Body core temberature, melatonin and cortisol exhibit different circadian rhythm profiles during septic shock depending on timing of onset

Background: Septic shock has been found to disrupt circadian rhythms. Moreover, timing of onset has been associated with different circadian profiles in experimental studies. Serum melatonin, its urine metabolite 6-Sulfatoxymelatonin (aMT6s), cortisol and core body temperature rhythms are considered as circadian biomarkers. Critically ill and septic shocked patients experience severe circadian deregulation.Material and Methods: In this prospective study, we enrolled 26 patients divided into two groups: Group A (N=15) included subjects who had septic shock at the time of ICU admission and Group B (N= 11) included patients who developed septic shock during ICU admission.Levels of aMT6s and cortisol were measured in urine samples every 4 hours over a 24-hour period. Two sets of samples were taken from Group A (entry/septic shock and exit) and three sets from Group B (entry, septic shock and exit). Core temperature was recorded every hour. Cosinor analysis of the data provided an evaluation of mesor (the mean value), amplitude (the difference between peak and mean values) and acrophase (the time of peak value) of circadian rhythms. Results: Temperature's circadian rhythm was maintained in both groups. In Group A, amplitude of aMT6s upon entry (septic shock) was reduced in relation with exit (437.2±309.2 vs 674.1±657.6 ng/4h, p<0.05). Peak time occurred earlier (10:00 p.m. vs 07:00 am, p<0.05) and correlated with higher APACHE II score and longer ICU stay. In Group B, aMT6s mean values were significantly increased during septic shock (2492.2± 1709.1ng/4h) compared to both entry (895.4±715.5 ng/4h) and exit (1308.6± 1214.4 ng/4h, p<0.05 for all comparisons). Amplitude of aMT6s was also elevated during septic shock (794.8±431.8 ng/4h) in relation with entry (293.1±275.9 ng/4h, p<0.05).Regarding cortisol rhythm in group A, during septic shock amplitude was increased compared to exit (13.3±31 ng/4h vs 8.7±21.2 ng/4h p<0.05) and correlated with reduced hospital length of stay. In Group B, cortisol mean values and amplitude during septic shock (10±5.3 and 3±1.8 ng/4h, respectively) were significantly reduced compared to both entry (30±57.9 and 12.3±27.3 ng/4h) and exit (14.4±20.7 and 6.6±8.7ng/4h, p<0.05 for all comparisons) and correlated with higher SOFA score and longer ICU and hospital stay. Conclusion: Septic shock induced inverse changes of aMT6s and cortisol circadian rhythm profiles both within and between different groups of patients, depending on timing of onset. Reduced rhythmicity was correlated with severity of disease and longer ICU stay.