Disintegration of the NuRD Complex in Primary Human Muscle Stem Cells in Critical Illness Myopathy.

Critical illness myopathy (CIM) is an acquired, devastating, multifactorial muscle-wasting disease with incomplete recovery. The impact on hospital costs and permanent loss of quality of life is enormous. Incomplete recovery might imply that the function of muscle stem cells (MuSC) is impaired. We tested whether epigenetic alterations could be in part responsible. We characterized human muscle stem cells (MuSC) isolated from early CIM and analyzed epigenetic alterations (CIM n = 15, controls n = 21) by RNA-Seq, immunofluorescence, analysis of DNA repair, and ATAC-Seq. CIM-MuSC were transplanted into immunodeficient NOG mice to assess their regenerative potential. CIM-MuSC exhibited significant growth deficits, reduced ability to differentiate into myotubes, and impaired DNA repair. The chromatin structure was damaged, as characterized by alterations in mRNA of histone 1, depletion or dislocation of core proteins of nucleosome remodeling and deacetylase complex, and loosening of multiple nucleosome-spanning sites. Functionally, CIM-MuSC had a defect in building new muscle fibers. Further, MuSC obtained from the electrically stimulated muscle of CIM patients was very similar to control MuSC, indicating the impact of muscle contraction in the onset of CIM. CIM not only affects working skeletal muscle but has a lasting and severe epigenetic impact on MuSC.

Key summary of German national treatment guidance for hospitalized COVID-19 patients : Key pharmacologic recommendations from a national German living guideline using an Evidence to Decision Framework (last updated 17.05.2021).

PURPOSE: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19. METHODS: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation. RESULTS: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D3 should not be used in COVID-19 routine care. CONCLUSION: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.

The role of cell-free hemoglobin and haptoglobin in acute kidney injury in critically ill adults with ARDS and therapy with VV ECMO.

BACKGROUND: Increased plasma concentrations of circulating cell-free hemoglobin (CFH) are supposed to contribute to the multifactorial etiology of acute kidney injury (AKI) in critically ill patients while the CFH-scavenger haptoglobin might play a protective role. We evaluated the association of CFH and haptoglobin with AKI in patients with an acute respiratory distress syndrome (ARDS) requiring therapy with VV ECMO. METHODS: Patients with CFH and haptoglobin measurements before initiation of ECMO therapy were identified from a cohort of 1044 ARDS patients and grouped into three CFH concentration groups using a risk stratification. The primary objective was to assess the association of CFH and haptoglobin with KDIGO stage 3 AKI. Further objectives included the identification of a target haptoglobin concentration to protect from CFH-associated AKI. MEASUREMENTS AND MAIN RESULTS: Two hundred seventy-three patients fulfilled the inclusion criteria. Of those, 154 patients (56.4%) had AKI at ECMO initiation. The incidence of AKI increased stepwise with increasing concentrations of CFH reaching a plateau at 15 mg/dl. Compared to patients with low [< 5 mg/dl] CFH concentrations, patients with moderate [5-14 mg/dl] and high [≥ 15 mg/dl] CFH concentrations had a three- and five-fold increased risk for AKI (adjusted odds ratio [OR] moderate vs. low, 2.69 [95% CI, 1.25-5.95], P = 0.012; and OR high vs. low, 5.47 [2.00-15.9], P = 0.001). Among patients with increased CFH concentrations, haptoglobin plasma levels were lower in patients with AKI compared to patients without AKI. A haptoglobin concentration greater than 2.7 g/l in the moderate and 2.4 g/l in the high CFH group was identified as clinical cutoff value to protect from CFH-associated AKI (sensitivity 89.5% [95% CI, 83-96] and 90.2% [80-97], respectively). CONCLUSIONS: In critically ill patients with ARDS requiring therapy with VV ECMO, an increased plasma concentration of CFH was identified as independent risk factor for AKI. Among patients with increased CFH concentrations, higher plasma haptoglobin concentrations might protect from CFH-associated AKI and should be subject of future research.

Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients.

