety analysis at 6 weeks and at the second time point showed a good safety profile of the treatment., Conclusion: Conventional RF of the genicular nerves was clinically successful in more than 30% of the study population refractory to conventional medical management. Overall, the treatment was well tolerated. The mean duration of effect was 8.3 months., (© 2021 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.)

Ischemic stroke leads to substantial mortality and morbidity worldwide. Door-to-CT time, door-to-needle time (DNT), and door-to-groin time (DGT) are important quality indicators of stroke care. However, patient characteristics remain important determinants of outcome as well. In this single-center study, we investigated the interaction between these quality indicators and stroke severity regarding long-term functional outcome. All consecutive stroke patients treated at the ZOL stroke center, Genk, Belgium, between 2017 and 2020 were included in this retrospective observational study. Stroke severity was graded as "mild" if National Institutes of Health Stroke Scale (NIHSS) was equal to or lower than 8, "moderate" if NIHSS was between 9 and 15, and "severe" if NIHSS was higher than 16. Modified Rankin Scale (mRS) scores were collected before and 3 months after stroke. Ordinal regression analysis with correction for patient characteristics of functional outcome was done. A total of 1255 patients were included, of which 84% suffered an ischemic CVA (n = 1052) and 16% a TIA (n = 203). The proportion of patients treated conservatively or with thrombolysis, thrombectomy, or the combination of both differed according to stroke severity (p < 0.0001). Door-to-CT time was longer in mild and moderate stroke (p < 0.0001). Median DNT also differed between stroke categories: 46 (IQR 31-70) min for mild vs. 36 (25-56) min for moderate vs. 30 (21-45) min for severe stroke (p = 0.0002). Median DGT did not differ between stroke severity categories (p = 0.15). NIHSS on admission and pre-stroke mRS were independently associated with mRS at 90 days. Operational performance, reflected in door-to-CT time and DNT, was worse in patients with mild and moderate stroke severity. DNT was also associated with functional outcome in our center, along with pre-stroke mRS, NIHSS on admission and age., (© 2021. Belgian Neurological Society.)

Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39-0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40-0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39-0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies., (© 2022. The Author(s).)

This study introduces machine learning predictive models to predict the future values of the monitored vital signs of COVID-19 ICU patients. The main vital sign predictors include heart rate, respiration rate, and oxygen saturation. We investigated the performances of the developed predictive models by considering different approaches. The first predictive model was developed by considering the following vital signs: heart rate, blood pressure (systolic, diastolic and mean arterial, pulse pressure), respiration rate, and oxygen saturation. Similar to the first approach, the second model was developed using the same vital signs, but it was trained and tested based on a leave-one-subject-out approach. The third predictive model was developed by considering three vital signs: heart rate (HR), respiration rate (RR), and oxygen saturation (SpO2). The fourth model was a leave-one-subject-out model for the three vital signs. Finally, the fifth predictive model was developed based on the same three vital signs, but with a five-minute observation rate, in contrast with the aforementioned four models, where the observation rate was hourly to bi-hourly. For the five models, the predicted measurements were those of the three upcoming observations (on average, three hours ahead). Based on the obtained results, we observed that by limiting the number of vital sign predictors (i.e., three vital signs), the prediction performance was still acceptable, with the average mean absolute percentage error (MAPE) being 12%,5%, and 21.4% for heart rate, oxygen saturation, and respiration rate, respectively. Moreover, increasing the observation rate could enhance the prediction performance to be, on average, 8%,4.8%, and 17.8% for heart rate, oxygen saturation, and respiration rate, respectively. It is envisioned that such models could be integrated with monitoring systems that could, using a limited number of vital signs, predict the health conditions of COVID-19 ICU patients in real-time.

Respiratory failure in coronavirus disease 2019 (COVID-19) patients is one of the most frequent causes for referral to the ICU. A significant percentage of these patients does not survive the infection due to thromboembolic complications. Furthermore, the vascular system seems also to be involved in the pathogenesis. To investigate the role of hemostasis and endothelium on the outcome of COVID-19 patients admitted to the ICU. Blood was drawn from 16 ICU COVID-19 patients for hemostatic analysis. Patients were followed-up till discharge (n = 11) or death (n = 5). Parameters related to both coagulation and fibrinolysis, though disturbed, were not associated with mortality. Contrarily, activated Von Willebrand factor was increased and ADAMTS13 levels were decreased by two-fold in nonsurvivors compared with survivors. Our data established the involvement of the Von Willebrand factor-ADAMTS13 axis in the COVID-19 pathogenesis, thereby demonstrating that these plasma proteins seem to be strong predictors for ICU mortality., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The innervation of the sacroiliac joint (SIJ) is complex, with a dual innervation originating from the lumbosacral plexus anteriorly as well as the sacral lateral branches posteriorly. Nociceptors are found in intra-articular structures as well as periarticular structures. In patients with SIJ pain, a fluoroscopy-guided SIJ injection is usually performed posteriorly into the bottom one-third of the joint with local anesthetic and corticosteroids, but this does not always reach all intra-articular structures. The correlation between a cranial contrast spread and clinical success is undetermined in patients with SIJ pain., Methods: In a tertiary referral pain center, electronic medical records of patients who underwent an SIJ injection were retrospectively analyzed. Only patients with at least three positive provocation maneuvers for SIJ pain were selected. Contrast images of the SIJ were classified as with or without cranial spread on fluoroscopy as a marker of intra-articular injection. Clinical success was defined as ≥50% improvement in the patient's global perceived effect after 3-4 weeks. The primary outcome was defined as the correlation between cranial contrast spread and clinical success after an SIJ injection., Results: 128 patients in total were included. In 68 patients (53.1%) fluoroscopy showed cranial contrast spread. Clinical success was higher in patients with cranial spread of contrast (55 of 68, 81%) versus those without (35 of 60, 58%) (p=0.0067). In a multivariable analysis with age, gender, presence of rheumatoid arthritis, side, and number of positive provocation maneuvers, the cranial spread of contrast remained the only independent factor of clinical success (p=0.006; OR 3.2, 95% CI 1.4 to 7.7)., Conclusion: In patients with SIJ pain, identified by positive pain provocation maneuvers, cranial contrast spread as a marker of intra-articular injection, with subsequent injection of 3 mL of local anesthetic and methylprednisolone 40 mg, was significantly correlated with clinical success up to 4 weeks. Therefore, attempts should be made to reach this final needle position before injecting local anesthetic and corticosteroids. This result needs to be confirmed in a high-quality prospective trial., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Many studies investigate the role of pharmacological treatments on disease course in Corona Virus Disease 2019 (COVID-19). Sex disparities in genetics, immunological responses, and hormonal mechanisms may underlie the substantially higher fatality rates reported in male COVID-19 patients. To optimise care for COVID-19 patients, prophylactic and therapeutic studies should include sex-specific design and analyses. Therefore, in this scoping review, we investigated whether studies on pharmacological treatment in COVID-19 were performed based on a priori sex-specific design or post-hoc sex-specific analyses., Methods: We systematically searched PubMed, EMBASE, UpToDate, clinical trial.org, and MedRxiv for studies on pharmacological treatment for COVID-19 until June 6th, 2020. We included case series, randomized controlled trials, and observational studies in humans (≥18 years) investigating antiviral, antimalarial, and immune system modulating drugs. Data were collected on 1) the proportion of included females, 2) whether sex stratification was performed (a priori by design or post-hoc), and 3) whether effect modification by sex was investigated., Findings: 30 studies were eligible for inclusion, investigating remdesivir ( n  = 2), lopinavir/ritonavir ( n  = 5), favipiravir ( n  = 1), umifenovir ( n  = 1), hydroxychloroquine/chloroquine ( n  = 8), convalescent plasma ( n  = 6), interleukin-6 (IL-6) pathway inhibitors ( n  = 5), interleukin-1 (IL-1) pathway inhibitors ( n  = 1) and corticosteroids ( n  = 3). Only one study stratified its data based on sex in a post-hoc analysis, whereas none did a priori by design. None of the studies investigated effect modification by sex. A quarter of the studies included twice as many males as females., Interpretation: Analyses assessing potential interference of sex with (side-)effects of pharmacological therapy for COVID-19 are rarely reported. Considering sex differences in case-fatality rates and genetic, immunological, and hormonal mechanisms, studies should include sex-specific analyses in their design to optimise COVID-19 care., Funding: None., Competing Interests: Dr. Marx reports grants and personal fees from Bbraun Melsungen AG, grants and personal fees from Sphingotec AG, grants and personal fees from 4TEEN4 Pharmaceuticals GmbH, outside the submitted work. In addition, Dr. Marx has a patent Modulation ofTLR4 signalling European Patent 2855519/US Patent: US9,745,369 B2 issued, and a patent Combination of C1-Inh and Lung surfactant for the treatment of respiratory disorders PatentÐo.: US 7053,176 B1 PCT/EP99/06845 issued. All other authors declare no interest. Furthermore, there are no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that all have approved the order of authors listed in the manuscript., (© 2020 The Authors.)

