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.

COVID-19-Associated Pulmonary Mucormycosis.

COVID-19-associated mucormycosis (CAM) emerged as an epidemic in certain parts of the world amidst the global COVID-19 pandemic. While rhino-orbital mucormycosis was well reported during the pandemic, in the absence of routine diagnostic facilities including lower airway sampling, pulmonary mucormycosis was probably under-recognized. In this review, we have focused on the epidemiology and management of COVID-19-associated pulmonary mucormycosis (CAPM). CAPM is a deadly disease and mortality can be as high as 80% in the absence of early clinical suspicion and treatment. While histopathological examination of tissue for angio-invasion and cultures have remained gold standard for diagnosis, there is an increasing interest in molecular and serological methods to facilitate diagnosis in critically ill patients and often, immune-suppressed hosts who cannot readily undergo invasive sampling. Combined medical and surgical treatment offers more promise than standalone medical therapy. Maintaining adequate glycemic control and prudent use of steroids which can be a double-edged sword in COVID-19 patients are the key preventative measures. We would like to emphasize the urgent need for the development and validation of reliable biomarkers and molecular diagnostics to facilitate early diagnosis.

A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae.

Interstitial lung disease and associated fibrosis occur in a proportion of individuals who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through unknown mechanisms. We studied individuals with severe coronavirus disease 2019 (COVID-19) after recovery from acute illness. Individuals with evidence of interstitial lung changes at 3 to 6 months after recovery had an up-regulated neutrophil-associated immune signature including increased chemokines, proteases, and markers of neutrophil extracellular traps that were detectable in the blood. Similar pathways were enriched in the upper airway with a concomitant increase in antiviral type I interferon signaling. Interaction analysis of the peripheral phosphoproteome identified enriched kinases critical for neutrophil inflammatory pathways. Evaluation of these individuals at 12 months after recovery indicated that a subset of the individuals had not yet achieved full normalization of radiological and functional changes. These data provide insight into mechanisms driving development of pulmonary sequelae during and after COVID-19 and provide a rational basis for development of targeted approaches to prevent long-term complications.

Autoptic identification of disseminated mucormycosis in a young male presenting with cerebrovascular event, multi-organ dysfunction and COVID-19 infection.

Among the secondary fungal infections in Coronavirus-19 (COVID-19) infection, Aspergillosis has been reported more often than Mucormycosis. Disseminated mucormycosis is almost always a disease of severely immunosuppressed hosts. We report a young obese Asian male who was admitted with an acute anterior cerebral artery (ACA) territory infarct and severe COVID-19 pneumonitis to the intensive care unit (ICU). He had a complicated stay with recurrent episodes of vasoplegic shock and multi-organ dysfunction. At autopsy, he was confirmed to have disseminated mucormycosis. We believe this to be the first documented case of disseminated mucormycosis in an immunocompetent host with COVID-19 infection. The lack of sensitive non-invasive modalities and biomarkers to diagnose mucormycosis, along with the extremely high mortality in untreated cases, present a unique challenge to clinicians dealing with critically ill patients with COVID-19.

Gastrointestinal Tolerance and Protein Absorption Markers with a New Peptide Enteral Formula Compared to a Standard Intact Protein Enteral Formula in Critically Ill Patients.

The aim of this exploratory study was to investigate gastrointestinal tolerance and protein absorption markers with a new enteral peptide formula (PF) compared to an isocaloric enteral intact protein standard formula (SF) containing the same amount of protein in ICU patients. Patients admitted to a cardio-thoracic intensive care unit expected to receive tube feeding for ≥5 days were randomized to receive either PF (1.5 kcal/mL) or SF in a double-blind manner for ≤14 days. Twenty-six patients were randomized (13 SF and 13 PF) and 23 (12 SF and 11 PF) completed at least 5 days of product administration. There were no statistically significant differences between the feeds during the first 5 days of intervention for diarrhea (SF:3 (23%); PF:5 (39%), p = 0.388), vomiting (SF:1 (8%); PF:2 (15%), p = 0.549), constipation (SF:7 (54%), PF:3 (23%), p = 0.115), and high gastric residual volume (>500 mL: SF:1 (8%); PF: 2 (15%), p = 0.535). There were no differences in plasma amino acids or urinary markers of protein absorption and metabolism. In conclusion, no major differences were found in tolerability and protein absorption markers between the standard intact protein formula and the peptide formula.