BACKGROUND: The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition. METHODS: A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (MSTN) expression levels in skeletal muscle (day 15) was performed. Associations of myostatin to clinical and electrophysiological outcomes, muscular metabolism and muscular atrophy pathways were investigated. RESULTS: MSTN gene expression (median [IQR] fold change: 1.00 [0.68-1.54] vs. 0.26 [0.11-0.80]; p = 0.004) and myostatin plasma concentrations were significantly reduced in all critically ill patients when compared to healthy controls. In critically ill patients, myostatin plasma concentrations increased over time (median [IQR] fold change: day 4: 0.13 [0.08/0.21] vs. day 8: 0.23 [0.10/0.43] vs. day 14: 0.40 [0.26/0.61]; p < 0.001). Patients with ICUAW versus without ICUAW showed significantly lower MSTN gene expression levels (median [IQR] fold change: 0.17 [0.10/0.33] and 0.51 [0.20/0.86]; p = 0.047). Myostatin levels were directly correlated with muscle strength (correlation coefficient 0.339; p = 0.020) and insulin sensitivity index (correlation coefficient 0.357; p = 0.015). No association was observed between myostatin plasma concentrations as well as MSTN expression levels and levels of mobilization, electrophysiological variables, or markers of atrophy pathways. CONCLUSION: Muscular gene expression and systemic protein levels of myostatin are downregulated during critical illness. The previously proposed therapeutic inhibition of myostatin does therefore not seem to have a pathophysiological rationale to improve muscle quality in critically ill patients. TRIAL REGISTRATION: ISRCTN77569430 -13th of February 2008 and ISRCTN19392591 17th of February 2011.

Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation.

BACKGROUND: Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. METHODS: 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. RESULTS: Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58-99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41-0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28-1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. CONCLUSIONS: Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. TRIAL REGISTRATION: Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022964 .

In vitro validation and characterization of pulsed inhaled nitric oxide administration during early inspiration.

PURPOSE: Admixture of nitric oxide (NO) to the gas inspired with mechanical ventilation can be achieved through continuous, timed, or pulsed injection of NO into the inspiratory limb. The dose and timing of NO injection govern the inspired and intrapulmonary effect site concentrations achieved with different administration modes. Here we test the effectiveness and target reliability of a new mode injecting pulsed NO boluses exclusively during early inspiration. METHODS: An in vitro lung model was operated under various ventilator settings. Admixture of NO through injection into the inspiratory limb was timed either (i) selectively during early inspiration ("pulsed delivery"), or as customary, (ii) during inspiratory time or (iii) the entire respiratory cycle. Set NO target concentrations of 5-40 parts per million (ppm) were tested for agreement with the yield NO concentrations measured at various sites in the inspiratory limb, to assess the effectiveness of these NO administration modes. RESULTS: Pulsed delivery produced inspiratory NO concentrations comparable with those of customary modes of NO administration. At low (450 ml) and ultra-low (230 ml) tidal volumes, pulsed delivery yielded better agreement of the set target (up to 40 ppm) and inspiratory NO concentrations as compared to customary modes. Pulsed delivery with NO injection close to the artificial lung yielded higher intrapulmonary NO concentrations than with NO injection close to the ventilator. The maximum inspiratory NO concentration observed in the trachea (68 ± 30 ppm) occurred with pulsed delivery at a set target of 40 ppm. CONCLUSION: Pulsed early inspiratory phase NO injection is as effective as continuous or non-selective admixture of NO to inspired gas and may confer improved target reliability, especially at low, lung protective tidal volumes.

A Global Survey on Diagnostic, Therapeutic and Preventive Strategies in Intensive Care Unit-Acquired Weakness.

Background and Objectives: Intensive care unit-acquired weakness (ICU-AW) is one of the most frequent neuromuscular complications in critically ill patients. We conducted a global survey to evaluate the current practices of diagnostics, treatment and prevention in patients with ICU-AW. Materials and Methods: A pre-survey was created with international experts. After revision, the final survey was endorsed by the European Society of Intensive Care Medicine (ESICM) using the online platform SurveyMonkey®. In 27 items, we addressed strategies of diagnostics, therapy and prevention. An invitation link was sent by email to all ESICM members. Furthermore, the survey was available on the ESICM homepage. Results: A total of 154 healthcare professionals from 39 countries participated in the survey. An ICU-AW screening protocol was used by 20% (28/140) of participants. Forty-four percent (62/141) of all participants reported performing routine screening for ICU-AW, using clinical examination as the method of choice (124/141, 87.9%). Almost 63% (84/134) of the participants reported using current treatment strategies for patients with ICU-AW. The use of treatment and prevention strategies differed between intensivists and non-intensivists regarding the reduction in sedatives (80.0% vs. 52.6%, p = 0.002), neuromuscular blocking agents (76.4% vs. 50%, p = 0.004), corticosteroids (69.1% vs. 37.2%, p < 0.001) and glycemic control regimes (50.9% vs. 23.1%, p = 0.002). Mobilization and physical activity are the most frequently reported treatment strategies for ICU-AW (111/134, 82.9%). The availability of physiotherapists (92/134, 68.7%) and the lack of knowledge about ICU-AW within the medical team (83/134, 61.9%) were the main obstacles to the implementation of the strategies. The necessity to develop guidelines for the screening, diagnosing, treatment and prevention of ICU-AW was recognized by 95% (127/133) of participants. Conclusions: A great heterogeneity regarding diagnostics, treatment and prevention of ICU-AW was reported internationally. Comprehensive guidelines with evidence-based recommendations for ICU-AW management are needed.