Background: To summarize new evidence regarding the methodological aspects of blood glucose control in the intensive care unit (ICU)., Methods: We reviewed the literature on blood glucose control in the ICU up to August 2019 through Ovid Medline and Pubmed., Results: Since the publication of the Leuven studies, the benefits of glycemic control have been recognized. However, the methodology of blood glucose control, notably the blood glucose measurement accuracy and the insulin titration protocol, plays an important but underestimated role. This may partially explain the negative results of the large, pragmatic multicenter trials and made everyone realize that tight glycemic control with less-frequent glucose measurements on less accurate blood glucose meters is neither feasible nor advisable in daily practice. Blood gas analyzers remain the gold standard. New generation point-of-care blood glucose meters may be an alternative when using whole blood of critically ill patients in combination with a clinically validated insulin dosing algorithm., Conclusion: When implementing blood glucose management in an ICU one needs to take into account the interaction between aimed glycemic target and blood glucose measurement methodology.

Background: Near-infrared spectroscopy non-invasively measures regional cerebral oxygen saturation. Intraoperative cerebral desaturations have been associated with worse neurological outcomes. We investigated whether perioperative cerebral desaturations are associated with postoperative delirium in older patients after cardiac surgery., Methods: Patients aged 70 yr and older scheduled for on-pump cardiac surgery were included between 2015 and 2017 in a single-centre, prospective, observational study. Baseline cerebral oxygen saturation was measured 1 day before surgery. Throughout surgery and after ICU admission, cerebral oxygen saturation was monitored continuously up to 72 h after operation. The presence of delirium was assessed using the confusion assessment method for the ICU. Association with delirium was evaluated with unadjusted analyses and multivariable logistic regression., Results: Ninety-six of 103 patients were included, and 29 (30%) became delirious. Intraoperative cerebral oxygen saturation was not significantly associated with postoperative delirium. The lowest postoperative cerebral oxygen saturation was lower in patients who became delirious (P=0.001). The absolute and relative postoperative cerebral oxygen saturation decreases were more marked in patients with delirium (13 [6]% and 19 [9]%, respectively) compared with patients without delirium (9 [4]% and 14 [5]%; P=0.002 and P=0.001, respectively). These differences in cerebral oxygen saturation were no longer present after excluding cerebral oxygen saturation values after patients became delirious. Older age, previous stroke, higher EuroSCORE II, lower preoperative Mini-Mental Status Examination, and more substantial absolute postoperative cerebral oxygen saturation decreases were independently associated with postoperative delirium incidence., Conclusions: Postoperative delirium in older patients undergoing cardiac surgery is associated with absolute decreases in postoperative cerebral oxygen saturation. These differences appear most detectable after the onset of delirium., Clinical Trial Registration: NCT02532530., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Purpose: To study the efficacy of bupivacaine liposome injectable suspension in prolonging sensory blocks of the median and ulnar nerves for subjects with Dupuytren contracture release by collagenase injection. We hypothesized that combining liposome bupivacaine and bupivacaine hydrochloride would extend the duration of blocks without added complications., Methods: We randomized 32 subjects scheduled for Dupuytren contracture release with collagenase Clostridium histolyticum injections to receive forearm blocks of the median and ulnar nerves with a mixture of 5 mL liposome bupivacaine 1.33% plus 2.5 mL bupivacaine hydrochloride 0.5% per nerve (n = 16) or 7.5 mL bupivacaine hydrochloride 0.5% alone per nerve (n = 16). Sensory block and analgesia were assessed through the first posttreatment week., Results: Sensory block was nearly 4 times longer in subjects who received the liposome bupivacaine mixture compared with subjects who received bupivacaine hydrochloride alone. Most subjects (13 of 16) who received the liposome bupivacaine mixture had adequate analgesia for finger manipulation to rupture the cords, whereas most subjects (15 of 16) who received bupivacaine hydrochloride alone required additional anesthesia. Subjects in the liposome mixture group reported lower pain scores through the first 3 days after treatment. There were no serious side effects., Conclusions: Addition of liposome bupivacaine to forearm blocks for Dupuytren contracture release prolonged sensory block and improved pain scores without increasing side effects or impairing hand function. Supplemental lidocaine injections for the painful phases of Dupuytren contracture release with collagenase C histolyticum injections were not required by most subjects who received liposome bupivacaine., Type of Study/level of Evidence: Therapeutic I., (© 2019 THE AUTHORS. Published by Elsevier Inc. on behalf of The American Society for Surgery of the Hand.)

