Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality.

INTRODUCTION: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) show limited systemic hyperinflammation, but immunomodulatory treatments are effective. Little is known about the inflammatory response in the lungs and if this could be targeted using high-dose steroids (HDS). We aimed to characterise the alveolar immune response in patients with COVID-19-related ARDS, to determine its association with mortality, and to explore the association between HDS treatment and the alveolar immune response. METHODS: In this observational cohort study, a comprehensive panel of 63 biomarkers was measured in repeated bronchoalveolar lavage (BAL) fluid and plasma samples of patients with COVID-19 ARDS. Differences in alveolar-plasma concentrations were determined to characterise the alveolar inflammatory response. Joint modelling was performed to assess the longitudinal changes in alveolar biomarker concentrations, and the association between changes in alveolar biomarker concentrations and mortality. Changes in alveolar biomarker concentrations were compared between HDS-treated and matched untreated patients. RESULTS: 284 BAL fluid and paired plasma samples of 154 patients with COVID-19 were analysed. 13 biomarkers indicative of innate immune activation showed alveolar rather than systemic inflammation. A longitudinal increase in the alveolar concentration of several innate immune markers, including CC motif ligand (CCL)20 and CXC motif ligand (CXCL)1, was associated with increased mortality. Treatment with HDS was associated with a subsequent decrease in alveolar CCL20 and CXCL1 levels. CONCLUSIONS: Patients with COVID-19-related ARDS showed an alveolar inflammatory state related to the innate host response, which was associated with a higher mortality. HDS treatment was associated with decreasing alveolar concentrations of CCL20 and CXCL1.

The Impact of Thoracic Ultrasound on Clinical Management of Critically Ill Patients (UltraMan): An International Prospective Observational Study.

OBJECTIVES: To investigate the impact of thoracic ultrasound (TUS) examinations on clinical management in adult ICU patients. DESIGN: A prospective international observational study. SETTING: Four centers in The Netherlands and Italy. PATIENTS: Adult ICU patients (> 18 yr) that received a clinically indicated lung ultrasound examination. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinicians performing TUS completed a pre- and post-examination case report form. Patient characteristics, TUS, and resulting clinical effects were recorded. First, change of management, defined as a TUS-induced change in clinical impression leading to a change in treatment plan, was reported. Second, execution of intended management changes within 8 hours was verified. Third, change in fluid balance after 8 hours was calculated. A total of 725 TUS performed by 111 operators across 534 patients (mean age 63 ± 15.0, 70% male) were included. Almost half of TUS caused a change in clinical impression, which resulted in change of management in 39% of cases. The remainder of TUS confirmed the clinical impression, while a minority (4%) did not contribute. Eighty-nine percent of management changes indicated by TUS were executed within 8 hours. TUS examinations that led to a change in fluid management also led to distinct and appropriate changes in patient's fluid balance. CONCLUSIONS: In this international observational study in adult ICU patients, use of TUS had a major impact on clinical management. These results provide grounds for future randomized controlled trials to determine if TUS-induced changes in decision-making also lead to improved health outcomes.

Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome.

Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19-related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19-related ARDS.

Lung Ultrasound Signs to Diagnose and Discriminate Interstitial Syndromes in ICU Patients: A Diagnostic Accuracy Study in Two Cohorts.