Timing, Outcome, and Risk Factors of Intracranial Hemorrhage in Acute Respiratory Distress Syndrome Patients During Venovenous Extracorporeal Membrane Oxygenation.

OBJECTIVES: Intracranial hemorrhage is a serious complication in patients receiving venovenous extracorporeal membrane oxygenation during treatment of the acute respiratory distress syndrome. We analyzed timing, outcome, and risk factors of intracranial hemorrhage in patients on venovenous extracorporeal membrane oxygenation. DESIGN: Retrospective cohort study. SETTING: Single acute respiratory distress syndrome referral center. PATIENTS: Patients receiving venovenous extracorporeal membrane oxygenation were identified from a cohort of 1,044 patients with acute respiratory distress syndrome. Patients developing an intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy were compared with patients without evidence for intracranial hemorrhage. The primary objective was to assess the association of intracranial hemorrhage with 60-day mortality. Further objectives included the identification of risk factors for intracranial hemorrhage and the evaluation of clinical cutoff values. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 444 patients treated with venovenous extracorporeal membrane oxygenation, 49 patients (11.0% [95% CI, 8.3-14.4%]) developed an intracranial hemorrhage. The median time to intracranial hemorrhage occurrence was 4 days (95% CI, 2-7 d). Patients who developed an intracranial hemorrhage had a higher 60-day mortality compared with patients without intracranial hemorrhage (69.4% [54.4-81.3%] vs 44.6% [39.6-49.6%]; odds ratio 3.05 [95% CI, 1.54-6.32%]; p = 0.001). A low platelet count, a high positive end expiratory pressure, and a major initial decrease of Paco2 were identified as independent risk factors for the occurrence of intracranial hemorrhage. A platelet count greater than 100/nL and a positive end expiratory pressure less than or equal to 14 cm H2O during the first 7 days of venovenous extracorporeal membrane oxygenation therapy as well as a decrease of Paco2 less than 24 mm Hg during venovenous extracorporeal membrane oxygenation initiation were identified as clinical cutoff values to prevent intracranial hemorrhage (sensitivity 91% [95% CI, 82-99%], 94% [85-99%], and 67% [48-81%], respectively). CONCLUSIONS: Intracranial hemorrhage occurs early during venovenous extracorporeal membrane oxygenation and is a determinant for 60-day mortality. Appropriate adjustment of identified modifiable risk factors might lower the prevalence of intracranial hemorrhage during venovenous extracorporeal membrane oxygenation therapy.

Long-term outcomes after critical illness: recent insights.

Intensive care survivors often experience post-intensive care sequelae, which are frequently gathered together under the term "post-intensive care syndrome" (PICS). The consequences of PICS on quality of life, health-related costs and hospital readmissions are real public health problems. In the present Viewpoint, we summarize current knowledge and gaps in our understanding of PICS and approaches to management.

Clinical management and outcome of adult patients with extracorporeal life support device-associated intracerebral hemorrhage-a neurocritical perspective and grading.

