Purpose: Severe ARDS is often associated with refractory hypoxemia, and early identification and treatment of hypoxemia is mandatory. For the management of severe ARDS ventilator settings, positioning therapy, infection control, and supportive measures are essential to improve survival. Methods and results:A precise definition of life-threating hypoxemia is not identified. Typical clinical determinations are: arterial partial pressure of oxygen < 60 mmHg and/or arterial oxygenation < 88 % and/or the ratio of PaO 2 /FIO 2 < 100. For mechanical ventilation specific settings are recommended: limitation of tidal volume (6 ml/ kg predicted body weight), adequate high PEEP (>12 cmH 2 O), a recruitment manoeuvre in special situations, and a 'balanced' respiratory rate (20-30/min). Individual bedside methods to guide PEEP/recruitment (e.g., transpulmonary pressure) are not (yet) available. Prone positioning [early (≤ 48 hrs after onset of severe ARDS) and prolonged (repetition of 16-hr-sessions)] improves survival. An advanced infection management/control includes early diagnosis of bacterial, atypical, viral and fungal specimen (blood culture, bronchoalveolar lavage), and of infection sources by CT scan, followed by administration of broad-spectrum anti-infectives. Neuromuscular blockage (Cisatracurium ≤ 48 hrs after onset of ARDS), as well as an adequate sedation strategy (score guided) is an important supportive therapy. A negative fluid balance is associated with improved lung function and the use of hemofiltration might be indicated for specific indications. Conclusions:A specific standard of care is required for the management of severe ARDS with refractory hypoxemia.

IntroductionNon-excitable muscle membrane indicates critical illness myopathy (CIM) during early critical illness. We investigated predisposing risk factors for non-excitable muscle membrane at onset of critical illness.MethodsWe performed sequential measurements of muscle membrane excitability after direct muscle stimulation (dmCMAP) in 40 intensive care unit (ICU) patients selected upon a simplified acute physiology (SAPS-II) score ≥ 20 on 3 successive days within 1 week after ICU admission. We then investigated predisposing risk factors, including the insulin-like growth factor (IGF)-system, inflammatory, metabolic and hemodynamic parameters, as well as suspected medical treatment prior to first occurrence of abnormal dmCMAP. Nonparametric analysis of two-factorial longitudinal data and multivariate analysis were used for statistical analysis.Results22 patients showed abnormal muscle membrane excitability during direct muscle stimulation within 7 (5 to 9.25) days after ICU admission. Significant risk factors for the development of impaired muscle membrane excitability in univariate analysis included inflammation, disease severity, catecholamine and sedation requirements, as well as IGF binding protein-1 (IGFBP-I), but did not include either adjunctive hydrocortisone treatment in septic shock, nor administration of neuromuscular blocking agents or aminoglycosides. In multivariate Cox regression analysis, interleukin-6 remained the significant risk factor for the development of impaired muscle membrane excitability (HR 1.006, 95%-CI (1.002 to 1.011), P = 0.002).ConclusionsSystemic inflammation during early critical illness was found to be the main risk factor for development of CIM during early critical illness. Inflammation-induced impairment of growth-factor mediated insulin sensitivity may be involved in the development of CIM.

Purpose: Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes.Methods: Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10.Results: Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1-8.7) and without TDM (8.2 points; 95% CI 7.5-9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5-1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5-6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7-7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9-6.9, p < 0.001).

Words: main text 3490, abstract 250 2 ABSTRACT Objectives: Neuromuscular dysfunction in critically ill patients is attributed to either critical illness myopathy (CIM) or critical illness polyneuropathy (CIP) or a combination of both. But it is unknown whether differential diagnosis has an impact on prognosis. This study investigates whether there is an association between the early differentiation of CIM versus CIP and clinical prognosis. Methods: We included mechanically ventilated patients who featured a Simplified AcutePhysiology Score II (SAPS-II) ≥ 20 on three consecutive days within the first week after ICU admission. 53 critically ill patients were enrolled and examined by conventional nerve conduction studies and direct muscle stimulation (184 examinations in total). The first examination was conducted within the first week after admission to the intensive care unit (ICU). Results: In this cohort of critically ill patients, CIM was more frequent (68%) than CIP (38%).Electrophysiological signs of CIM preceded electrophysiological signs of CIP (median at day 7 in CIM patients vs. day 10 in CIP patients, p<0.001). Most patients with CIP featured concomitant CIM. At discharge from ICU, 25% of patients with isolated CIM showed electrophysiological signs of recovery and significantly lower degrees of weakness. Recovery could not be observed in patients with combined CIM/CIP even though ICU length of stay was significantly longer (mean 35 days in CIM/CIP vs. mean 19 days in CIM, p<0.001). Conclusion:Prognoses of patients differ depending on electrophysiological findings during early critical illness: Early electrophysiological differentiation of ICU acquired neuromuscular disorder enhances the evaluation of clinical prognosis during critical illness.

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