Εισαγωγή: Η σήψη έχει φανεί πως διαταράσσει τους κιρκάδιους ρυθμούς. Μάλιστα, σε πολλές πειραματικές μελέτες ο χρόνος εγκατάστασης της σήψης έχει συσχετισθεί με διαφορετικά κιρκαδιανά πρότυπα διακύμανσης. Τα επίπεδα της μελατονίνης στο αίμα, της 6-σουλφατοξυμελατονίνης (aMT6s) και της κορτιζόλης στα ούρα, καθώς επίσης και η θερμοκρασία του σώματος αποτελούν βιοδείκτες κιρκαδιανής ρυθμικότητας. Οι βαρέως πάσχοντες ασθενείς της ΜΕΘ και οι πάσχοντες από σηπτική καταπληξία βιώνουν σοβαρή κιρκαδιανή απορύθμιση. Υλικό - Μέθοδος: Σε αυτή την προοπτική μελέτη παρατήρησης συμπεριλήφθηκαν 26 ασθενείς, που χωρίσθηκαν σε δύο ομάδες: στην ομάδα A (N=15) περιλήφθηκαν άτομα με σηπτική καταπληξία τη στιγμή της εισαγωγής τους στην ΜΕΘ και στην ομάδα B (N= 11) άτομα που ανέπτυξαν σηπτικό shock κατά την διάρκεια νοσηλείας τους στην ΜΕΘ, όπου εισήχθηκαν για άλλο λόγο εκτός από σήψη.Τα επίπεδα της aMT6s και της κορτιζόλης προσδιορίσθηκαν σε δείγματα ούρων που λήφθηκαν σε μεσοδιαστήματα 4 ωρών, στη διάρκεια ενός 24-ώρου. Δύο σειρές δειγμάτων λήφθηκαν από τους ασθενείς της ομάδας A (κατά την είσοδο/σηπτικό shock και στην έξοδο) και τρεις σειρές δειγμάτων από την ομάδα B (στην είσοδο, κατά το σηπτικό shock και στην έξοδο). Η θερμοκρασία της ουροδόχου κύστης καταγράφονταν κάθε ώρα στα ίδια χρονικά διαστήματα που γινόταν η δειγματοληψία των ούρων. Με συνημιτονοειδή ανάλυση (Cosinor analysis) των δεδομένων προσδιορίσθηκαν ο mesor (μέση τιμή), η amplitude (διαφορά της μέσης και της μέγιστης τιμής) και η acrophase (χρόνος εμφάνισης της μέγιστης τιμής) των κιρκαδιανών ρυθμών όλων των μεταβλητών που μετρήθηκαν.Αποτελέσματα: Η κιρκαδιανή ρυθμικότητα της θερμοκρασίας διατηρήθηκε και στις δύο ομάδες ασθενών. Στην ομάδα A, η amplitude της aMT6s κατά την είσοδο (σηπτικό shock) ήταν ελαττωμένη σε σχέση με την έξοδο (437.2±309.2 αντί 674.1±657.6 ng/4h, p<0.05). Η μέγιστη τιμή επιτεύχθηκε νωρίτερα (10:00 μ.μ. αντί 07:00 π.μ, p<0.05) και σχετίσθηκε με υψηλότερο APACHE II score και μεγαλύτερη διάρκεια νοσηλείας στην ΜΕΘ. Στην ομάδα Β, οι μέσες τιμές της aMT6s ήταν σημαντικά αυξημένες κατά την διάρκεια του σηπτικού shock (2492.2± 1709.1 ng/4h) σε σύγκριση τόσο με την είσοδο (895.4±715.5 ng/4h) όσο και με την έξοδο (1308.6± 1214.4 ng/4h, p<0.05 για όλες τις συγκρίσεις). Η amplitude της aMT6s ήταν επίσης αυξημένη κατά το σηπτικό shock (794.8±431.8 ng/4h) σε σχέση με την είσοδο (293.1±275.9 ng/4h, p<0.05).4Αναφορικά με την ρυθμικότητα της κορτιζόλης στην ομάδα A, η amplitude στο σηπτικό shock ήταν αυξημένη συγκριτικά με την έξοδο (13.3±31 ng/4h αντί 8.7±21.2 ng/4h p<0.05) και σχετίσθηκε με μειωμένη διάρκεια παραμονής στο νοσοκομείο. Στην ομάδα B, η μέση τιμή της κορτιζόλης και η amplitude κατά το σηπτικό shock (10±5.3 και 3±1.8 ng/4h, αντίστοιχα) ήταν σημαντικά μειωμένη σε σχέση τόσο με την είσοδο (30±57.9 και 12.3±27.3 ng/4h) όσο και με την έξοδο (14.4±20.7 και 6.6±8.7 ng/4h, p<0.05 για όλες τις συγκρίσεις) και σχετίσθηκε με υψηλότερο SOFA score και μεγαλύτερη διάρκεια νοσηλείας στην ΜΕΘ και στο νοσοκομείο. Συμπεράσματα: Η σηπτική καταπληξία προκαλεί αντίστροφες αλλαγές στην κιρκαδιανή διακύμανση της aMT6s και της κορτιζόλης σε διάφορες ομάδες ασθενών, ανάλογα με την ώρα έναρξης. Η μειωμένη ρυθμικότητα σχετίσθηκε με την βαρύτητα της νόσου και με παράταση της νοσηλεία στην ΜΕΘ