Intracerebral hemorrhage (ICH) is a devastating complication in patients treated with extracorporeal membrane oxygenation (ECMO) due to respiratory or cardiac issues. Neurosurgical evaluation and management of such cases has only insufficiently been studied. We conducted a retrospective, cohort study of adult patients treated with ECMO between January 2007 and January 2017 in a tertiary healthcare center. Demographics, clinical data, coagulation status, ICH characteristics, and treatment modalities were analyzed. The primary outcome parameter was defined as mortality caused by ICH during ECMO. 525 patients with ECMO therapy were eligible for analysis. An overall incidence for any type of intracranial bleeding of 12.3% was found. Small hemorrhages accounted for 6.4% and acute subdural and epidural hematoma for 1.2%. Twenty-four (4.6%) patients developed ICH, and 11 patients (46%) died due to the ICH. Mortality was significantly higher in patients with larger ICH volumes (86.8 ± 34.8 ml vs 9.9 ± 20.3 ml, p < 0.001), intraventricular hemorrhage (83% vs 8%, p = 0.01), and a fluid level inside the ICH (75% vs 31%, p = 0.04). All patients were classified according to the bleeding pattern on the initial CT scan into 3 types. Patients with type 1 bleeding were statistically more likely to die (p < 0.001). In 15 out of 24 patients (63%), correction of the coagulation status was possible within 12 h after ICH onset. Seven out of 9 patients (78%) without early coagulation correction died compared to 2 out of 15 patients (13%), in whom early coagulation correction was successful (p = 0.01). This is the first study evaluating the course and management of patients experiencing an ICH under ECMO therapy and establishing an ICH classification based on the bleeding patterns. Early correction of the coagulation is of paramount importance in the treatment of these patients.

Studying the pathophysiology of coronavirus disease 2019: a protocol for the Berlin prospective COVID-19 patient cohort (Pa-COVID-19).

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. METHODS: Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. RESULTS: Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. CONCLUSION: We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00021688).

Perioperatively Acquired Weakness.

BACKGROUND: Skeletal muscle failure in critical illness (intensive care unit-acquired weakness) is a well-known complication developing early during intensive care unit stay. However, muscle weakness during the perioperative setting has not yet been investigated. METHODS: We performed a subgroup investigation of a prospective observational trial to investigate perioperative muscle weakness. Eighty-nine patients aged 65 years or older were assessed for handgrip strength preoperatively, on the first postoperative day, at intensive care unit discharge, at hospital discharge, and at 3-month follow-up. Functional status was evaluated perioperatively via Barthel index, instrumental activities of daily living, Timed Up and Go test, and functional independence measure. After exclusion of patients with intensive care unit-acquired weakness or intensive care unit stay of ≥72 hours, 59 patients were included into our analyses. Of these, 14 patients had additional pulmonary function tests preoperatively and on postoperative day 1. Blood glucose was measured intraoperatively every 20 minutes. RESULTS: Handgrip strength significantly decreased after surgery on postoperative day 1 by 16.4% (P < .001). Postoperative pulmonary function significantly decreased by 13.1% for vital capacity (P = .022) and 12.6% for forced expiratory volume in 1 second (P = .001) on postoperative day 1. Handgrip strength remained significantly reduced at hospital discharge (P = .016) and at the 3-month follow-up (P = .012). Perioperative glucose levels showed no statistically significant impact on muscle weakness. Instrumental activities of daily living (P < .001) and functional independence measure (P < .001) were decreased at hospital discharge, while instrumental activities of daily living remained decreased at the 3-month follow-up (P = .026) compared to preoperative assessments. CONCLUSIONS: Perioperatively acquired weakness occurred, indicated by a postoperatively decreased handgrip strength, decreased respiratory muscle function, and impaired functional status, which partly remained up to 3 months.

Prolonged Weaning: S2k Guideline Published by the German Respiratory Society.