OBJECTIVES: To determine the diagnostic accuracy of lung ultrasound signs for both the diagnosis of interstitial syndrome and for the discrimination of noncardiogenic interstitial syndrome (NCIS) from cardiogenic pulmonary edema (CPE) in a mixed ICU population. DESIGN: A prospective diagnostic accuracy study with derivation and validation cohorts. SETTING: Three academic mixed ICUs in the Netherlands. PATIENTS: Consecutive adult ICU patients that received a lung ultrasound examination. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULT: The reference standard was the diagnosis of interstitial syndrome (NCIS or CPE) or noninterstitial syndromes (other pulmonary diagnoses and no pulmonary diagnoses) based on full post-hoc clinical chart review except lung ultrasound. The index test was a lung ultrasound examination performed and scored by a researcher blinded to clinical information. A total of 101 patients were included in the derivation and 122 in validation cohort. In the derivation cohort, patients with interstitial syndrome ( n = 56) were reliably discriminated from other patients based on the presence of a B-pattern (defined as greater than or equal to 3 B-lines in one frame) with an accuracy of 94.7% (sensitivity, 90.9%; specificity, 91.1%). For discrimination of NCIS ( n = 29) from CPE ( n = 27), the presence of bilateral pleural line abnormalities (at least two: fragmented, thickened or irregular) had the highest diagnostic accuracy (94.6%; sensitivity, 89.3%; specificity, 100%). A diagnostic algorithm (Bedside Lung Ultrasound for Interstitial Syndrome Hierarchy protocol) using B-pattern and bilateral pleural abnormalities had an accuracy of 0.86 (95% CI, 0.77-0.95) for diagnosis and discrimination of interstitial syndromes. In the validation cohort, which included 122 patients with interstitial syndrome, bilateral pleural line abnormalities discriminated NCIS ( n = 98) from CPE ( n = 24) with a sensitivity of 31% (95% CI, 21-40%) and a specificity of 100% (95% CI, 86-100%). CONCLUSIONS: Lung ultrasound can diagnose and discriminate interstitial syndromes in ICU patients with moderate-to-good accuracy. Pleural line abnormalities are highly specific for NCIS, but sensitivity is limited.

Lung- and Diaphragm-Protective Ventilation by Titrating Inspiratory Support to Diaphragm Effort: A Randomized Clinical Trial.

OBJECTIVES: Lung- and diaphragm-protective ventilation is a novel concept that aims to limit the detrimental effects of mechanical ventilation on the diaphragm while remaining within limits of lung-protective ventilation. The premise is that low breathing effort under mechanical ventilation causes diaphragm atrophy, whereas excessive breathing effort induces diaphragm and lung injury. In a proof-of-concept study, we aimed to assess whether titration of inspiratory support based on diaphragm effort increases the time that patients have effort in a predefined "diaphragm-protective" range, without compromising lung-protective ventilation. DESIGN: Randomized clinical trial. SETTING: Mixed medical-surgical ICU in a tertiary academic hospital in the Netherlands. PATIENTS: Patients (n = 40) with respiratory failure ventilated in a partially-supported mode. INTERVENTIONS: In the intervention group, inspiratory support was titrated hourly to obtain transdiaphragmatic pressure swings in the predefined "diaphragm-protective" range (3-12 cm H2O). The control group received standard-of-care. MEASUREMENTS AND MAIN RESULTS: Transdiaphragmatic pressure, transpulmonary pressure, and tidal volume were monitored continuously for 24 hours in both groups. In the intervention group, more breaths were within "diaphragm-protective" range compared with the control group (median 81%; interquartile range [64-86%] vs 35% [16-60%], respectively; p < 0.001). Dynamic transpulmonary pressures (20.5 ± 7.1 vs 18.5 ± 7.0 cm H2O; p = 0.321) and tidal volumes (7.56 ± 1.47 vs 7.54 ± 1.22 mL/kg; p = 0.961) were not different in the intervention and control group, respectively. CONCLUSIONS: Titration of inspiratory support based on patient breathing effort greatly increased the time that patients had diaphragm effort in the predefined "diaphragm-protective" range without compromising tidal volumes and transpulmonary pressures. This study provides a strong rationale for further studies powered on patient-centered outcomes.

Early Restrictive Fluid Strategy Impairs the Diaphragm Force in Lambs with Acute Respiratory Distress Syndrome.

