Circadian rhythms in septic shock patients.

BACKGROUND: Despite the intensive efforts to improve the diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate whether the rhythmicity of clock gene expression is altered in patients with septic shock. METHODS: This prospective pilot study was performed at the university hospital Charité-Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK). We included 20 patients with septic shock between May 2014 and January 2018, from whom blood was drawn every 4 h over a 24-h period to isolate CD14-positive monocytes and to measure the expression of 17 clock and clock-associated genes. Of these patients, 3 whose samples expressed fewer than 8 clock genes were excluded from the final analysis. A rhythmicity score SP was calculated, which comprises values between -1 (arrhythmic) and 1 (rhythmic), and expression data were compared to data of a healthy study population additionally. RESULTS: 77% of the measured clock genes showed inconclusive rhythms, i.e., neither rhythmic nor arrhythmic. The clock genes NR1D1, NR1D2 and CRY2 were the most rhythmic, while CLOCK and ARNTL were the least rhythmic. Overall, the rhythmicity scores for septic shock patients were significantly (p < 0.0001) lower (0.23 ± 0.26) compared to the control group (12 healthy young men, 0.70 ± 0.18). In addition, the expression of clock genes CRY1, NR1D1, NR1D2, DBP, and PER2 was suppressed in septic shock patients and CRY2 was significantly upregulated compared to controls. CONCLUSION: Molecular rhythms in immune cells of septic shock patients were substantially altered and decreased compared to healthy young men. The decrease in rhythmicity was clock gene-dependent. The loss of rhythmicity and down-regulation of clock gene expression might be caused by sepsis and might further deteriorate immune responses and organ injury, but further studies are necessary to understand underlying pathophysiological mechanisms. Trail registration Clinical trial registered with www.ClinicalTrials.gov (NCT02044575) on 24 January 2014.

German-wide prospective DACAPO cohort of survivors of the acute respiratory distress syndrome (ARDS): a cohort profile.

PURPOSE: While most research focuses on the association between medical characteristics and residual morbidity of survivors of the acute respiratory distress syndrome (ARDS), little is known about the relation between potentially modifiable intensive care unit (ICU) features and the course of health-related quality of life (HRQoL). Accordingly, the DACAPO study was set up to elucidate the influence of quality of intensive care on HRQoL and return to work (RtW) in survivors of ARDS. The continued follow-up of these former ICU patients leads to the establishment of the DACAPO (survivor) cohort. PARTICIPANTS: Sixty-one ICUs all over Germany recruited patients with ARDS between September 2014 and April 2016. Inclusion criteria were: (1) age older than 18 years and (2) ARDS diagnosis according to the 'Berlin definition'. No further inclusion or exclusion criteria were applied. 1225 patients with ARDS could be included in the DACAPO ICU sample. Subsequently, the 876 survivors at ICU discharge form the actual DACAPO cohort. FINDINGS TO DATE: The recruitment of the participants of the DACAPO cohort and the baseline data collection has been completed. The care-related data of the DACAPO cohort reveal a high proportion of adverse events (in particular, hypoglycaemia and reintubation). However, evidence-based supportive measures were applied frequently. FUTURE PLANS: Three months, 6 months and 1 year after ICU admission a follow-up assessment is conducted. The instruments of the follow-up questionnaires comprise the domains: (A) HRQoL, (B) RtW, (C) general disability, (D) psychiatric symptoms and (E) social support. Additionally, an annual follow-up of the DACAPO cohort focusing on HRQoL, psychiatric symptoms and healthcare utilisation will be conducted. Furthermore, several add-on projects affecting medical issues are envisaged. TRIAL REGISTRATION NUMBER: NCT02637011.