Mechanical ventilation (MV) is an essential part of modern intensive care medicine. MV is performed in patients with severe respiratory failure caused by respiratory muscle insufficiency and/or lung parenchymal disease; that is, when other treatments such as medication, oxygen administration, secretion management, continuous positive airway pressure (CPAP), or nasal high-flow therapy have failed. MV is required for maintaining gas exchange and allows more time to curatively treat the underlying cause of respiratory failure. In the majority of ventilated patients, liberation or "weaning" from MV is routine, without the occurrence of any major problems. However, approximately 20% of patients require ongoing MV, despite amelioration of the conditions that precipitated the need for it in the first place. Approximately 40-50% of the time spent on MV is required to liberate the patient from the ventilator, a process called "weaning". In addition to acute respiratory failure, numerous factors can influence the duration and success rate of the weaning process; these include age, comorbidities, and conditions and complications acquired during the ICU stay. According to international consensus, "prolonged weaning" is defined as the weaning process in patients who have failed at least 3 weaning attempts, or require more than 7 days of weaning after the first spontaneous breathing trial (SBT). Given that prolonged weaning is a complex process, an interdisciplinary approach is essential for it to be successful. In specialised weaning centres, approximately 50% of patients with initial weaning failure can be liberated from MV after prolonged weaning. However, the heterogeneity of patients undergoing prolonged weaning precludes the direct comparison of individual centres. Patients with persistent weaning failure either die during the weaning process, or are discharged back to their home or to a long-term care facility with ongoing MV. Urged by the growing importance of prolonged weaning, this Sk2 Guideline was first published in 2014 as an initiative of the German Respiratory Society (DGP), in conjunction with other scientific societies involved in prolonged weaning. The emergence of new research, clinical study findings and registry data, as well as the accumulation of experience in daily practice, have made the revision of this guideline necessary. The following topics are dealt with in the present guideline: Definitions, epidemiology, weaning categories, underlying pathophysiology, prevention of prolonged weaning, treatment strategies in prolonged weaning, the weaning unit, discharge from hospital on MV, and recommendations for end-of-life decisions. Special emphasis was placed on the following themes: (1) A new classification of patient sub-groups in prolonged weaning. (2) Important aspects of pulmonary rehabilitation and neurorehabilitation in prolonged weaning. (3) Infrastructure and process organisation in the care of patients in prolonged weaning based on a continuous treatment concept. (4) Changes in therapeutic goals and communication with relatives. Aspects of paediatric weaning are addressed separately within individual chapters. The main aim of the revised guideline was to summarize both current evidence and expert-based knowledge on the topic of "prolonged weaning", and to use this information as a foundation for formulating recommendations related to "prolonged weaning", not only in acute medicine but also in the field of chronic intensive care medicine. The following professionals served as important addressees for this guideline: intensivists, pulmonary medicine specialists, anaesthesiologists, internists, cardiologists, surgeons, neurologists, paediatricians, geriatricians, palliative care clinicians, rehabilitation physicians, intensive/chronic care nurses, physiotherapists, respiratory therapists, speech therapists, medical service of health insurance, and associated ventilator manufacturers.

Influence of quality of intensive care on quality of life/return to work in survivors of the acute respiratory distress syndrome: prospective observational patient cohort study (DACAPO).

BACKGROUND: Significant long-term reduction in health-related quality of life (HRQoL) is often observed in survivors of the acute respiratory distress syndrome (ARDS), and return to work (RtW) is limited. There is a paucity of data regarding the relationship between the quality of care (QoC) in the intensive care unit (ICU) and both HRQoL and RtW in ARDS survivors. Therefore, the aim of our study was to investigate associations between indicators of QoC and HRQoL and RtW in a cohort of survivors of ARDS. METHODS: To determine the influence of QoC on HRQoL and RtW 1 year after ICU-discharge, ARDS patients were recruited into a prospective multi-centre patient cohort study and followed up regularly after discharge. Patients were asked to complete self-report questionnaires on HRQoL (Short Form 12 physical component scale (PCS) and mental component scale (MCS)) and RtW. Indicators of QoC pertaining to volume, structural and process quality, and general characteristics were recorded on ICU level. Associations between QoC indicators and HrQoL and RtW were investigated by multivariable linear and Cox regression modelling, respectively. B values and hazard ratios (HRs) are reported with corresponding 95% confidence intervals (CIs). RESULTS: 877 (of initially 1225 enrolled) people with ARDS formed the DACAPO survivor cohort, 396 were finally followed up to 1 year after discharge. The twelve-month survivors were characterized by a reduced HRQoL with a greater impairment in the physical component (Md 41.2 IQR [34-52]) compared to the mental component (Md 47.3 IQR [33-57]). Overall, 50% of the patients returned to work. The proportion of ventilated ICU patients showed significant negative associations with both 12 months PCS (B = - 11.22, CI -20.71; - 1,74) and RtW (HR = 0,18, CI 0,04;0,80). All other QoC indicators were not significantly related to outcome. CONCLUSIONS: Associations between ICU QoC and long-term HrQoL and RtW were weak and largely non-significant. Residual confounding by case mix, treatment variables before or during ICU stay and variables pertaining to the post intensive care period (e.g. rehabilitation) cannot be ruled out. TRIAL REGISTRATION: Clinicaltrials.govNCT02637011. (December 22, 2015, retrospectively registered).

Differential contractile response of critically ill patients to neuromuscular electrical stimulation.