BACKGROUND: The effect of fluid management strategies in critical illness-associated diaphragm weakness are unknown. This study hypothesized that a liberal fluid strategy induces diaphragm muscle fiber edema, leading to reduction in diaphragmatic force generation in the early phase of experimental pediatric acute respiratory distress syndrome in lambs. METHODS: Nineteen mechanically ventilated female lambs (2 to 6 weeks old) with experimental pediatric acute respiratory distress syndrome were randomized to either a strict restrictive fluid strategy with norepinephrine or a liberal fluid strategy. The fluid strategies were maintained throughout a 6-h period of mechanical ventilation. Transdiaphragmatic pressure was measured under different levels of positive end-expiratory pressure (between 5 and 20 cm H2O). Furthermore, diaphragmatic microcirculation, histology, inflammation, and oxidative stress were studied. RESULTS: Transdiaphragmatic pressures decreased more in the restrictive group (-9.6 cm H2O [95% CI, -14.4 to -4.8]) compared to the liberal group (-0.8 cm H2O [95% CI, -5.8 to 4.3]) during the application of 5 cm H2O positive end-expiratory pressure (P = 0.016) and during the application of 10 cm H2O positive end-expiratory pressure (-10.3 cm H2O [95% CI, -15.2 to -5.4] vs. -2.8 cm H2O [95% CI, -8.0 to 2.3]; P = 0.041). In addition, diaphragmatic microvessel density was decreased in the restrictive group compared to the liberal group (34.0 crossings [25th to 75th percentile, 22.0 to 42.0] vs. 46.0 [25th to 75th percentile, 43.5 to 54.0]; P = 0.015). The application of positive end-expiratory pressure itself decreased the diaphragmatic force generation in a dose-related way; increasing positive end-expiratory pressure from 5 to 20 cm H2O reduced transdiaphragmatic pressures with 27.3% (17.3 cm H2O [95% CI, 14.0 to 20.5] at positive end-expiratory pressure 5 cm H2O vs. 12.6 cm H2O [95% CI, 9.2 to 15.9] at positive end-expiratory pressure 20 cm H2O; P < 0.0001). The diaphragmatic histology, markers for inflammation, and oxidative stress were similar between the groups. CONCLUSIONS: Early fluid restriction decreases the force-generating capacity of the diaphragm and diaphragmatic microcirculation in the acute phase of pediatric acute respiratory distress syndrome. In addition, the application of positive end-expiratory pressure decreases the force-generating capacity of the diaphragm in a dose-related way. These observations provide new insights into the mechanisms of critical illness-associated diaphragm weakness.

Rbm20ΔRRM Mice, Expressing a Titin Isoform with Lower Stiffness, Are Protected from Mechanical Ventilation-Induced Diaphragm Weakness.

Diaphragm weakness frequently develops in mechanically ventilated critically ill patients and is associated with increased morbidity, including ventilator weaning failure, mortality, and health care costs. The mechanisms underlying diaphragm weakness are incompletely understood but may include the elastic properties of titin, a giant protein whose layout in the muscle's sarcomeres makes it an ideal candidate to sense ventilation-induced diaphragm unloading, resulting in downstream signaling through titin-binding proteins. In the current study, we investigated whether modulating titin stiffness affects the development of diaphragm weakness during mechanical ventilation. To this end, we ventilated genetically engineered mice with reduced titin stiffness (Rbm20ΔRRM), and robust (TtnΔIAjxn) or severely (TtnΔ112-158) increased titin stiffness for 8 h, and assessed diaphragm contractility and protein expression of titin-binding proteins. Mechanical ventilation reduced the maximum active tension of the diaphragm in WT, TtnΔIAjxn and TtnΔ112-158 mice. However, in Rbm20ΔRRM mice maximum active tension was preserved after ventilation. Analyses of titin binding proteins suggest that muscle ankyrin repeat proteins (MARPs) 1 and 2 may play a role in the adaptation of the diaphragm to mechanical ventilation, and the preservation of diaphragm contractility in Rbm20ΔRRM mice. Thus, Rbm20ΔRRM mice, expressing titin isoforms with lower stiffness, are protected from mechanical ventilation-induced diaphragm weakness, suggesting that titin elasticity may modulate the diaphragm's response to unloading during mechanical ventilation.