Background & Aims: Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)α, which controls both lipid metabolism and inflammation. We aimed to elucidate the previously unknown role of hepatic PPARα in the response to sepsis., Methods: Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Ppara-deficiency and their controls. The systemic and hepatic metabolic response was analyzed using biochemical, transcriptomic and functional assays. PPARα expression was analyzed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters., Results: Both whole body and non-hematopoietic Ppara-deficiency in mice decreased survival upon bacterial infection. Livers of septic Ppara-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers., Conclusion: During sepsis, Ppara-deficiency in hepatocytes is deleterious as it impairs the adaptive metabolic shift from glucose to FA utilization. Metabolic control by PPARα in hepatocytes plays a key role in the host defense against infection., Lay Summary: As the main cause of death in critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have mostly been overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARα in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: We previously validated simplified electroencephalogram (EEG) tracings obtained by a bispectral index (BIS) device against standard EEG. This retrospective study now investigated whether BIS EEG tracings can predict neurological outcome after cardiac arrest (CA)., Methods: Bilateral BIS monitoring (BIS VISTA™, Aspect Medical Systems, Inc. Norwood, USA) was started following intensive care unit admission. Six, 12, 18, 24, 36 and 48 h after targeted temperature management (TTM) at 33 °C was started, BIS EEG tracings were extracted and reviewed by two neurophysiologists for the presence of slow diffuse rhythm, burst suppression, cerebral inactivity and epileptic activity (defined as continuous, monomorphic, > 2 Hz generalized sharp activity or continuous, monomorphic, < 2 Hz generalized blunt activity). At 180 days post-CA, neurological outcome was determined using cerebral performance category (CPC) classification (CPC1-2: good and CPC3-5: poor neurological outcome)., Results: Sixty-three out-of-hospital cardiac arrest patients were enrolled for data analysis of whom 32 had a good and 31 a poor neurological outcome. Epileptic activity within 6-12 h predicted CPC3-5 with a positive predictive value (PPV) of 100%. Epileptic activity within time frames 18-24 and 36-48 h showed a PPV for CPC3-5 of 90 and 93%, respectively. Cerebral inactivity within 6-12 h predicted CPC3-5 with a PPV of 57%. In contrast, cerebral inactivity between 36 and 48 h predicted CPC3-5 with a PPV of 100%. The pattern with the worst predictive power at any time point was burst suppression with PPV of 44, 57 and 40% at 6-12 h, at 18-24 h and at 36-48 h, respectively. Slow diffuse rhythms at 6-12 h, at 18-24 h and at 36-48 h predicted CPC1-2 with PPV of 74, 76 and 80%, respectively., Conclusion: Based on simplified BIS EEG, the presence of epileptic activity at any time and cerebral inactivity after the end of TTM may assist poor outcome prognostication in successfully resuscitated CA patients. A slow diffuse rhythm at any time after CA was indicative for a good neurological outcome.

Background: In the initial hours after out-of-hospital cardiac arrest (OHCA), it remains difficult to estimate whether the degree of post-ischemic brain damage will be compatible with long-term good neurological outcome. We aimed to construct prognostic models able to predict good neurological outcome of OHCA patients within 48 h after CCU admission using variables that are bedside available., Methods: Based on prospectively gathered data, a retrospective data analysis was performed on 107 successfully resuscitated OHCA patients with a presumed cardiac cause of arrest. Targeted temperature management at 33 °C was initiated at CCU admission. Prediction models for good neurological outcome (CPC1-2) at 180 days post-CA were constructed at hour 1, 12, 24 and 48 after CCU admission. Following multiple imputation, variables were selected using the elastic-net method. Each imputed dataset was divided into training and validation sets (80% and 20% of patients, respectively). Logistic regression was fitted on training sets and prediction performance was evaluated on validation sets using misclassification rates., Results: The prediction model at hour 24 predicted good neurological outcome with the lowest misclassification rate (21.5%), using a cut-off probability of 0.55 (sensitivity = 75%; specificity = 82%). This model contained sex, age, diabetes status, initial rhythm, percutaneous coronary intervention, presence of a BIS 0 value, mean BIS value and lactate as predictive variables for good neurological outcome., Discussion: This study shows that good neurological outcome after OHCA can be reasonably predicted as early as 24 h following ICU admission using parameters that are bedside available. These prediction models could identify patients who would benefit the most from intensive care.