BACKGROUND: Neuromuscular electrical stimulation (NMES) has been investigated as a preventative measure for intensive care unit-acquired weakness. Trial results remain contradictory and therefore inconclusive. As it has been shown that NMES does not necessarily lead to a contractile response, our aim was to characterise the response of critically ill patients to NMES and investigate potential outcome benefits of an adequate contractile response. METHODS: This is a sub-analysis of a randomised controlled trial investigating early muscle activating measures together with protocol-based physiotherapy in patients with a SOFA score ≥ 9 within the first 72 h after admission. Included patients received protocol-based physiotherapy twice daily for 20 min and NMES once daily for 20 min, bilaterally on eight muscle groups. Electrical current was increased up to 70 mA or until a contraction was detected visually or on palpation. Muscle strength was measured by a blinded assessor at the first adequate awakening and ICU discharge. RESULTS: One thousand eight hundred twenty-four neuromuscular electrical stimulations in 21 patients starting on day 3.0 (2.0/6.0) after ICU admission were included in this sub-analysis. Contractile response decreased from 64.4% on day 1 to 25.0% on day 7 with a significantly lower response rate in the lower extremities and proximal muscle groups. The electrical current required to elicit a contraction did not change over time (day 1, 50.2 [31.3/58.8] mA; day 7, 45.3 [38.0/57.5] mA). The electrical current necessary for a contractile response was higher in the lower extremities. At the first awakening, patients presented with significant weakness (3.2 [2.5/3.8] MRC score). When dividing the cohort into responders and non-responders (> 50% vs. ≤ 50% contractile response), we observed a significantly higher SOFA score in non-responders. The electrical current necessary for a muscle contraction in responders was significantly lower (38.0 [32.8/42.9] vs. 54.7 [51.3/56.0] mA, p < 0.001). Muscle strength showed higher values in the upper extremities of responders at ICU discharge (4.4 [4.1/4.6] vs. 3.3 [2.8/3.8] MRC score, p = 0.036). CONCLUSION: Patients show a differential contractile response to NMES, which appears to be dependent on the severity of illness and also relevant for potential outcome benefits. TRIAL REGISTRATION: ISRCTN ISRCTN19392591 , registered 17 February 2011.

Innovative ICU Solutions to Prevent and Reduce Delirium and Post-Intensive Care Unit Syndrome.

Delirium, the most common form of acute brain dysfunction affecting up to 80% of intensive care unit (ICU) patients, has been shown to predict long-term cognitive impairment, one of the domains in "Post-ICU Syndrome" (PICS). The ICU environment affects several potentially modifiable risk factors for delirium, such as disorientation and disruption, of the sleep-wake cycle. Innovative solutions aim to transform standard concepts of ICU room design to limit potential stressors, and utilizing the patient care space as a treatment tool, exerting positive, therapeutic effects. The main areas affected by most architectural and interior design modifications are sound environment, light control, floor planning, and room arrangement. Implementation of corresponding solutions is challenging considering the significant medical and technical demands of ICUs. This article discusses innovative concepts and promising approaches in ICU design that may be used to prevent stress and to support the healing process of patients, potentially limiting the impact of delirium and PICS.

Clinical Guideline for Treating Acute Respiratory Insufficiency with Invasive Ventilation and Extracorporeal Membrane Oxygenation: Evidence-Based Recommendations for Choosing Modes and Setting Parameters of Mechanical Ventilation.

For patients with acute respiratory insufficiency, mechanical ("invasive") ventilation is a fundamental therapeutic measure to ensure sufficient gas exchange. Despite decades of strong research efforts, central questions on mechanical ventilation therapy are still answered incompletely. Therefore, many different ventilation modes and settings have been used in daily clinical practice without scientifically sound bases. At the same time, implementation of the few evidence-based therapeutic concepts (e.g., "lung protective ventilation") into clinical practice is still insufficient. The aim of our guideline project "Mechanical ventilation and extracorporeal gas exchange in acute respiratory insufficiency" was to develop an evidence-based decision aid for treating patients with and on mechanical ventilation. It covers the whole pathway of invasively ventilated patients (including indications of mechanical ventilation, ventilator settings, additional and rescue therapies, and liberation from mechanical ventilation). To assess the quality of scientific evidence and subsequently derive recommendations, we applied the Grading of Recommendations, Assessment, Development and Evaluation method. For the first time, using this globally accepted methodological standard, our guideline contains recommendations on mechanical ventilation therapy not only for acute respiratory distress syndrome patients but also for all types of acute respiratory insufficiency. This review presents the two main chapters of the guideline on choosing the mode of mechanical ventilation and setting its parameters. The guideline group aimed that - by thorough implementation of the recommendations - critical care teams may further improve the quality of care for patients suffering from acute respiratory insufficiency. By identifying relevant gaps of scientific evidence, the guideline group intended to support the development of important research projects.