Divergent SARS-CoV-2-specific T- and B-cell responses in severe but not mild COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. Understanding the immune response that provides specific immunity but may also lead to immunopathology is crucial for the design of potential preventive and therapeutic strategies. Here, we characterized and quantified SARS-CoV-2-specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4+ T-cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. Furthermore, in these critically ill patients, a massive influx of circulating T cells into the lungs was observed, overwhelming the local T-cell compartment, and indicative of vascular leakage. The observed disparate T- and B-cell responses could be indicative of a deregulated immune response in critically ill COVID-19 patients.

Lung ultrasound in a tertiary intensive care unit population: a diagnostic accuracy study.

BACKGROUND: Evidence from previous studies comparing lung ultrasound to thoracic computed tomography (CT) in intensive care unit (ICU) patients is limited due to multiple methodologic weaknesses. While addressing methodologic weaknesses of previous studies, the primary aim of this study is to investigate the diagnostic accuracy of lung ultrasound in a tertiary ICU population. METHODS: This is a single-center, prospective diagnostic accuracy study conducted at a tertiary ICU in the Netherlands. Critically ill patients undergoing thoracic CT for any clinical indication were included. Patients were excluded if time between the index and reference test was over eight hours. Index test and reference test consisted of 6-zone lung ultrasound and thoracic CT, respectively. Hemithoraces were classified by the index and reference test as follows: consolidation, interstitial syndrome, pneumothorax and pleural effusion. Sensitivity, specificity, positive and negative likelihood ratio were estimated. RESULTS: In total, 87 patients were included of which eight exceeded the time limit and were subsequently excluded. In total, there were 147 respiratory conditions in 79 patients. The estimated sensitivity and specificity to detect consolidation were 0.76 (95%CI: 0.68 to 0.82) and 0.92 (0.87 to 0.96), respectively. For interstitial syndrome they were 0.60 (95%CI: 0.48 to 0.71) and 0.69 (95%CI: 0.58 to 0.79). For pneumothorax they were 0.59 (95%CI: 0.33 to 0.82) and 0.97 (95%CI: 0.93 to 0.99). For pleural effusion they were 0.85 (95%CI: 0.77 to 0.91) and 0.77 (95%CI: 0.62 to 0.88). CONCLUSIONS: In conclusion, lung ultrasound is an adequate diagnostic modality in a tertiary ICU population to detect consolidations, interstitial syndrome, pneumothorax and pleural effusion. Moreover, one should be careful not to interpret lung ultrasound results in deterministic fashion as multiple respiratory conditions can be present in one patient. Trial registration This study was retrospectively registered at Netherlands Trial Register on March 17, 2021, with registration number NL9344.

Thinking Out-of-the-Box: A Non-Standard Application of Standard Pulse-Oximetry and Standard Near-Infrared Spectroscopy in a COVID-19 Patient.

PURPOSE: Purpose of this report is to describe the feasibility of lingual pulse oximetry and lingual near-infrared spectroscopy (NIRS) in a COVID-19 patient to assess lingual tissue viability after several days of mechanical ventilation in the prone position. MATERIALS & METHODS: In a COVID-19 ICU-patient, the tongue became grotesquely swollen, hardened and protruding from the oral cavity after 20 h of mechanical ventilation uninterrupted in the prone position. To assess the doubtful viability of the tongue, pulse-oximetric hemoglobin O2-saturation (SpO2; Nellcor, OxiMax MAX-NI, Covidien, MA, USA) and NIRS-based, regional tissue O2-saturation measurements (rSO2; SenSmart, Nonin, MN, USA) were performed at the tongue. RESULTS: At the tongue, regular pulse-oximetric waveforms with a pulse-oximetric hemoglobin O2-saturation (SpO2) of 88% were recorded, i.e. only slightly lower than the SpO2 reading at the extremities at that time (90%). Lingual NIRS-based rSO2 measurements yielded stable tissue rSO2-values of 76-78%, i.e. values expected also in other adequately perfused and oxygenated (muscle-) tissues. CONCLUSION: Despite the alarming, clinical finding of a grotesquely swollen, rubber-hard tongue and clinical concerns on the adequacy of the tongue perfusion and oxygenation, our measurements of both arterial pulsatility (SpO2) and NIRS-based tissue oxygenation (rSO2) suggested adequate perfusion and oxygenation of the tongue, rendering non-vitality of the tongue, e.g. by lingual venous thrombosis, unlikely. To our knowledge, this is the first clinical report of lingual rSO2 measurement.