Efficacy and safety of argatroban in patients with acute respiratory distress syndrome and extracorporeal lung support.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) or pumpless extracorporeal lung assist (pECLA) requires effective anticoagulation. Knowledge on the use of argatroban in patients with acute respiratory distress syndrome (ARDS) undergoing ECMO or pECLA is limited. Therefore, this study assessed the feasibility, efficacy and safety of argatroban in critically ill ARDS patients undergoing extracorporeal lung support. METHODS: This retrospective analysis included ARDS patients on extracorporeal lung support who received argatroban between 2007 and 2014 in a single ARDS referral center. As controls, patients who received heparin were matched for age, sex, body mass index and severity of illness scores. Major and minor bleeding complications, thromboembolic events, administered number of erythrocyte concentrates, thrombocytes and fresh-frozen plasmas were assessed. The number of extracorporeal circuit systems and extracorporeal lung support cannulas needed due to clotting was recorded. Also assessed was the efficacy to reach the targeted activated partial thromboplastin time (aPTT) in the first consecutive 14 days of therapy, and the controllability of aPTT values is within a therapeutic range of 50-75 s. Fisher's exact test, Mann-Whitney U tests, Friedman tests and multivariate nonparametric analyses for longitudinal data (MANOVA; Brunner's analysis) were applied where appropriate. RESULTS: Of the 535 patients who met the inclusion criteria, 39 receiving argatroban and 39 matched patients receiving heparin (controls) were included. Baseline characteristics were similar between the two groups, including severity of illness and organ failure scores. There were no significant differences in major and minor bleeding complications. Rates of thromboembolic events were generally low and were similar between the two groups, as were the rates of transfusions required and device-associated complications. The controllability of both argatroban and heparin improved over time, with a significantly increasing probability to reach the targeted aPTT corridor over the first days (p < 0.001). Over time, there were significantly fewer aPTT values below the targeted aPTT goal in the argatroban group than in the heparin group (p < 0.05). Both argatroban and heparin reached therapeutic aPTT values for adequate application of extracorporeal lung support. CONCLUSIONS: Argatroban appears to be a feasible, effective and safe anticoagulant for critically ill ARDS patients undergoing extracorporeal lung support.

Treatment of MRSA pneumonia: Clinical and economic comparison of linezolid vs. vancomycin - a retrospective analysis of medical charts and re-imbursement data of real-life patient populations.

Objectives: To supplement the data collected in randomized clinical trials, the present study in patients with methicillin resistant Staphylococcus aureus (MRSA) pneumonia was conducted to explore the clinical effectiveness of linezolid and vancomycin in a routine clinical setting. Further, the overall costs of the patients' stay in the intensive care unit (ICU) were compared. Methods: This was a retrospective analysis of medical and reimbursement data of adult patients who were treated for MRSA pneumonia with linezolid or vancomycin. Since the subjects were not randomly assigned to treatments, propensity score adjustment was applied to reduce a potential selection bias. Results: In total, 226 patients were included; 95 received linezolid and 131 received vancomycin as initial therapy for MRSA pneumonia. Switches to another antibiotic were observed in 4 patients (4.2%) receiving linezolid and in 23 patients (17.6%) receiving vancomycin (logistic regression analysis; odds ratio linezolid/vancomycin: 0.183; 95% confidence interval [CI]: 0.052-0.647; p<0.01). All-cause in-hospital mortality was also lower in patients receiving linezolid (22 patients [23.2%] vs. 54 patients [41.2%]) (logistic regression analysis; odds ratio linezolid/vancomycin: 0.351; 95% CI: 0.184-0.671; p<0.01). The analysis of the total costs of stay in ICU did not reveal any major differences between the two treatment groups (cost ratio linezolid/vancomycin: 1.29; 95% CI: 0.84-1.98; p=0.24). Conclusions: These findings confirm in a routine clinical setting that linezolid is a valuable therapeutic alternative to vancomycin for the treatment of MRSA pneumonia. However, prospective studies in real-life patient populations are warranted.

Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial.

Importance: Adjunctive hydrocortisone therapy is suggested by the Surviving Sepsis Campaign in refractory septic shock only. The efficacy of hydrocortisone in patients with severe sepsis without shock remains controversial. Objective: To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted from January 13, 2009, to August 27, 2013, with a follow-up of 180 days until February 23, 2014. The trial was performed in 34 intermediate or intensive care units of university and community hospitals in Germany, and it included 380 adult patients with severe sepsis who were not in septic shock. Interventions: Patients were randomly allocated 1:1 either to receive a continuous infusion of 200 mg of hydrocortisone for 5 days followed by dose tapering until day 11 (n = 190) or to receive placebo (n = 190). Main Outcomes and Measures: The primary outcome was development of septic shock within 14 days. Secondary outcomes were time until septic shock, mortality in the intensive care unit or hospital, survival up to 180 days, and assessment of secondary infections, weaning failure, muscle weakness, and hyperglycemia (blood glucose level >150 mg/dL [to convert to millimoles per liter, multiply by 0.0555]). Results: The intention-to-treat population consisted of 353 patients (64.9% male; mean [SD] age, 65.0 [14.4] years). Septic shock occurred in 36 of 170 patients (21.2%) in the hydrocortisone group and 39 of 170 patients (22.9%) in the placebo group (difference, -1.8%; 95% CI, -10.7% to 7.2%; P = .70). No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days (15 of 171 patients [8.8%] vs 14 of 170 patients [8.2%], respectively; difference, 0.5%; 95% CI, -5.6% to 6.7%; P = .86), 90 days (34 of 171 patients [19.9%] vs 28 of 168 patients [16.7%]; difference, 3.2%; 95% CI, -5.1% to 11.4%; P = .44), and 180 days (45 of 168 patients [26.8%] vs 37 of 167 patients [22.2%], respectively; difference, 4.6%; 95% CI, -4.6% to 13.7%; P = .32). In the hydrocortisone vs placebo groups, 21.5% vs 16.9% had secondary infections, 8.6% vs 8.5% had weaning failure, 30.7% vs 23.8% had muscle weakness, and 90.9% vs 81.5% had hyperglycemia. Conclusions and Relevance: Among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days. These findings do not support the use of hydrocortisone in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT00670254.