Long-term outcome after the acute respiratory distress syndrome: different from general critical illness?

PURPOSE OF REVIEW: To review the current research data on long-term outcome and health-related quality of life in survivors of the acute respiratory distress syndrome (ARDS) and to compare these findings with those from non-ARDS patients surviving critical illness. RECENT FINDINGS: Between 6 months and 2 years after discharge from ICU, survivors of ARDS present with substantial impairments of the levels of body function (muscle strength, walking capacity and/or physical activity (physical SF-36 score). In contrast to non-ARDS patients from surgical ICUs, a standardized intensified physical therapy during early course of illness in ARDS patients could not show an improvement of long-term physical function performance. Furthermore, a substantial part of further ARDS patients suffer from depression (26-33%), anxiety (38-44%) or posttraumatic stress disorder (22-24%). In general, the level of functional autonomy and daily life activities was reduced, and in one study, 6 months after ICU-discharge this level was significantly lower in ARDS patients compared with non-ARDS patients. In a recent study, 44% of ARDS survivors were jobless 1 year after critical illness, whereas half of previously employed patients returned to work within 4 months after hospital discharge. General health-related quality of life was significantly reduced compared with a matched population in all studies. SUMMARY: Surviving ARDS is associated with a long-term substantial reduction in health-related quality of life and such a reduction does not differ from findings in patients surviving other critical illness. In further research, a special attention should be paid to prevention measures of the 'post intensive care syndrome' as well as to patient important domains, which might better explain the patient's and families' demands.

Secreted Frizzled-Related Protein 2 and Inflammation-Induced Skeletal Muscle Atrophy.

OBJECTIVE: In sepsis, the disease course of critically ill patients is often complicated by muscle failure leading to ICU-acquired weakness. The myokine transforming growth factor-ß1 increases during inflammation and mediates muscle atrophy in vivo. We observed that the transforming growth factor-ß1 inhibitor, secreted frizzled-related protein 2, was down-regulated in skeletal muscle of ICU-acquired weakness patients. We hypothesized that secreted frizzled-related protein 2 reduction enhances transforming growth factor-ß1-mediated effects and investigated the interrelationship between transforming growth factor-ß1 and secreted frizzled-related protein 2 in inflammation-induced atrophy. DESIGN: Observational study and prospective animal trial. SETTING: Two ICUs and research laboratory. PATIENTS/SUBJECTS: Twenty-six critically ill patients with Sequential Organ Failure Assessment scores greater than or equal to 8 underwent a skeletal muscle biopsy from the vastus lateralis at median day 5 in ICU. Four patients undergoing elective orthopedic surgery served as controls. To search for signaling pathways enriched in muscle of ICU-acquired weakness patients, a gene set enrichment analysis of our recently published gene expression profiles was performed. Quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry were used to analyze secreted frizzled-related protein 2 expression and protein content. A mouse model of inflammation-induced skeletal muscle atrophy due to polymicrobial sepsis and cultured myocytes were used for mechanistic analyses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Gene set enrichment analysis uncovered transforming growth factor-ß1 signaling activation in vastus lateralis from ICU-acquired weakness patients. Muscular secreted frizzled-related protein 2 expression was reduced after 5 days in ICU. Likewise, muscular secreted frizzled-related protein 2 expression was decreased early and continuously in mice with inflammation-induced atrophy. In muscle, secreted frizzled-related protein 2 was predominantly contained in fast twitch/type II myofibers. Secreted frizzled-related protein 2 physically interacted and colocalized with transforming growth factor-ß1 through its cysteine-rich domain. Finally, secreted frizzled-related protein 2 prevented transforming growth factor-ß1-induced atrophy in C2C12 myotubes. CONCLUSIONS: Muscular secreted frizzled-related protein 2 is down-regulated in ICU-acquired weakness patients and mice with inflammation-induced muscle atrophy. Decreased secreted frizzled-related protein 2 possibly establishes a positive feedback loop enhancing transforming growth factor-ß1-mediated atrophic effects in inflammation-induced atrophy.