Cyclophosphamide for interstitial lung disease-associated acute respiratory failure: mortality, clinical response and radiological characteristics.

BACKGROUND: Treatment for interstitial lung disease (ILD) patients with acute respiratory failure (ARF) is challenging, and literature to guide such treatment is scarce. The reported in-hospital mortality rates of ILD patients with ARF are high (62-66%). Cyclophosphamide is considered a second-line treatment in steroid-refractory ILD-associated ARF. The first aim of this study was to evaluate the in-hospital mortality in patients with ILD-associated ARF treated with cyclophosphamide. The second aim was to compare computed tomographic (CT) patterns and physiological and ventilator parameters between survivors and non-survivors. METHODS: Retrospective analysis of patients with ILD-associated ARF treated with cyclophosphamide between February 2016 and October 2017. Patients were categorized into three subgroups: connective tissue disease (CTD)-associated ILD, other ILD or vasculitis. In-hospital mortality was evaluated in the whole cohort and in these subgroups. Clinical response was determined using physiological and ventilator parameters: Sequential Organ Failure Assessment Score (SOFA), PaO2/FiO2 (P/F) ratio and dynamic compliance (Cdyn) before and after cyclophosphamide treatment. The following CT features were quantified: ground-glass opacification (GGO) proportion, reticulation proportion, overall extent of parenchymal disease and fibrosis coarseness score. RESULTS: Fifteen patients were included. The overall in-hospital mortality rate was 40%. In-hospital mortality rates for CTD-associated ILD, other ILD and vasculitis were 20, 57, and 33%, respectively. The GGO proportion (71% vs 45%) was higher in non-survivors. There were no significant differences in the SOFA score, P/F ratio or Cdyn between survivors and non-survivors. However, in survivors the P/F ratio increased from 129 to 220 mmHg and Cdyn from 75 to 92 mL/cmH2O 3 days after cyclophosphamide treatment. In non-survivors the P/F ratio hardly changed (113-114 mmHg) and Cdyn even decreased (27-20 mL/cmH2O). CONCLUSION: In this study, we found a mortality rate of 40% in patients treated with cyclophosphamide for ILD-associated ARF. Connective tissue disease-associated ILD and vasculitis were associated with a lower risk of death. In non-survivors, the CT GGO proportion was significantly higher. The P/F ratio and Cdyn in survivors increased after 3 days of cyclophosphamide treatment.

First, do no harm: bilateral radial artery occlusion in a COVID-19 patient.

OBJECTIVE: Objective of this case report is to draw attention to a less known thrombotic complication associated with COVID-19, i.e., thrombosis of both radial arteries, with possible (long-term) consequences. THE CASE: In our COVID-19 ICU a 49-year-old male patient was admitted, with past medical history of obesity, smoking and diabetes, but no reported atherosclerotic complications. The patient had been admitted with severe hypoxemia and multiple pulmonary emboli were CT-confirmed. ICU-treatment included mechanical ventilation and therapeutic anticoagulation. Preparing the insertion of a new radial artery catheter for invasive blood pressure measurement and blood sampling, we detected that both radial arteries were non-pulsating and occluded: (a) Sonography showed the typical anatomical localization of both radial and ulnar arteries. However, Doppler-derived flow-signals could only be obtained from the ulnar arteries. (b) To test collateral arterial supply of the hand, a pulse-oximeter was placed on the index finger. Thereafter, the ulnar artery at the wrist was compressed. This compression caused an immediate loss of the finger's pulse-oximetry perfusion signal. The effect was reversible upon release of the ulnar artery. (c) To test for collateral perfusion undetectable by pulse-oximetry, we measured regional oxygen saturation (rSO2) of the thenar muscle by near-infrared spectroscopy (NIRS). Confirming our findings above, ulnar arterial compression demonstrated that thenar rSO2 was dependent on ulnar artery flow. The described development of bilateral radial artery occlusion in a relatively young and therapeutically anticoagulated patient with no history of atherosclerosis was unexpected. CONCLUSIONS: Since COVID-19 patients are at increased risk for arterial occlusion, it appears advisable to meticulously check for adequacy of collateral (hand-) perfusion, avoiding the harm of hand ischemia if interventions (e.g., catheterizations) at the radial or ulnar artery are intended.