Traumatic asphyxia due to blunt chest trauma: a case report and literature review

Abstract Introduction Crush asphyxia is different from positional asphyxia, as respiratory compromise in the latter is caused by splinting of the chest and/or diaphragm, thus preventing normal chest expansion. There are only a few cases or small case series of crush asphyxia in the literature, reporting usually poor outcomes. Case presentation We present the case of a 44-year-old Caucasian man who developed traumatic asphyxia with severe thoracic injury and mild brain edema after being crushed under heavy auto vehicle mechanical parts. He remained unconscious for an unknown time. The treatment included oropharyngeal intubation and mechanical ventilation, bilateral chest tube thoracostomies, treatment of brain edema and other supportive measures. Our patient’s outcome was good. Traumatic asphyxia is generally under-reported and most authors apply supportive measures, while the final outcome seems to be dependent on the length of time of the chest compression and on the associated injuries. Conclusion Treatment for traumatic asphyxia is mainly supportive with special attention to the re-establishment of adequate oxygenation and perfusion; treatment of the concomitant injuries might also affect the final outcome.</p

Melatonin and cortisol exhibit different circadian rhythm profiles during septic shock depending on timing of onset: a prospective observational study

Abstract Background Septic shock has been found to disrupt circadian rhythms. Moreover, timing of onset has been associated with different circadian profiles in experimental studies. Results In this prospective study, we enrolled 26 patients divided into two groups: Group A (N = 15) included subjects who had septic shock at the time of ICU admission and Group B (N = 11) included patients who developed septic shock during ICU admission. 6-Sulfatoxymelatonin (aMT6s) and cortisol levels were measured in urine samples every 4 h over a 24-h period. Two sets of samples were taken from Group A (entry/septic shock and exit) and three sets from Group B (entry, septic shock and exit). Mean, amplitude that is the difference between peak and mean values, as well as peak time, were estimated for both aMT6s and cortisol. In Group A, amplitude of aMT6s upon entry (septic shock) was reduced in relation to exit (437.2 ± 309.2 vs. 674.1 ± 657.6 ng/4 h, p < 0.05). Peak time occurred earlier (10:00 p.m. vs. 07:00 a.m, p < 0.05) and correlated with higher APACHE II score and longer ICU stay. In Group B, aMT6s mean values were significantly increased during septic shock (2492.2 ± 1709.1 ng/4 h) compared to both entry (895.4 ± 715.5 ng/4 h) and exit (1308.6 ± 1214.4 ng/4 h, p < 0.05 for all comparisons). Amplitude of aMT6s was also elevated during septic shock (794.8 ± 431.8 ng/4 h) in relation to entry (293.1 ± 275.9 ng/4 h, p < 0.05). Regarding cortisol rhythm in Group A, during septic shock amplitude was increased compared to exit (13.3 ± 31 ng/4 h vs. 8.7 ± 21.2 ng/4 h p < 0.05) and correlated with reduced hospital length of stay. In Group B, cortisol mean values and amplitude during septic shock (10 ± 5.3 and 3 ± 1.8 ng/4 h, respectively) were significantly reduced compared to both entry (30 ± 57.9 and 12.3 ± 27.3 ng/4 h) and exit (14.4 ± 20.7 and 6.6 ± 8.7 ng/4 h, p < 0.05 for all comparisons) and correlated with higher SOFA score and longer ICU and hospital stay. Conclusions Septic shock induced inverse changes of aMT6s and cortisol circadian rhythm profiles both within and between different groups of patients, depending on timing of onset. Reduced rhythmicity was correlated with severity of disease and longer ICU stay

Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort

Objectives: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged- infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT 65MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving \u3b2-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P=0.012]. Additionally, in patients with a SOFA score of 65 9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P=0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P=0.025]. Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infection

Epidemiology of intra-abdominal infection and sepsis in critically ill patients: "AbSeS", a multinational observational cohort study and ESICM Trials Group Project

PURPOSE: To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). METHODS: We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. RESULTS: The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. CONCLUSION: This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection.status: publishe

Antimicrobial Lessons From a Large Observational Cohort on Intra-abdominal Infections in Intensive Care Units

evere intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by disease-specific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed.Severe intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by diseasespecific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed

Poor timing and failure of source control are risk factors for mortality in critically ill patients with secondary peritonitis

Purpose: To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. Methods: Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (&lt; 2 h), 'urgent' (2-6 h), and 'delayed' (&gt; 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). Results: The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value ≤ 4-55.4% for a value &gt; 12, p &lt; 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (&lt; 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). Conclusion: 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome

Epidemiology of intra-abdominal infection and sepsis in critically ill patients: "AbSeS", a multinational observational cohort study and ESICM Trials Group Project

Purpose To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). Methods We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. Results The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. Conclusion This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection