Correlation of Serum and Urine Midazolam Levels with Consciousness Tests after Discontinuation of Sedation in the Intensive Care Unit

Title: Correlation of serum and urine midazolam levels with observed level of consciousness after discontinuation of midazolam sedation in the intensive care unit   Marilena Papadaki1, Maria Pratikaki2, Achilleas Giannopoulos1, Theodora Ntaidou1, Eleftheria Mizi1, Marios Kougias1, Georgios Bouboulis1, Aikaterini Sarri1 and Charikleia S Vrettou1   1  1st Department of Intensive Care, Evangelismos Hospital, University of Athens Medical School, 45-47 Ipsilantou Str., 106 76 Athens, Greece 2 Department of Clinical Biochemistry, Evangelismos Hospital, Athens, Greece   Introduction: Continuous infusion of midazolam is related to prolonged activity and delayed awakening in the critically ill. Serum benzodiazepine levels can be helpful in differentiating residual benzodiazepine activity from other causes of impaired level of consciousness (LOC) [1]. Although benzodiazepine levels can also be measured in the urine, the relationship between serum and urine levels with the observed LOC has not been studied in clinical practice. Objectives: To investigate the correlation between serum and urine benzodiazepine levels in the critically ill and their correlation with the observed level of consciousness estimated with the Glasgow Coma Scale (GCS) and the Full Outline of UnResponsiveness Score (FOUR score). Patients and Methods: This prospective observational study involved patients admitted to a 30 bed General Intensive Care Unit, who were intubated and mechanically ventilated, with GCS prior to intubation > 8. Midazolam infusion was discontinued for at least 12 hours before sampling. Serum and urine sampling and clinical evaluation to calculate the GCS and FOUR score were done simultaneously. Gathered data included age, sex, weight and height, reason for admission to intensive care, renal function, daily fluid balance, daily and hourly urine output, liver function, serum proteins, hemoglobin and the application of renal replacement therapy. Serum benzodiazepine measurements were performed on the Integra system (Roche), which is suitable for semiquantitative detection of benzodiazepines in the serum. Urine benzodiazepine levels were measured with the Cobas C501 system, which is suitable for semiquantitative detection of benzodiazepines in human urine. The Scientific and Ethics committee of Evangelismos hospital approved the study protocol. Results: Twenty patients were included in the study, 10 male and 10 female. Reasons for ICU admission were septic shock (n=7), respiratory failure and ARDS (n=7), and acute surgery and trauma (n=6). Patients’ age ranged from 20 to 90 years old (median 66 years) and their weight from 45 to 160 Kg  (median 77.5 Kg). The SOFA score ranged from 4 to 15 (median 8). The GCS score from 3 to 14 (median 7) and the FOUR score from 3 to 15 (median 10). Six patients were on continuous veno-venous haemodiafiltration (CVVHD) at sampling time. Serum benzodiazepine levels correlate moderately with the GCS (R =-0.496, p=0.026) and better with the FOUR score (R =-0.685, p=0.001), but did not correlate with measured levels in the urine (R =-0.029 p=0.904), even when patients without AKI were analysed separately (n= 12, R = 0.173, p=0.572). Figure 1 presents the scatter plot of measured urine and serum benzodiazepine levels in our sample. Conclusions: In patients treated in the intensive care unit, after discontinuation of midazolam sedation, the LOC (GCS and FOUR score) correlate significantly with the benzodiazepine levels measured in the serum. Urine benzodiazepine levels do not correlate with serum levels or with the observed LOC and therefore cannot be helpful in the differential diagnosis of drowsiness or coma in this population. References: (1) Rosich Andreu et al. Intensive Care Medicine Experimental 2015, 3(Suppl 1):A330     &nbsp

Η επίδραση της άσκησης στη σύνθεση και τη λειτουργία του μικροβιώματος.