Background: Low back pain (LBP) is the symptom of a group of syndromes with heterogeneous underlying mechanisms and molecular pathologies, making treatment selection and patient prognosis very challenging. Moreover, symptoms and prognosis of LBP are influenced by age, gender, occupation, habits, and psychological factors. LBP may be characterized by an underlying inflammatory process. Previous studies indicated a connection between inflammatory response and total plasma N-glycosylation. We wanted to identify potential changes in total plasma N-glycosylation pattern connected with chronic low back pain (CLBP), which could give an insight into the pathogenic mechanisms of the disease., Methods: Plasma samples of 1128 CLBP patients and 760 healthy controls were collected in clinical centers in Italy, Belgium and Croatia and used for N-glycosylation profiling by hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) after N-glycans release, fluorescent labeling and clean-up. Observed N-glycosylation profiles have been compared with a cohort of 126 patients with acute inflammation that underwent abdominal surgery., Results: We have found a statistically significant increase in the relative amount of high-branched (tri-antennary and tetra-antennary) N-glycan structures on CLBP patients' plasma glycoproteins compared to healthy controls. Furthermore, relative amounts of disialylated and trisialylated glycan structures were increased, while high-mannose and glycans containing bisecting N-acetylglucosamine decreased in CLBP., Conclusions: Observed changes in CLBP on the plasma N-glycome level are consistent with N-glycosylation changes usually seen in chronic inflammation., General Significance: To our knowledge, this is a first large clinical study on CLBP patients and plasma N-glycome providing a new glycomics perspective on potential disease pathology., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: To date, monitoring options during pre-hospital advanced life support (ALS) are limited. Regional cerebral saturation (rSO 2 ) may provide more information concerning the brain during ALS. We hypothesized that an increase in rSO 2 during ALS in out-of hospital cardiac arrest (OHCA) patients is associated with return of spontaneous circulation (ROSC)., Methods: A prospective, non-randomized multicenter study was conducted in the pre-hospital setting of six hospitals in Belgium. Cerebral saturation was measured during pre-hospital ALS by a medical emergency team in OHCA patients. Cerebral saturation was continuously measured until ALS efforts were terminated or until the patient with sustained ROSC (>20 min) arrived at the emergency department. To take the longitudinal nature of the data into account, a linear mixed model was used. The correlation between the repeated measures of a patient was handled by means of ​a random intercept and a random slope. Our primary analysis tested the association of rSO 2 with ROSC., Results: Of the 329 patients 110 (33%) achieved ROSC. First measured rSO 2 was 30% ± 18 in the ROSC group and 24% ± 15 in the no-ROSC group (p = .004; mean ± SD). Higher mean rSO 2 values were observed in the ROSC group compared to the no-ROSC group (41% ± 13 versus 33% ± 13 respectively; p < 0.001). The median increase in rSO 2, measured from start until two minutes before ROSC, was higher in the ROSC group (ROSC group 17% (IQR 6-29)) than in the no-ROSC group (8% (IQR 2-13); p < 0.001). An increase in rSO 2 above 15% was associated with ROSC (OR 4.5; 95%CI 2.747-7.415; p < 0.001)., Conclusion: Regional cerebral saturation measurements can be used during pre-hospital ALS as an additional marker to predict ROSC. An increase of at least 15% in rSO 2 during ALS is associated with a higher probability of ROSC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: We aimed to validate retrospectively the accuracy of simplified electroencephalography (EEG) monitoring derived from the bispectral index (BIS) monitor in post-cardiac arrest (CA) patients., Methods: Successfully resuscitated CA patients were transferred to the Catherization Lab followed by percutaneous coronary intervention when indicated. On arrival at the coronary care unit, bilateral BIS monitoring was started and continued up to 72 h. Raw simplified EEG tracings were extracted from the BIS monitor at a time point coinciding with the registration of standard EEG monitoring. BIS EEG tracings were reviewed by two neurophysiologists, who were asked to indicate the presence of following patterns: diffuse slowing rhythm, burst suppression pattern, cerebral inactivity, periodic epileptiform discharges and status epilepticus (SE). Additionally, these simplified BIS EEG tracings were analysed by two inexperienced investigators, who were asked to indicate the presence of SE only., Results: Thirty-two simplified BIS EEG samples were analysed. Compared to standard EEG, neurophysiologists interpreted all simplified EEG samples with a sensitivity of 86%, a specificity of 100% and an interobserver variability of 0.843. Furthermore, SE was identified with a sensitivity of 80% and a specificity of 94% by two unexperienced physicians., Conclusion: Using a simple classification system, raw simplified EEG derived from a BIS monitoring device is comparable to standard EEG monitoring. Moreover, investigators without EEG experience were capable to identify SE in post-CA patients. Future studies will be warranted to confirm our results and to determine the added value of using simplified BIS EEG in terms of prognostic and therapeutic implications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: We investigated the ability of bispectral index (BIS) monitoring to predict poor neurological outcome in out-of-hospital cardiac arrest (OHCA) patients fully treated according to guidelines., Results: In this prospective, observational study, 77 successfully resuscitated OHCA patients were enrolled in whom BIS, suppression ratio (SR) and electromyographic (EMG) values were continuously monitored during the first 36 h after the initiation of targeted temperature management at 33 °C. The Cerebral Performance Category (CPC) scale was used to define patients' outcome at 180 days after OHCA (CPC 1-2: good-CPC 3-5: poor neurological outcome). Using mean BIS and SR values calculated per hour, receiver operator characteristics curves were constructed to determine the optimal time point and threshold to predict poor neurological outcome. At 180 days post-cardiac arrest, 39 patients (51%) had a poor neurological outcome. A mean BIS value ≤ 25 at hour 12 predicted poor neurological outcome with a sensitivity of 49% (95% CI 30-65%), a specificity of 97% (95% CI 85-100%) and false positive rate (FPR) of 6% (95% CI 0-29%) [AUC: 0.722 (0.570-0.875); p = 0.006]. A mean SR value ≥ 3 at hour 23 predicted poor neurological with a sensitivity of 74% (95% CI 56-87%), a specificity of 92% (95% CI 78-98%) and FPR of 11% (95% CI 3-29%) [AUC: 0.836 (0.717-0.955); p < 0.001]. No relationship was found between mean EMG and BIS < 25 (R 2  = 0.004; p = 0.209)., Conclusion: This study found that mean BIS ≤ 25 at hour 12 and mean SR ≥ 3 at hour 23 might be used to predict poor neurological outcome in an OHCA population with a presumed cardiac cause. Since no correlation was observed between EMG and BIS < 25, our calculated BIS threshold might assist with poor outcome prognostication following OHCA.

Background: The multicentre randomised controlled PEPaNIC trial showed that withholding parenteral nutrition (PN) during the first week of critical illness in children was clinically superior to providing early PN. This study describes the cost-effectiveness of this new nutritional strategy., Methods: Direct medical costs were calculated with use of a micro-costing approach. We compared the costs of late versus early initiation of PN (n = 673 versus n = 670 patients) in the Belgian and Dutch study populations from a hospital perspective, using Student's t test with bootstrapping. Main cost drivers were identified and the impact of new infections on the total costs was assessed., Results: Mean direct medical costs for patients receiving late PN (€26.680, IQR €10.090-28.830 per patient) were 21% lower (-€7.180, p = 0.007) than for patients receiving early PN (€33.860, IQR €11.080-34.720). Since late PN was more effective and less costly, this strategy was superior to early PN. The lower costs for PN only contributed 2.1% to the total cost reduction. The main cost driver was intensive care hospitalisation costs (-€4.120, p = 0.003). The patients who acquired a new infection (14%) were responsible for 41% of the total costs. Sensitivity analyses confirmed consistency across both healthcare systems., Conclusions: Late initiation of PN decreased the direct medical costs for hospitalisation in critically ill children, beyond the expected lower costs for withholding PN. Avoiding new infections by late initiation of PN yielded a large cost reduction. Hence, late initiation of PN was superior to early initiation of PN largely via its effect on new infections., Trial Registration: ClinicalTrials.gov, NCT01536275 . Registered on 16 February 2012.