Extracorporeal lung support in H1N1 provoked acute respiratory failure: the experience of the German ARDS Network.

BACKGROUND: During the H1N1 pandemic of 2009 and 2010, the large number of patients with severe respiratory failure due to H1N1 infection strained the capacities of treatment facilities for extracorporeal membrane oxygenation (ECMO) around the world. No data on this topic have yet been published for Germany. METHODS: During the pandemic, the German ARDS Network (a task force of the DIVI's respiratory failure section) kept track of the availability of ECMO treatment facilities with a day-to-day, Internet-based capacity assessment. In cooperation with the Robert Koch Institute, epidemiological and clinical data were obtained on all patients treated for influenza in intensive care units. RESULTS: 116 patients were identified who had H1N1 disease and were treated in the intensive care units of 9 university hospitals and 3 other maximum medical care hospitals. 61 of them received ECMO. The overall mortality was 38% (44 of 116 patients); among patients receiving ECMO, the mortality was 54% (33 of 61 patients). The mortality was higher among patients who had an accompanying malignancy or immune deficiency (72.2%). CONCLUSION: Even persons without any other accompanying disease developed life-threatening respiratory failure as a result of H1N1 infection, and many of these patients needed ECMO. This study reveals for the first time that the mortality of H1N1 infection in Germany is comparable to that in other countries. H1N1 patients with acute respiratory failure had a worse outcome if they also had serious accompanying diseases.

Lower tidal volume strategy (≈3 ml/kg) combined with extracorporeal CO2 removal versus 'conventional' protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study.

BACKGROUND: Acute respiratory distress syndrome is characterized by damage to the lung caused by various insults, including ventilation itself, and tidal hyperinflation can lead to ventilator induced lung injury (VILI). We investigated the effects of a low tidal volume (V(T)) strategy (V(T) ≈ 3 ml/kg/predicted body weight [PBW]) using pumpless extracorporeal lung assist in established ARDS. METHODS: Seventy-nine patients were enrolled after a 'stabilization period' (24 h with optimized therapy and high PEEP). They were randomly assigned to receive a low V(T) ventilation (≈3 ml/kg) combined with extracorporeal CO2 elimination, or to a ARDSNet strategy (≈6 ml/kg) without the extracorporeal device. The primary outcome was the 28-days and 60-days ventilator-free days (VFD). Secondary outcome parameters were respiratory mechanics, gas exchange, analgesic/sedation use, complications and hospital mortality. RESULTS: Ventilation with very low V(T)'s was easy to implement with extracorporeal CO2-removal. VFD's within 60 days were not different between the study group (33.2 ± 20) and the control group (29.2 ± 21, p = 0.469), but in more hypoxemic patients (PaO2/FIO2 ≤150) a post hoc analysis demonstrated significant improved VFD-60 in study patients (40.9 ± 12.8) compared to control (28.2 ± 16.4, p = 0.033). The mortality rate was low (16.5%) and did not differ between groups. CONCLUSIONS: The use of very low V(T) combined with extracorporeal CO2 removal has the potential to further reduce VILI compared with a 'normal' lung protective management. Whether this strategy will improve survival in ARDS patients remains to be determined (Clinical trials NCT 00538928).

Weaning from mechanical ventilation and sedation.

PURPOSE OF REVIEW: Guidelines for weaning from sedation and weaning from ventilator gained increasing interest in recent years. This includes patients with acute respiratory distress syndrome, as well as other mechanically ventilated patients. This review will give an overview of the current literature and practice guidelines in ventilator and sedation weaning. RECENT FINDINGS: Sedation and ventilator weaning are closely linked. Weaning protocols for both sedation and ventilator weaning should be implemented in daily routine. The essential element of such algorithm should be a daily spontaneous awakening trial and spontaneous breathing trial. Furthermore, regularly monitoring for deepness of sedation and delirium should be implemented. Too deep sedation, as well as prolonged delirium is associated with higher mortality. SUMMARY: The most important conclusion we come to from recent randomized controlled trials is that only using an integrative algorithm for sedation and ventilator weaning can improve survival of ICU patients.