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

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation 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 heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac 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, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

Non-invasive ventilation (NIV) in the clinical management of acute COPD in 233 UK hospitals: results from the RCP/BTS 2003 National COPD Audit.

Non-invasive ventilation (NIV) is a clinically proven, cost-effective intervention for acidotic exacerbations of COPD that is recommended by UK national guidelines. This study examines the extent to which these recommendations are being followed in the UK. Between August and October 2003 a national audit of COPD exacerbations was conducted by the Royal College of Physicians and the British Thoracic Society. 233 (94%) UK hospitals submitted data for 7,529 prospectively recruited acute COPD admissions, documenting process of care and outcomes from a retrospective case note audit. They also completed a resources and organisation of care proforma. Nineteen hospitals (8%) reported they did not offer NIV. There was no access to NIV in 92 (39%) intensive care units in 88 (36%), high-dependency units or on general wards of 85 (34%) hospitals. In 74 (30%) NIV was available on all 3 sites. A low pH (<7.35) was noted at some time during admission for 26% (1714/6544) of patients and NIV was administered to 31%. Patients receiving NIV were more often admitted under a respiratory physician, or seen at some stage by a respiratory specialist and had more severe disease (higher PaCO2 (median 9.8 v 7.8 kPa), lower oxygen tension (median 8.8 v 9.8 kPa), higher incidence of peripheral oedema (48% v 39%), of pneumonia (27% v 16%), higher in-hospital mortality (26% v 14%) and at 90 days (37% v 24%) and longer hospital stays (median 9 v 7 days) than those not receiving NIV. Hospitals with least usage of NIV had similar mortality rates to those using NIV more often. A comprehensive NIV service is not available in many hospitals admitting patients with acute respiratory failure secondary to COPD. Access to acute NIV is inadequate and does not conform with NICE and BTS guidelines. These observational audit data do not demonstrate benefits of NIV on survival when compared to conventional management, contrary to results from randomised trials. Reasons for this are unclear but unmeasured confounding factors and poor patient selection for NIV are likely explanations.

Short-Term Therapies for Treatment of Acute and Advanced Heart Failure-Why so Few Drugs Available in Clinical Use, Why Even Fewer in the Pipeline?

Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but-per definition-causes the rise in age of patients experiencing acute decompensations, since nothing at the moment helps avoiding an acute or final stage in the elderly population. To complicate the picture, acute heart failure syndromes are a collection of symptoms, signs and markers, with different aetiologies and different courses, also due to overlapping morbidities and to the plethora of chronic medications. The palette of cardio- and vasoactive drugs used in the hospitalization phase to stabilize the patient's hemodynamic is scarce and even scarcer is the evidence for the agents commonly used in the practice (e.g. catecholamines). The pipeline in this field is poor and the clinical development chronically unsuccessful. Recent set backs in expected clinical trials for new agents in acute heart failure (AHF) (omecamtiv, serelaxine, ularitide) left a field desolately empty, where only few drugs have been approved for clinical use, for example, levosimendan and nesiritide. In this consensus opinion paper, experts from 26 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, The Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, U.K. and Ukraine) analyse the situation in details also by help of artificial intelligence applied to bibliographic searches, try to distil some lesson-learned to avoid that future projects would make the same mistakes as in the past and recommend how to lead a successful development project in this field in dire need of new agents.

Mechanical ventilation after lung transplantation.

INTRODUCTION: To explore the hypothesis that early ventilation strategies influence clinical outcomes in lung transplantation, we have examined our routine ventilation practices in terms of tidal volumes (Vt) and inflation pressures. METHODS: A total of 124 bilateral lung transplants between 2010 and 2013 were retrospectively assigned to low (<6 mL/kg), medium (6-8 mL/kg), and high (>8 mL/kg) Vt groups based on ventilation characteristics during the first 6 hours after surgery. Those same 124 patients were also stratified to low-pressure (<25 cm H2O) and high-pressure (≥25 cm H2O) groups. RESULTS: Eighty percent of patients were ventilated using pressure control mode. Low, medium, and high Vt were applied to 10%, 43%, and 47% of patients, respectively. After correcting for patients requiring extracorporeal support, there was no difference in short-term to midterm outcomes among the different Vt groups. Low inflation pressures were applied to 61% of patients, who had a shorter length of intensive care unit stay (5 vs 12 days; P = .012), higher forced expiratory volume in 1 second at 3 months (77.8% vs 60.3%; P < .001), and increased 6-month survival rate (95% vs 77%; P = .008). CONCLUSION: Low Vt ventilation has not been fully adopted in our practice. Ventilation with higher inflation pressures, but not Vt, was significantly associated with poorer outcomes after lung transplantation.