Background: Blood glucose control in the intensive care unit (ICU) has the potential to save lives. However, maintaining blood glucose concentrations within a chosen target range is difficult in clinical practice and holds risk of potentially harmful hypoglycemia. Clinically validated computer algorithms to guide insulin dosing by nurses have been advocated for better and safer blood glucose control., Methods: We conducted an international, multicenter, randomized controlled trial involving 1550 adult, medical and surgical critically ill patients, requiring blood glucose control. Patients were randomly assigned to algorithm-guided blood glucose control (LOGIC-C, n = 777) or blood glucose control by trained nurses (Nurse-C, n = 773) during ICU stay, according to the local target range (80-110 mg/dL or 90-145 mg/dL). The primary outcome measure was the quality of blood glucose control, assessed by the glycemic penalty index (GPI), a measure that penalizes hypoglycemic and hyperglycemic deviations from the chosen target range. Incidence of severe hypoglycemia (<40 mg/dL) was the main safety outcome measure. New infections in ICU, duration of hospital stay, landmark 90-day mortality and quality of life were clinical safety outcome measures., Results: The median GPI was lower in the LOGIC-C (10.8 IQR 6.2-16.1) than in the Nurse-C group (17.1 IQR 10.6-26.2) (P < 0.001). Mean blood glucose was 111 mg/dL (SD 15) in LOCIC-C versus 119 mg/dL (SD 21) in Nurse-C, whereas the median time-in-target range was 67.0% (IQR 52.1-80.1) in LOGIC-C versus 47.1% (IQR 28.1-65.0) in the Nurse-C group (both P < 0.001). The fraction of patients with severe hypoglycemia did not differ between LOGIC-C (0.9%) and Nurse-C (1.2%) (P = 0.6). The clinical safety outcomes did not differ between groups. The sampling interval was 2.3 h (SD 0.5) in the LOGIC-C group versus 3.0 h (SD 0.8) in the Nurse-C group (P < 0.001)., Conclusions: In a randomized controlled trial of a mixed critically ill patient population, the use of the LOGIC-Insulin blood glucose control algorithm, compared with blood glucose control by expert nurses, improved the quality of blood glucose control without increasing hypoglycemia., Trial Registration: ClinicalTrials.gov, NCT02056353 . Registered on 4 February 2014.

Background and Objectives: We examined whether liposome bupivacaine (Exparel) given in the interscalene brachial plexus block lowers pain in the setting of multimodal postoperative pain management for major shoulder surgery., Methods: Fifty-two adult patients were randomized to receive either 5 mL of 0.25% bupivacaine HCl immediately followed by 10 mL of liposome bupivacaine 133 mg (n = 26) or 15 mL of 0.25% standard bupivacaine alone (n = 26) in interscalene brachial plexus block. The primary outcome (worst pain in the first postoperative week) was assessed by the Modified Brief Pain Inventory short form. Secondary outcomes were overall satisfaction with analgesia (OBAS), functionality of the surgical arm, sleep duration, time to first opioid (tramadol) request and opioid consumption (mEq), sensory-motor block characteristics, and the occurrence of adverse effects., Results: Worst pain was lower in patients given liposome bupivacaine added to standard bupivacaine than in patients given standard bupivacaine alone (generalized estimating equation [GEE] estimated marginal mean values, 3.6 ± 0.3 vs 5.3 ± 0.4 points on the Numeric Rating Scale, respectively, although the effect was modest, 1.6 ± 0.5; 95% confidence interval, 0.8-2.5). Total OBAS scores indicated greater satisfaction (GEE estimated marginal mean values, 1.8 ± 0.3 vs 3.3 ± 0.4 on total OBAS, respectively, with modest effect, difference, 1.4 ± 0.5; 95% confidence interval, 0.5-2.4). There were no differences in any of the other secondary outcomes., Conclusions: Liposome bupivacaine added to standard bupivacaine may lower pain and enhance patient's satisfaction in the first postoperative week even in the setting of multimodal analgesia for major shoulder surgery.This study was registered with clinicaltrials.gov (NCT02554357) on July 11, 2015, by Principal Investigator Catherine Vandepitte, MD.

Background and Aims: During hospitalization in a pediatric intensive care unit (PICU), critically ill children are fed artificially. Administered via the preferred enteral route, caloric targets are often not reached. Hence, parenteral nutrition is given to this patient population. In this review we analyzed the available evidence from randomized controlled trials (RCTs) that supports the use of parenteral nutrition in children during critical illness., Methods: A search strategy in Ovid MEDLINE and Ovid EMBASE was created and trial registries were screened to identify the relevant RCTs. Studies were included if they were randomized controlled trials, involved pediatric patients admitted to PICU, and compared different dosing/compositions of parenteral nutrition. Descriptive studies and reviews were excluded., Results: Of the 584 articles identified by the search strategy, only 114 articles were retained after title screening. Further abstract and full text screening identified 6 small RCTs that compared two dosing/composition strategies of parenteral nutrition. These trials reported differences in surrogate endpoints without an effect on hard clinical endpoints. The RCTs observed improvements in these surrogate endpoints with the use of more calories or when parenteral glutamine or fish oil was added., Conclusions: The few RCTs suggest that surrogate endpoints can be affected by providing parenteral nutrition to critically ill children, but the studies were not statistically powered to draw meaningful clinical conclusions. Large RCTs with clinically relevant outcome measures are urgently needed to support the current nutritional guidelines that advise the use of parenteral nutrition in the PICU., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Muscle wasting starts already within the first week in critically patients and is strongly related to poor outcome. Nevertheless, the early detection of muscle wasting is difficult. Therefore, we investigated the reliability and accuracy of ultrasonography to evaluate skeletal muscle wasting in critically ill children and adults., Methods: This prospective observational study enrolled 30 sedated critically ill children and 14 critically ill adults. Two independent investigators made 210 ultrasonographical assessments of muscle thigh thickness. Inter- and intraobserver reliability and cutoff levels were calculated as a function of muscle thickness and the expected reduction in muscle size (predefined at 20% and 30%)., Results: Mean ± SD muscle thickness was 1.67 ± 0.55 cm in the pediatric and 2.10 ± 0.85 cm in the adult population. The median absolute interobserver variability was 0.07 cm (interquartile range [IQR], 0.04-0.20 cm) in the pediatric population and 0.05 cm (IQR, 0.03-0.09 cm) in the adult population. However, the absolute intraobserver accuracy had a 95% confidence interval of 0.43 cm in children and 0.22 cm in adults. Only a 30% decrease (0.50 cm) in muscle thickness can be detected in critically ill children., Conclusion: Although the interobserver variability is acceptable in the pediatric population, the intraobserver variability is too large with respect to the expected reduction in muscle thickness. In adults, ultrasonography may be a reliable tool for early detection of muscle mass wasting., (© 2015 American Society for Parenteral and Enteral Nutrition.)