Ultrasound to Detect Central Venous Catheter Placement Associated Complications: A Multicenter Diagnostic Accuracy Study.

BACKGROUND: Mechanical complications arising after central venous catheter placement are mostly malposition or pneumothorax. To date, to confirm correct position and detect pneumothorax, chest x-ray film has been the reference standard, while ultrasound might be an accurate alternative. The aim of this study was to evaluate diagnostic accuracy of ultrasound to detect central venous catheter malposition and pneumothorax. METHODS: This was a prospective, multicenter, diagnostic accuracy study conducted at the intensive care unit and postanesthesia care unit. Adult patients who underwent central venous catheterization of the internal jugular vein or subclavian vein were included. Index test consisted of venous, cardiac, and lung ultrasound. Standard reference test was chest x-ray film. Primary outcome was diagnostic accuracy of ultrasound to detect malposition and pneumothorax; for malposition, sensitivity, specificity, and other accuracy parameters were estimated. For pneumothorax, because chest x-ray film is an inaccurate reference standard to diagnose it, agreement and Cohen's κ-coefficient were determined. Secondary outcomes were accuracy of ultrasound to detect clinically relevant complications and feasibility of ultrasound. RESULTS: In total, 758 central venous catheterizations were included. Malposition occurred in 23 (3.3%) out of 688 cases included in the analysis. Ultrasound sensitivity was 0.70 (95% CI, 0.49 to 0.86) and specificity 0.99 (95% CI, 0.98 to 1.00). Pneumothorax occurred in 5 (0.7%) to 11 (1.5%) out of 756 cases according to chest x-ray film and ultrasound, respectively. In 748 out of 756 cases (98.9%), there was agreement between ultrasound and chest x-ray film with a Cohen's κ-coefficient of 0.50 (95% CI, 0.19 to 0.80). CONCLUSIONS: This multicenter study shows that the complication rate of central venous catheterization is low and that ultrasound produces a moderate sensitivity and high specificity to detect malposition. There is moderate agreement with chest x-ray film for pneumothorax. In conclusion, ultrasound is an accurate diagnostic modality to detect malposition and pneumothorax.

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Physiology of the Respiratory Drive in ICU Patients: Implications for Diagnosis and Treatment.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.

Breath-synchronized electrical stimulation of the expiratory muscles in mechanically ventilated patients: a randomized controlled feasibility study and pooled analysis.