Εισαγωγή Το εντερικό μικροβίωμα περιλαμβάνει μια μεγάλη ποικιλία μικροοργανισμών που συμβιωτικά κατοικούν στο ανθρώπινο πεπτικό σύστημα. Μέχρι σήμερα, η έρευνα έχει δώσει αρκετά δεδομένα σχετικά με την πιθανή σχέση μεταξύ της άσκησης και μιας υγιούς σύνθεσης της ανθρώπινης εντερικής μικροχλωρίδας. Αυτή η ανασκόπηση έχει ως στόχο να συνοψίσει τα αποτελέσματα ανθρώπινων μελετών που συγκρίνουν τη σύνθεση μικροβιώματος ατόμων με διαφορετικά επίπεδα φυσικής δραστηριότητας. Μεθοδολογία Η ηλεκτρονική αναζήτηση πραγματοποιήθηκε χρησιμοποιώντας τους εξής αγγλικούς όρους: (Microbiome[Title/Abstract]) AND (Exercise[Title/Abstract]) στη βάση δεδομένων NIH/PubMed. Στην ανασκόπηση αυτή περιλαμβάνονται: (α) μελέτες που επικεντρώθηκαν στη σύγκριση του μικροβιώματος του εντέρου μεταξύ ατόμων με διαφορετικά επίπεδα φυσικής δραστηριότητας, από αθλητές έως ανενεργά άτομα, (β) μελέτες που περιγράφουν τις αλλαγές της μικροχλωρίδας του εντέρου σε οποιοδήποτε είδος ερεθίσματος άσκησης, (γ) μελέτες που περιλαμβάνουν ενήλικες γυναίκες και άνδρες και (δ) μελέτες γραμμένες στα αγγλικά. Αποτελέσματα Συνολικά 13 μελέτες ήταν επιλέξιμες για να συμπεριληφθούν στην ανασκόπηση αυτή. Τα κύρια αποτελέσματα ποικίλλουν ανάλογα με το επίπεδο της φυσικής δραστηριότητας, ωστόσο εντοπίστηκαν αλλαγές στην ποικιλομορφία και τη σχετική αφθονία ορισμένων βακτηρίων καθώς και σε μεταβολίτες στα ενεργά άτομα. Συμπέρασμα Εν κατακλείδι, η άσκηση και μάλιστα σε διαφορετικά επίπεδα δραστηριότητας φαίνεται να έχει θετική επίδραση στη σύνθεση του εντερικού μικροβιώματος. Καθώς η βιβλιογραφία σε αυτόν τον τομέα αυξάνεται ταχέως, είναι σημαντικό οι μελέτες να ενσωματώνουν διάφορες μεθόδους για την αξιολόγηση άλλων πτυχών που σχετίζονται με τον ενεργό τρόπο ζωής, όπως η διατροφή. Η εξερεύνηση άλλων τύπων μικροοργανισμών μπορεί να οδηγήσει σε καλύτερη κατανόηση της προσαρμογής της μικροχλωρίδας του εντέρου στη σωματική δραστηριότητα και τον αθλητισμό.Introduction The intestinal microbiome contains a wide variety of microorganisms that symbiotically inhabit the human digestive system. To date, research has provided enough data on the possible association between exercise and a healthy composition of human intestinal microbiota. This review aims to summarize the results of human studies comparing the microbiome of individuals with different levels of physical activity. Methodology The following English terms: (Microbiome [Title / Abstract]) AND (Exercise [Title / Abstract]) were used during the electronic search in the NIH / PubMed database. This review includes: (a) studies focusing on comparing the gut microbiome between individuals with different levels of physical activity, from athletes to inactive individuals; (b) studies describing changes in the gut microbiota to any type of exercise stimulus; (c) studies involving adult women and men and (d) studies written in English. Results A total of 13 studies were selected to be included in this review. The main results vary according to the level of physical activity, however there are changes in diversity and relative abundance of certain bacteria as well as metabolites in active people. Conclusion In conclusion, exercise even at different levels of activity seems to have a beneficial effect on the composition of the intestinal microbiome. As literature in this field is rapidly growing, it is important that studies incorporate various methods for evaluating other aspects of active lifestyle, such as diet. Exploration of other types of microorganisms may lead to a better understanding of gut microbiota adaptation to physical activity and sports

Depression Levels Influence the Rate of Asthma Exacerbations in Females

Background: Anxiety and depression are common psychological disturbances among asthmatic patients. The aim of the present study is the assessment of anxiety and depression in asthmatic patients and their correlation with symptoms control level and number of exacerbations per year. Methods: One hundred patients with asthma diagnosis, according to the Global Initiative for Asthma (GINA), aged > 18 years old, having a stable disease, were included. Emotional status was evaluated using the Hospital Anxiety Depression Scale (HADS). Patients were followed up for a year to assess the number and severity of exacerbations. Results: Most of our patients were female (58%), middle-aged (mean = 54 ± 13), and married (81%), with low frequency of smoking habits (smokers, ex-smokers and non-smokers were 26%, 30% and 37%, respectively) and low levels of both anxiety and depression [median (interquartile range (IQR)) = 4(2) and median (IQR) = 4(2), respectively]. At the low and moderate level of the depression subscale, female patients experienced asthma exacerbations more frequently compared to male patients (adjusted Incidence Rate Ratio (aIRR) = 4.30; 95% Confidence Interval (CI): 1.94–9.53 and aIRR = 1.82; 95% CI: 1.07–3.13, respectively). Conclusions. Clinicians should evaluate asthma patients for depression, as gender differentially influences outcomes among those with low and moderate levels of depression, with female asthmatics presenting more frequent exacerbations