Objectives: Children with congenital heart disease (CHD) often have neurocognitive deficits, sometimes with a detrimental impact on daily and school functioning. These deficits may increase through childhood. In this study, we investigated whether children with CHD, who underwent heart surgery as infants, show more neurocognitive deficits, especially in the executive functions, as they get older, compared with healthy controls., Methods: In this longitudinal follow-up study, 107 children with CHD and 77 healthy control children underwent extensive neurocognitive testing at 4 years of age. Ninety-three percent of the children (100 patients with CHDs and 72 controls) underwent a second neurocognitive testing 3 years later. Intelligence, visual-motor integration (VMI), alertness, motor coordination, executive functions, and psychosocial functioning were assessed., Results: IQ scores were consistently lower in the CHD group (P < .001); however, the difference of 11.7 IQ points between both groups at follow-up 1 decreased to 7 IQ points at follow-up 2 (P = .003). Inhibition reaction time had improved in both study groups at follow-up 2 (P < .001) and did not differ between both groups from follow-up 1 to follow-up 2 (P = .849). Deficits in VMI, alertness, motor coordination, and psychosocial functioning also did not worsen for patients with CHDs at follow-up 2, compared with healthy controls., Conclusions: Children with CHD, who underwent heart surgery as infants, do not show an increase of neurocognitive deficits between the ages of 4 and 7 years, compared with healthy controls. Patients with CHDs keep deficits in intelligence, VMI, and psychosocial functioning, but seem to partially grow out of their deficits., (Copyright © 2016 by the American Academy of Pediatrics.)

Background: Recent trials have questioned the benefit of early parenteral nutrition in adults. The effect of early parenteral nutrition on clinical outcomes in critically ill children is unclear., Methods: We conducted a multicenter, randomized, controlled trial involving 1440 critically ill children to investigate whether withholding parenteral nutrition for 1 week (i.e., providing late parenteral nutrition) in the pediatric intensive care unit (ICU) is clinically superior to providing early parenteral nutrition. Fluid loading was similar in the two groups. The two primary end points were new infection acquired during the ICU stay and the adjusted duration of ICU dependency, as assessed by the number of days in the ICU and as time to discharge alive from ICU. For the 723 patients receiving early parenteral nutrition, parenteral nutrition was initiated within 24 hours after ICU admission, whereas for the 717 patients receiving late parenteral nutrition, parenteral nutrition was not provided until the morning of the 8th day in the ICU. In both groups, enteral nutrition was attempted early and intravenous micronutrients were provided., Results: Although mortality was similar in the two groups, the percentage of patients with a new infection was 10.7% in the group receiving late parenteral nutrition, as compared with 18.5% in the group receiving early parenteral nutrition (adjusted odds ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66). The mean (±SE) duration of ICU stay was 6.5±0.4 days in the group receiving late parenteral nutrition, as compared with 9.2±0.8 days in the group receiving early parenteral nutrition; there was also a higher likelihood of an earlier live discharge from the ICU at any time in the late-parenteral-nutrition group (adjusted hazard ratio, 1.23; 95% CI, 1.11 to 1.37). Late parenteral nutrition was associated with a shorter duration of mechanical ventilatory support than was early parenteral nutrition (P=0.001), as well as a smaller proportion of patients receiving renal-replacement therapy (P=0.04) and a shorter duration of hospital stay (P=0.001). Late parenteral nutrition was also associated with lower plasma levels of γ-glutamyltransferase and alkaline phosphatase than was early parenteral nutrition (P=0.001 and P=0.04, respectively), as well as higher levels of bilirubin (P=0.004) and C-reactive protein (P=0.006)., Conclusions: In critically ill children, withholding parenteral nutrition for 1 week in the ICU was clinically superior to providing early parenteral nutrition. (Funded by the Flemish Agency for Innovation through Science and Technology and others; ClinicalTrials.gov number, NCT01536275.).

Hyperglycemia, hypoglycemia, and glycemic variability are all independently associated with morbidity and mortality of critically ill patients. A strategy aiming at normoglycemia (so-called tight glycemic control) could improve outcomes of critically ill patients, but results from randomized controlled trials of tight glycemic control are conflicting. Strict glycemic control is associated with an increased risk of hypoglycemia, which could offset the benefit of this intervention. Notably, the risk of hypoglycemia is not necessarily removed with less tight glucose control regimens. The best targets of blood glucose control in critically ill patients, therefore, remain a matter of debate. It should be realized that blood glucose control is a complex intervention, consisting of many critical aspects that have the potential to affect its efficacy and safety. Efficacy, and in particular safety, of blood glucose control could still improve. First, glucose algorithms could overcome the lack of knowledge and skills of nursing staff when they are less experienced in safe and efficient blood glucose control. Several computerized glucose control algorithms have been developed over recent years, but they all need clinical validation. Also, the workload induced by such algorithms should be evaluated. Second, continuous blood glucose monitoring has the potential to improve safety and efficacy. Until recently, blood glucose levels were monitored manually using point-of-care devices with significant inaccuracies. Various continuous monitoring systems have been developed, but studies testing their accuracies and usefulness in an intensive care unit setting are highly needed., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To assess current nutritional practices in critically ill children worldwide., Design: A two-part online, international survey. The first part, "the survey", was composed of 59 questions regarding nutritional strategies and protocols (July-November 2013). The second part surveyed the "point prevalence" of nutritional data of patients present in a subgroup of the responding PICUs (May-September 2014)., Setting: Members of the World Federation of Pediatric Intensive and Critical Care Societies were asked to complete the survey., Subjects: Pediatric critical care providers., Interventions: Survey., Measurements and Main Results: We analyzed 189 responses from 156 PICUs in 52 countries (survey). We received nutritional data on 295 patients from 41 of these 156 responding PICUs in 27 countries (point prevalence). According to the "survey", nutritional protocols and support teams were available in 52% and 57% of the PICUs, respectively. Various equations were in use to estimate energy requirements; only in 14% of PICUs, indirect calorimetry was used. Nutritional targets for macronutrients, corrected for age/weight, varied widely. Enteral nutrition would be started early (within 24 hr of admission) in 60% of PICUs, preferably by the gastric route (88%). In patients intolerant to enteral nutrition, parenteral nutrition would be started within 48 hours in 55% of PICUs. Overall, in 72% of PICUs supplemental parenteral nutrition would be used if enteral nutrition failed to meet at least 50% of energy delivery goal. Several differences between the intended (survey) and the actual (point prevalence) nutritional practices were found in the responding PICUs, predominantly overestimating the ability to adequately feed patients., Conclusion: Nutritional practices vary widely between PICUs worldwide. There are significant differences in macronutrient goals, estimating energy requirements, timing of nutrient delivery, and threshold for supplemental parenteral nutrition. Uniform consensus-based nutrition practices, preferably guided by evidence, are desirable in the PICU.