BACKGROUND: Expiratory muscle weakness leads to difficult ventilator weaning. Maintaining their activity with functional electrical stimulation (FES) may improve outcome. We studied feasibility of breath-synchronized expiratory population muscle FES in a mixed ICU population ("Holland study") and pooled data with our previous work ("Australian study") to estimate potential clinical effects in a larger group. METHODS: Holland: Patients with a contractile response to FES received active or sham expiratory muscle FES (30 min, twice daily, 5 days/week until weaned). Main endpoints were feasibility (e.g., patient recruitment, treatment compliance, stimulation intensity) and safety. Pooled: Data on respiratory muscle thickness and ventilation duration from the Holland and Australian studies were combined (N = 40) in order to estimate potential effect size. Plasma cytokines (day 0, 3) were analyzed to study the effects of FES on systemic inflammation. RESULTS: Holland: A total of 272 sessions were performed (active/sham: 169/103) in 20 patients (N = active/sham: 10/10) with a total treatment compliance rate of 91.1%. No FES-related serious adverse events were reported. Pooled: On day 3, there was a between-group difference (N = active/sham: 7/12) in total abdominal expiratory muscle thickness favoring the active group [treatment difference (95% confidence interval); 2.25 (0.34, 4.16) mm, P = 0.02] but not on day 5. Plasma cytokine levels indicated that early FES did not induce systemic inflammation. Using a survival analysis approach for the total study population, median ventilation duration and ICU length of stay were 10 versus 52 (P = 0.07), and 12 versus 54 (P = 0.03) days for the active versus sham group. Median ventilation duration of patients that were successfully extubated was 8.5 [5.6-12.2] versus 10.5 [5.3-25.6] days (P = 0.60) for the active (N = 16) versus sham (N = 10) group, and median ICU length of stay was 10.5 [8.0-14.5] versus 14.0 [9.0-19.5] days (P = 0.36) for those active (N = 16) versus sham (N = 8) patients that were extubated and discharged alive from the ICU. During ICU stay, 3/20 patients died in the active group versus 8/20 in the sham group (P = 0.16). CONCLUSION: Expiratory muscle FES is feasible in selected ICU patients and might be a promising technique within a respiratory muscle-protective ventilation strategy. The next step is to study the effects on weaning and ventilator liberation outcome. TRIAL REGISTRATION: ClinicalTrials.gov, ID NCT03453944. Registered 05 March 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03453944 .

Potential of the Cardiovascular Drug Levosimendan in the Management of Amyotrophic Lateral Sclerosis: An Overview of a Working Hypothesis.

Levosimendan is a calcium sensitizer that promotes myocyte contractility through its calcium-dependent interaction with cardiac troponin C. Administered intravenously, it has been used for nearly 2 decades to treat acute and advanced heart failure and to support the heart function in various therapy settings characterized by low cardiac output. Effects of levosimendan on noncardiac muscle suggest a possible new application in the treatment of people with amyotrophic lateral sclerosis (ALS), a neuromuscular disorder characterized by progressive weakness, and eventual paralysis. Previous attempts to improve the muscle response in ALS patients and thereby maintain respiratory function and delay progression of disability have produced some mixed results. Continuing this line of investigation, levosimendan has been shown to enhance in vitro the contractility of the diaphragm muscle fibers of non-ALS patients and to improve in vivo diaphragm neuromuscular efficiency in healthy subjects. Possible positive effects on respiratory function in people with ALS were seen in an exploratory phase 2 study, and a phase 3 clinical trial is now underway to evaluate the potential benefit of an oral form of levosimendan on both respiratory and overall functions in patients with ALS. Here, we will review the various known pharmacologic effects of levosimendan, considering their relevance to people living with ALS.

Abdominal functional electrical stimulation to assist ventilator weaning in critical illness: a double-blinded, randomised, sham-controlled pilot study.

BACKGROUND: For every day a person is dependent on mechanical ventilation, respiratory and cardiac complications increase, quality of life decreases and costs increase by > $USD 1500. Interventions that improve respiratory muscle function during mechanical ventilation can reduce ventilation duration. The aim of this pilot study was to assess the feasibility of employing an abdominal functional electrical stimulation (abdominal FES) training program with critically ill mechanically ventilated patients. We also investigated the effect of abdominal FES on respiratory muscle atrophy, mechanical ventilation duration and intensive care unit (ICU) length of stay. METHODS: Twenty critically ill mechanically ventilated participants were recruited over a 6-month period from one metropolitan teaching hospital. They were randomly assigned to receive active or sham (control) abdominal FES for 30 min, twice per day, 5 days per week, until ICU discharge. Feasibility was assessed through participant compliance to stimulation sessions. Abdominal and diaphragm muscle thickness were measured using ultrasound 3 times in the first week, and weekly thereafter by a blinded assessor. Respiratory function was recorded when the participant could first breathe independently and at ICU discharge, with ventilation duration and ICU length of stay also recorded at ICU discharge by a blinded assessor. RESULTS: Fourteen of 20 participants survived to ICU discharge (8, intervention; 6, control). One control was transferred before extubation, while one withdrew consent and one was withdrawn for staff safety after extubation. Median compliance to stimulation sessions was 92.1% (IQR 5.77%) in the intervention group, and 97.2% (IQR 7.40%) in the control group (p = 0.384). While this pilot study is not adequately powered to make an accurate statistical conclusion, there appeared to be no between-group thickness changes of the rectus abdominis (p = 0.099 at day 3), diaphragm (p = 0.652 at day 3) or combined lateral abdominal muscles (p = 0.074 at day 3). However, ICU length of stay (p = 0.011) and ventilation duration (p = 0.039) appeared to be shorter in the intervention compared to the control group. CONCLUSIONS: Our compliance rates demonstrate the feasibility of using abdominal FES with critically ill mechanically ventilated patients. While abdominal FES did not lead to differences in abdominal muscle or diaphragm thickness, it may be an effective method to reduce ventilation duration and ICU length of stay in this patient group. A fully powered study into this effect is warranted. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry, ACTRN12617001180303. Registered 9 August 2017.