TRPV4 Inhibition Exerts Protective Effects Against Resistive Breathing Induced Lung Injury

Introduction: TRPV4 channels are calcium channels, activated by mechanical stress, that have been implicated in the pathogenesis of pulmonary inflammation. During resistive breathing (RB), increased mechanical stress is imposed on the lung, inducing lung injury. The role of TRPV4 channels in RB-induced lung injury is unknown. Materials and Methods: Spontaneously breathing adult male C57BL/6 mice were subjected to RB by tracheal banding. Following anaesthesia, mice were placed under a surgical microscope, the surface area of the trachea was measured and a nylon band was sutured around the trachea to reduce area to half. The specific TRPV4 inhibitor, HC-067047 (10 mg/kg ip), was administered either prior to RB and at 12 hrs following initiation of RB (preventive) or only at 12 hrs after the initiation of RB (therapeutic protocol). Lung injury was assessed at 24 hrs of RB, by measuring lung mechanics, total protein, BAL total and differential cell count, KC and IL-6 levels in BAL fluid, surfactant Protein (Sp)D in plasma and a lung injury score by histology. Results: RB decreased static compliance (Cst), increased total protein in BAL (p < 0.001), total cell count due to increased number of both macrophages and neutrophils, increased KC and IL-6 in BAL (p < 0.001 and p = 0.01, respectively) and plasma SpD (p < 0.0001). Increased lung injury score was detected. Both preventive and therapeutic HC-067047 administration restored Cst and inhibited the increase in total protein, KC and IL-6 levels in BAL fluid, compared to RB. Preventive TRPV4 inhibition ameliorated the increase in BAL cellularity, while therapeutic TRPV4 inhibition exerted a partial effect. TRPV4 inhibition blunted the increase in plasma SpD (p < 0.001) after RB and the increase in lung injury score was also inhibited. Conclusion: TRPV4 inhibition exerts protective effects against RB-induced lung injury

Regulation of breathing pattern by IL-10

Proinflammatory cytokines like interleukin-1 beta (IL-1 beta) affect the control of breathing. Our aim is to determine the effect of the anti-inflammatory cytokine IL-10 on the control of breathing. IL-10 knockout mice (IL-10(-/-), n = 10) and wild-type mice (IL-10(+/+), n = 10) were exposed to the following test gases: hyperoxic hypercapnia 7% CO2-93% O-2, normoxic hypercapnia 7% CO2-21% O-2, hypoxic hypercapnia 7% CO2-10% O-2, and hypoxic normocapnia 3% CO2-10% O-2. The ventilatory function was assessed using whole body plethysmography. Recombinant mouse IL-10 (rIL-10; 10 mu/kg) was administered intraperitoneally to wild-type mice (n = 10) 30 min before the onset of gas challenge. IL-10 was administered in neonatal medullary slices (10-30 ng/ml, n = 8). We found that IL-10(-/-) mice exhibited consistently increased frequency and reduced tidal volume compared with IL-10(+/+) mice during room air breathing and in all test gases (by 23.62 to 33.2%, P < 0.05 and -36.23 to -41.69%, P < 0.05, respectively). In all inspired gases, the minute ventilation of IL-10(-/-) mice was lower than IL-10(+/+) (by -15.67 to -22.74%, P < 0.05). The rapid shallow breathing index was higher in IL-10(-/-) mice compared with IL-10(+/+) mice in all inspired gases (by 50.25 to 57.5%, P < 0.05). The intraperitoneal injection of rIL-10 caused reduction of the respiratory rate and augmentation of the tidal volume in room air and also in all inspired gases (by -12.22 to -29.53 and 32.18 to 45.11%, P < 0.05, respectively). IL-10 administration in neonatal rat (n = 8) in vitro rhythmically active medullary slice preparations did not affect either rhythmicity or peak amplitude of hypoglossal nerve discharge. In conclusion, IL-10 may induce a slower and deeper pattern of breathing

A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that “escape” from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying “escape” from oncogene-induced senescence

A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that escape from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying escape from oncogene-induced senescence