Background: We verified the analytical performance of strip-based handheld glucose meters (GM) for prescription use, in a comparative split-sample protocol using blood gas samples from a surgical intensive care unit (ICU)., Methods: Freestyle Precision Pro (Abbott), StatStrip Connectivity Meter (Nova), ACCU-CHEK Inform II (Roche) were evaluated for recovery/linearity, imprecision/repeatability. The GMs and the ABL90 (Radiometer) blood gas analyzer (BGA) were tested for relative accuracy vs. the comparator hexokinase glucose-6-phosphate-dehydrogenase (HK/G6PDH) assay on a Cobas c702 analyzer (Roche)., Results: Recovery of spiked glucose was linear up to 19.3 mmol/L (347 mg/dL) with a slope of 0.91-0.94 for all GMs. Repeatability estimated by pooling duplicate measurements on samples below (n=9), in (n=51) or above (n=80) the 4.2-5.9 mM (74-106 mg/dL) range were for Freestyle Precision Pro: 4.2%, 4.0%, 3.6%; StatStrip Connectivity Meter: 4.0%, 4.3%, 4.5%; and ACCU-CHEK Inform II: 1.4%, 2.5%, 3.5%. GMs were in agreement with the comparator method. The BGA outperformed the GMs, with a MARD of 3.9% compared to 6.5%, 5.8% and 4.4% for the FreeStyle, StatStrip and ACCU-CHEK, respectively. Zero % of the BGA results deviated more than the FDA 10% criterion as compared to 9.4%, 3.7% and 2.2% for the FreeStyle, StatStrip and ACCU-CHEK, respectively. For all GMs, icodextrin did not interfere. Variation in the putative influence factors hematocrit and O2 tension could not explain observed differences with the comparator method., Conclusions: GMs quantified blood glucose in whole blood at about the 10% total error criterion, proposed by the FDA for prescription use.

Objective: In ICU patients, abnormal liver tests are common. Markers of cholestasis are associated with adverse outcome. Research has focused on the possibility that mild hyperbilirubinemia, instead of indicating inadvertent cholestasis, may be adaptive and beneficial. These new insights are reviewed and integrated in the state-of-the-art knowledge on hepatobiliary alterations during sepsis and other critical illnesses., Data Sources: Relevant publications were searched in Medline with search terms bile, bile acids, cholestasis, critical illness, intensive care, sepsis, alone or in combination., Data Synthesis: Studies have shown that bilirubin, but also bile acids, the main active constitutes of bile, are increased in plasma of patients with critical illnesses. In particular the conjugated fractions of bilirubin and bile acids are high, indicating that during critical illness the liver is capable of converting these molecules to less toxic forms. In human liver biopsies of prolonged critically ill patients, expression of bile acid excretion pumps towards the bile canaliculi was lower, while alternative transporters towards the systemic circulation were upregulated. Remarkably, in the presence of increased circulating bile acids, expression of enzymes controlling synthesis of bile acids was not suppressed. This suggested loss of feedback inhibition of bile acids synthesis, possibly explained by the observed cytoplasmic retention of the nuclear FXR/RXR heterodimer. As macronutrient restriction during acute critical illness, an intervention that improved outcome, was found to further increase plasma bilirubin while reducing other markers of cholestasis, a potentially protective role of hyperbilirubinemia was suggested., Conclusion: The increase in circulating levels of conjugated bile acids and bilirubin in response to acute sepsis/critical illnesses may not necessarily point to cholestasis as a pathophysiological entity. Instead it may be the result of an adaptively altered bile acid production and transport back towards the systemic circulation. How these changes could be beneficial for survival should be further investigated.

Unlabelled: Children with congenital heart disease (CHD) often experience difficulties in academic and daily functioning, which have been associated with intelligence and neurocognitive skills, including executive functions (EFs), attention and memory. We report the neurocognitive data of children with CHD who were included in the Leuven glucose control trial (LGC trial). Through a systematic review and meta-analysis, we aimed to find which neurocognitive functions are most consistently and prominently affected. 365 children with CHD and 216 healthy control children underwent extensive neurocognitive testing in the LGC trial. A comprehensive search of electronic databases PubMed, EMBASE and Cochrane was conducted for studies measuring intelligence, EFs, attention and memory in children who underwent heart surgery for CHD. Standardised mean differences (SMDs) between the CHD group and a healthy control group were calculated for these neurocognitive functions. LGC trial data were included in the meta-analysis. Twelve studies with a healthy control group were included in the meta-analysis, involving 647 patients with CHD and 633 controls. The CHD group (median age 7.35 years at testing) had worse scores than healthy control children, for all investigated neurocognitive functions. A medium SMD was found for intelligence (SMD=-0.53 (95% CI -0.68 to -0.38), p<0.00001). Alertness, an attentional function, was also consistently poorer in the CHD group. Memory was less affected, while EF had a medium SMD with large heterogeneity. Children with CHD risk displayed lower performance on intelligence and alertness assessment, which may contribute to difficulties in daily life and school. Heterogeneity in neurocognitive assessment and small sizes in most studies limit the interpretation., Trial Registration Number: clinicaltrials.gov Identifier NCT00214916.

Blood glucose management in people with acute myocardial infarction and critical illness has always attracted controversy. Compared with the era before 2001 when no attention was given to blood glucose management, DIGAMI-1 in 1995 and the first Leuven study in 2001 showed improved outcomes with strict control of blood glucose, thereby suggesting a causal association between hyperglycaemia and mortality risk. These landmark trials have set the standard in clinical practice that excessive hyperglycaemia is not acceptable. Multicentre trials contradicted the benefits of tight control of patients' blood glucose and results showed that different standard operating procedures for blood glucose control (eg, blood glucose meters or algorithms), divergent concomitant feeding strategies, and varying patient populations are important confounders. The general consensus now is that excessive hyperglycaemia (>10 mmol/L) and severe hypoglycaemia (<2·2 mmol/L) should be avoided in critically ill adults. If adequate blood glucose meters and clinically validated protocols for insulin-dosing are available, targeting of blood glucose concentrations to less than 8 mmol/L (moderate glycaemic control), while avoiding mild hypoglycaemia (<3·9 mmol/L), is a reasonable strategy in adult patients who are critically ill. This recommendation is not based on findings from randomised controlled trials, but merely represents a very common, pragmatic approach by physicians at the bedside. As a result of the few properly validated technologies for tighter blood glucose control, targeting blood glucose concentrations to less than 6 mmol/L is not recommended, because its risk-to-benefit ratio becomes questionable. Because blood glucose control in the target of adult ranges does not improve patient outcomes for children in the intensive care unit, glucose management in this patient population should be limited to avoid excessive hyperglycaemia (>10 mmol/L)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery., Methods/design: The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only., Discussion: Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in the clinical effects of omitting PN during the first week of critical illness in children., Trial Registration: ClinicalTrials.gov: NCT01536275 on 16 February 2012.