Positive End-Expiratory Pressure Ventilation Induces Longitudinal Atrophy in Diaphragm Fibers.

RATIONALE: Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown. OBJECTIVES: To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in the caudal direction and reducing the length of fibers. METHODS: We studied structure and function of diaphragm fibers of mechanically ventilated critically ill patients and mechanically ventilated rats with normal and increased titin compliance. MEASUREMENTS AND MAIN RESULTS: PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length. Diaphragm fibers of 18-hour mechanically ventilated rats (PEEP of 2.5 cm H2O) adapt to the reduced length by absorbing serially linked sarcomeres, the smallest contractile units in muscle (i.e., longitudinal atrophy). Increasing the compliance of titin molecules reduces longitudinal atrophy. CONCLUSIONS: Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response that is modulated by the elasticity of the giant sarcomeric protein titin. We postulate that longitudinal atrophy, in concert with the aforementioned cross-sectional atrophy, hampers spontaneous breathing trials in critically ill patients: during these efforts, end-expiratory lung volume is reduced, and the shortened diaphragm fibers are stretched to excessive sarcomere lengths. At these lengths, muscle fibers generate less force, and diaphragm weakness ensues.

Respiratory Muscle Effort during Expiration in Successful and Failed Weaning from Mechanical Ventilation.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Respiratory muscle weakness in critically ill patients is associated with difficulty in weaning from mechanical ventilation. Previous studies have mainly focused on inspiratory muscle activity during weaning; expiratory muscle activity is less well understood. The current study describes expiratory muscle activity during weaning, including tonic diaphragm activity. The authors hypothesized that expiratory muscle effort is greater in patients who fail to wean compared to those who wean successfully. METHODS: Twenty adult patients receiving mechanical ventilation (more than 72 h) performed a spontaneous breathing trial. Tidal volume, transdiaphragmatic pressure, diaphragm electrical activity, and diaphragm neuromechanical efficiency were calculated on a breath-by-breath basis. Inspiratory (and expiratory) muscle efforts were calculated as the inspiratory esophageal (and expiratory gastric) pressure-time products, respectively. RESULTS: Nine patients failed weaning. The contribution of the expiratory muscles to total respiratory muscle effort increased in the "failure" group from 13 ± 9% at onset to 24 ± 10% at the end of the breathing trial (P = 0.047); there was no increase in the "success" group. Diaphragm electrical activity (expressed as the percentage of inspiratory peak) was low at end expiration (failure, 3 ± 2%; success, 4 ± 6%) and equal between groups during the entire expiratory phase (P = 0.407). Diaphragm neuromechanical efficiency was lower in the failure versus success groups (0.38 ± 0.16 vs. 0.71 ± 0.36 cm H2O/µV; P = 0.054). CONCLUSIONS: Weaning failure (vs. success) is associated with increased effort of the expiratory muscles and impaired neuromechanical efficiency of the diaphragm but no difference in tonic activity of the diaphragm.