Computed tomography findings from patients with ARDS due to Influenza A (H1N1) virus-associated pneumonia.

PURPOSE: The purpose of this study was to retrospectively evaluate whether computed tomography (CT) findings have prognostic value for the prediction of mortality and severity of the clinical course in patients presenting with early stage of acute respiratory distress syndrome (ARDS) due to swine-origin influenza A (S-OIV). MATERIALS AND METHODS: Chest CT (16-/64-row multidetector CT) of 23 patients (of whom 9 patients died) were retrospectively reviewed by three independent blinded observers. The CT findings were graded on a 3-point scale (1: normal attenuation, 2: ground-glass attenuation, 3: consolidation). The extent of each abnormality was determined by visually estimating the percentage (to the nearest 10%) of the affected lung parenchyma in each zone and multiplied by the CT-score described above. RESULTS: All patients presented with a mixture of bilateral patchy consolidations and ground glass opacities. Spearman rank correlation in evaluation of the presence and extent of lung abnormalities by the three different observers was good (correlation coefficient, 0.876-0.922; p < 0.001). The overall CT-score in survivors (mean, 96.0 (± 26.2); range, 53-158) was significantly lower than that in non-survivors (mean, 116.2 (± 14.0); range, 101-139). ROC analysis revealed an area under curve of 0.79 (p = 0.021) for the CT score with an optimal cutoff value of a CT-score of 100 for prediction of survival, with a sensitivity of 100% and a specificity of 64% (accuracy, 78%). For this optimal cutoff, Kaplan-Meier estimator showed a significant difference for the survival ratio (p = 0.011). CONCLUSION: In patients with severe ARDS due to S-OIV-infection, the CT-score has a prognostic value in the prediction of mortality.

Magnetic resonance imaging analysis of the subscapularis muscle after arthroscopic and open shoulder stabilization.

To evaluate the subscapularis muscle (SSC) after arthroscopic and open shoulder stabilization, three groups [after arthroscopic (A), after open shoulder stabilization (B), healthy volunteers (0)] underwent magnetic resonance imaging. Magnetic resonance parameters were compared with clinical SSC tests and shoulder scores. From Group 0 to B, the diameters of the SSC decreased, and the fatty degeneration of the upper SSC increased (P<.05) from Group 0 and A to B according to clinical findings. The functional shoulder scores did not differ (P>.05). Magnetic resonance analysis provides reasons of postoperative SSC dysfunction.

Combined vs. Isoflurane/Fentanyl anesthesia for major abdominal surgery: Effects on hormones and hemodynamics.

BACKGROUND: Combination of epidural and general anesthesia (combined anesthesia) avoids the intraoperative use of intravenous analgesics and may reduce the surgical stress response during major abdominal surgery. This study examines the differences in intraoperative hemodynamic stability, cortisol levels and activity of cardiovascular hormones between combined anesthesia and isoflurane/fentanyl anesthesia. MATERIAL/METHODS: Sixty ASA I-II patients were prospectively randomized to receive either combined anesthesia, i.e, isoflurane anesthesia combined with thoracic epidural analgesia (bolus of 12 ml 0.2% ropivacaine containing 1 microg/ml sufentanil 30 min before incision, followed by continuous infusion at 6 ml/h) or isoflurane/fentanyl anesthesia (IV fentanyl as required) for major abdominal surgery. Depth of anesthesia was monitored using Bispectral Index. Administration of fluids and of vasopressors was directed by a standardized protocol. Blood samples for angiotensin II, vasopressin, catecholamines, and cortisol were drawn before anesthesia, after induction (but before using the epidural catheter), and 40 min after skin incision. RESULTS: After induction of anesthesia, mean arterial pressure decreased by 12-20 mmHg in both groups and angiotensin-II concentrations increased. Vasopressin increased predominantly after opening the abdomen in both groups. Under combined anesthesia, intraoperative epinephrine and cortisol concentrations were considerably lower. Intraoperative crystalloid fluid substitution, blood loss and urine output did not differ between groups. There were more hypotensive periods and the demand for colloids and low-dose continuous norepinephrine was greater under combined anesthesia. CONCLUSIONS: Combined anesthesia reduces the intraoperative stress response, but moderate hemodynamic instability is relatively common and has to be compensated for by adequate volume replacement and vasopressor support.