Background: Effective and safe glycemic control in critically ill patients requires accurate glucose sensors and adequate insulin dosage calculators. The LOGIC-Insulin calculator for glycemic control has recently been validated in the LOGIC-1 randomized controlled trial. In this study, we aimed to determine the allowable error for intermittent and continuous glucose sensors, on the basis of the LOGIC-Insulin calculator., Methods: A gaussian simulation model with a varying bias (0%-20%) and CV (-20% to +20%) simulated blood glucose values from the LOGIC-1 study (n = 149 patients) in 10 Monte Carlo steps. A clinical error grid system was developed to compare the simulated LOGIC-Insulin-directed intervention with the nominal intervention (0% bias, 0% CV). The severity of error measuring the clinical effect of the simulated LOGIC-Insulin intervention was graded as type B, C, and D errors. Type D errors were classified as acutely life-threatening (0% probability preferred)., Results: The probability of all types of errors was lower for continuous sensors compared with intermittent sensors. The maximum total error (TE), defined as the first TE introducing a type B/C/D error, was similar for both sensor types. To avoid type D errors, TEs <15.7% for intermittent sensors and <17.8% for continuous sensors were required. Mean absolute relative difference thresholds for type C errors were 7.1% for intermittent and 11.0% for continuous sensors., Conclusions: Continuous sensors had a lower probability for clinical errors than intermittent sensors at the same accuracy level. These simulations demonstrated the suitability of the LOGIC-Insulin control system for use with continuous, as well as intermittent, sensors., (© 2014 American Association for Clinical Chemistry.)

Rationale: Intensive care unit (ICU)-acquired weakness is a frequent complication of critical illness. It is unclear whether it is a marker or mediator of poor outcomes., Objectives: To determine acute outcomes, 1-year mortality, and costs of ICU-acquired weakness among long-stay (≥8 d) ICU patients and to assess the impact of recovery of weakness at ICU discharge., Methods: Data were prospectively collected during a randomized controlled trial. Impact of weakness on outcomes and costs was analyzed with a one-to-one propensity-score-matching for baseline characteristics, illness severity, and risk factor exposure before assessment. Among weak patients, impact of persistent weakness at ICU discharge on risk of death after 1 year was examined with multivariable Cox proportional hazards analysis., Measurements and Main Results: A total of 78.6% were admitted to the surgical ICU; 227 of 415 (55%) long-stay assessable ICU patients were weak; 122 weak patients were matched to 122 not-weak patients. As compared with matched not-weak patients, weak patients had a lower likelihood for live weaning from mechanical ventilation (hazard ratio [HR], 0.709 [0.549-0.888]; P = 0.009), live ICU (HR, 0.698 [0.553-0.861]; P = 0.008) and hospital discharge (HR, 0.680 [0.514-0.871]; P = 0.007). In-hospital costs per patient (+30.5%, +5,443 Euro per patient; P = 0.04) and 1-year mortality (30.6% vs. 17.2%; P = 0.015) were also higher. The 105 of 227 (46%) weak patients not matchable to not-weak patients had even worse prognosis and higher costs. The 1-year risk of death was further increased if weakness persisted and was more severe as compared with recovery of weakness at ICU discharge (P < 0.001)., Conclusions: After careful matching the data suggest that ICU-acquired weakness worsens acute morbidity and increases healthcare-related costs and 1-year mortality. Persistence and severity of weakness at ICU discharge further increased 1-year mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Unlabelled: Cholestatic liver dysfunction (CLD) and biliary sludge often occur during critical illness and are allegedly aggravated by parenteral nutrition (PN). Delaying initiation of PN beyond day 7 in the intensive care unit (ICU) (late PN) accelerated recovery as compared with early initiation of PN (early PN). However, the impact of nutritional strategy on biliary sludge and CLD has not been fully characterized. This was a preplanned subanalysis of a large randomized controlled trial of early PN versus late PN (n = 4,640). In all patients plasma bilirubin (daily) and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [ALP], twice weekly; n = 3,216) were quantified. In a random predefined subset of patients, plasma bile acids (BAs) were also quantified at baseline and on days 3, 5, and last ICU-day (n = 280). Biliary sludge was ultrasonographically evaluated on ICU-day 5 (n = 776). From day 1 after randomization until the end of the 7-day intervention window, bilirubin was higher in the late PN than in the early PN group (P < 0.001). In the late PN group, as soon as PN was started on day 8 bilirubin fell and the two groups became comparable. Maximum levels of GGT, ALP, and ALT were lower in the late PN group (P < 0.01). Glycine/taurine-conjugated primary BAs increased over time in ICU (P < 0.01), similarly for the two groups. Fewer patients in the late PN than in the early PN group developed biliary sludge on day 5 (37% versus 45%; P = 0.04)., Conclusion: Tolerating substantial caloric deficit by withholding PN until day 8 of critical illness increased plasma bilirubin but reduced the occurrence of biliary sludge and lowered GGT, ALP, and ALT. These results suggest that hyperbilirubinemia during critical illness does not necessarily reflect cholestasis and instead may be an adaptive response that is suppressed by early PN., (© 2014 by the American Association for the Study of Liver Diseases.)

Achieving adequate glucose control in critically ill patients is a complex but important part of optimal patient management. Until relatively recently, intermittent measurements of blood glucose have been the only means of monitoring blood glucose levels. With growing interest in the possible beneficial effects of continuous over intermittent monitoring and the development of several continuous glucose monitoring (CGM) systems, a round table conference was convened to discuss and, where possible, reach consensus on the various aspects related to glucose monitoring and management using these systems. In this report, we discuss the advantages and limitations of the different types of devices available, the potential advantages of continuous over intermittent testing, the relative importance of trend and point accuracy, the standards necessary for reporting results in clinical trials and for recognition by official bodies, and the changes that may be needed in current glucose management protocols as a result of a move towards increased use of CGM. We close with a list of the research priorities in this field, which will be necessary if CGM is to become a routine part of daily practice in the management of critically ill patients.