The role of levosimendan in acute heart failure complicating acute coronary syndrome: A review and expert consensus opinion.

Acute heart failure and/or cardiogenic shock are frequently triggered by ischemic coronary events. Yet, there is a paucity of randomized data on the management of patients with heart failure complicating acute coronary syndrome, as acute coronary syndrome and cardiogenic shock have frequently been defined as exclusion criteria in trials and registries. As a consequence, guideline recommendations are mostly driven by observational studies, even though these patients have a particularly poor prognosis compared to heart failure patients without signs of coronary artery disease. In acute heart failure, and especially in cardiogenic shock related to ischemic conditions, vasopressors and inotropes are used. However, both pathophysiological considerations and available clinical data suggest that these treatments may have disadvantageous effects. The inodilator levosimendan offers potential benefits due to a range of distinct effects including positive inotropy, restoration of ventriculo-arterial coupling, increases in tissue perfusion, and anti-stunning and anti-inflammatory effects. In clinical trials levosimendan improves symptoms, cardiac function, hemodynamics, and end-organ function. Adverse effects are generally less common than with other inotropic and vasoactive therapies, with the notable exception of hypotension. The decision to use levosimendan, in terms of timing and dosing, is influenced by the presence of pulmonary congestion, and blood pressure measurements. Levosimendan should be preferred over adrenergic inotropes as a first line therapy for all ACS-AHF patients who are under beta-blockade and/or when urinary output is insufficient after diuretics. Levosimendan can be used alone or in combination with other inotropic or vasopressor agents, but requires monitoring due to the risk of hypotension.

Extracorporeal life support in patients with refractory cardiogenic shock: keep them awake.

OBJECTIVES: Traditionally, patients on extracorporeal life support (ECLS) are sedated and mechanically ventilated and therefore prone to complications related to immobility and ventilation. We adopted this 'Awake ECLS' strategy for the patients with refractory cardiogenic shock (RCS) as a bridge to decision. METHODS: Sixty-eight patients with RCS were supported by ECLS (All veno-arterial) in years 2010-2014. Patients that could not survive 24 h after ECLS implantation (9 patients) were excluded from the study. Study population constituted 59 patients-'Awake' group (n = 18; maintained awake without intubation) and 'Control' group (n = 41; intubated and required mechanical ventilation). RESULTS: Nine (50%) patients were awake at implantation, with 5 of them remaining free of sedation and ventilator support through to explantation. Nine patients were ventilated at the time of implantation but subsequently extubated and remained non-intubated and ventilator free. Post-ECLS survival at 1 month was 78 and 42% while the survival to discharge was 78 and 37% in awake and control group, respectively. CONCLUSIONS: ECLS as a bridge to decision in RCS is effective in restoring adequate systemic perfusion and recovering end-organ function. ECLS can be initiated in awake patients with RCS and patients can be awakened on ECLS. The 'awake ECLS' strategy may avoid complications related to mechanical ventilation, sedation and immobilization. RCS patients supported on ECLS without severe metabolic acidosis, multiorgan failure, intra-aortic balloon pump or uncertain neurological status are more likely to be weaned from the ventilator. Patients that are awake at the time of ECLS implantation are more likely to remain awake during ECLS.

A case of spontaneous intestinal perforation in osteogenesis imperfecta.

UNLABELLED: A 51-year-old male with known osteogenesis imperfecta (OI) (type 1) presented with symptoms and signs of infective endocarditis. Transthoracic echocardiography showed chordal rupture and free mitral regurgitation, resulting in an emergency mitral valve repair. The surgical procedure was largely uneventful but subsequent clinical course on the intensive care unit was complicated by bowel perforation requiring two laparatomies for a colonic resection and loop ileostomy formation. Histology of the excised tissue demonstrated absent musculature with no evidence of ischemia. Spontaneous non-ischemic bowel perforation as a complication of osteogenesis imperfecta is to date unreported. Our case highlights the need for a high index of suspicion of non-ischemic bowel perforation in patients with connective tissue disorders. KEYWORDS: Osteogenesis imperfecta; Bowel perforation; Collagen; Non-ischemic; Connective tissue disorders; Pathogenesis; Collagen vascular disorder; Acute abdomen.