Das akute Lungenversagen des Erwachsenen (ARDS) - klinische Risikobewertung und experimentelle Intervention

Das "Adult Respiratory Distress Syndrom" (ARDS) ist das akute Lungenversagen des Erwachsenen, dessen klinisches Leitsymptom die schwere, teils lebensbedrohliche Hypoxämie ist. Spezifische, pharmakologische Therapien für dieses relevante, intensivmedizinische Krankheitsbild existieren bislang nicht. Trotz intensiver Forschungsbemühungen und erheblicher Fortschritte in den Behandlungsmöglichkeiten ist das ARDS auch heute noch mit einer hohen Mortalitätsrate behaftet und bleibt eine Herausforderung für die moderne Intensivmedizin. Die vorliegende Habilitationsschrift nähert sich dem akuten Lungenversagen sowohl von klinischer, als auch von grundlagenwissenschaftlich-experimenteller Seite. Die hier vorgestellten Arbeiten befassen sich im ersten Teil schwerpunktmäßig mit der Bewertung des Mortalitätsrisikos von Patienten im akuten Lungenversagen. Klinische Faktoren und funktionelle Parameter des pulmonalen Gasaustausches werden auf ihre Wertigkeit bei der Einschätzung von Risiko und Prognose im ARDS überprüft. Die vorgestellten Untersuchungen zeigen dabei, dass die Betrachtung der pulmonalen Funktionalität unter Berücksichtigung der verwendeten Beatmungsinvasivität valide Aussagen über die Prognose des Patienten im ARDS liefern kann. Der Oxygenierungsindex OI, in dessen Berechnung der mittlere Atemwegsdruck eingeht, erscheint hierbei als ein gut geeigneter Parameter zur Einschätzung des Mortalitätsrisikos von Patienten mit ARDS. Eine Abschätzung der Prognose anhand intensivmedizinischer Scoringsysteme oder kategorialer Einteilungen der Patienten nach derzeit gültigen ARDS-Definitionen liefert nur unscharfe Aussagen. Eine weitere klinisch-retrospektive Arbeit zu diesem Thema zeigt, dass die Zahl der im peripheren Blut nachweisbaren Erythroblasten eine hohe prognostische Wertigkeit bei der Einschätzung des Mortalitätsrisikos von ARDS-Patienten aufweist. Das Vorhandensein dieser Zellen im Blut ist mit der Schwere des ARDS und dessen klinischen Verlauf assoziiert. Im zweiten Teil dieser Habilitationsschrift sind experimentelle Arbeiten zusammengefasst, die eine pharmakologische Therapieoption evaluieren, die auf die pulmonale Inflammation als wesentlichen Mechanismus der Pathophysiologie im ARDS abzielt. Hierzu wurde zunächst ein Modell des akuten Lungenversagens hinsichtlich der pulmonalen Inflammation charakterisiert. In weiteren experimentellen Arbeiten wird gezeigt, dass der Angiotensin II AT2-Rezeptor Agonist Compound 21 (C21) sowohl in vitro als auch in vivo anti-inflammatorisches Wirkpotential hat und effektiv die Produktion pro-inflammatorischer Zytokine wie TNF- hemmen kann. Abschließend wird das Prinzip einer AT2-Rezeptor-vermittelten Hemmung der Inflammation auf das zuvor charakterisierte Modell des akuten Lungenversagens angewendet. Die Ergebnisse dieser experimentellen Arbeit zeigen, dass durch die Anwendung von C21 im Modell des akuten Lungenversagens zwar die pulmonale Inflammation signifikant abgemildert werden kann, es aber unter den gegebenen Bedingungen nicht zu einer messbaren Verbesserung des pulmonalen Ödems und des Gasaustausches kommt. Im Rahmen der in dieser Habilitationsschrift zusammengefassten Studien und Untersuchungen konnte das Verständnis des akuten Lungenversagens erweitert werden. Zukünftige Studien müssen zeigen, ob Erythroblasten tatsächlich geeignet sind, als neuer Biomarker im ARDS zu fungieren. Ebenso bleibt abzuwarten, ob in Zukunft evidenzbasierte, pharmakologische Therapiestrategien entwickelt werden können, die über eine Stimulation des AT2-Rezeptors die Prognose von Patienten mit akutem Lungenversagen verbessern können

Dynamic thromboembolic left ventricular outflow tract obstruction after aggressive procoagulant treatment in hemorrhagic shock: a case report

Background: In cases of hypertrophic obstructive cardiomyopathy (HOCM), the systolic anterior motion of the mitral valve apparatus results in an obstruction of the left ventricular outflow tract (LVOT), which is known as the SAM [systolic anterior motion] phenomenon. Hypothetically, a pathological obstruction of the LVOT of a different etiology would result in a comparable hemodynamic instability, which would be refractory to inotrope therapy, and may be detectable through echocardiography. Case presentation: We observed a severely impaired left ventricular function due to a combination of a thrombotic LVOT obstruction and distinctive mitral regurgitation in a 56-year-old Caucasian, female patient after massive transfusion with aggressive procoagulant therapy. Initially, the patient had to be resuscitated due to cardiac arrest after a long-distance flight. The resuscitation attempts in combination with lysis therapy due to suspected pulmonary artery embolism were initially successful but resulted in traumatic liver injury, hemorrhagic shock and subsequent acute respiratory distress syndrome (ARDS). Oxygenation was stabilized with veno-venous extracorporeal membrane oxygenation (ECMO), but the hemodynamic situation deteriorated further. Transesophageal echocardiography (TEE) showed a massive, dynamic LVOT obstruction. Two thrombi were attached to the anterior leaflet of the mitral valve, resulting in a predominantly systolic obstruction. Unfortunately, the patient died of multiple-organ failure despite another round of lysis therapy and escalation of the ECMO circuit to a veno-venoarterial cannulation for hemodynamic support. Conclusion: Massive transfusion with aggressive procoagulant therapy resulted in mitral valve leaflet thrombosis with dynamic, predominantly systolic LVOT obstruction, comparable to the SAM phenomenon. The pathology was only detectable with a TEE investigation

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

A Recurrent Neural Network Model for Predicting Activated Partial Thromboplastin Time After Treatment With Heparin: Retrospective Study

Background: Anticoagulation therapy with heparin is a frequent treatment in intensive care units and is monitored by activated partial thromboplastin clotting time (aPTT). It has been demonstrated that reaching an established anticoagulation target within 24 hours is associated with favorable outcomes. However, patients respond to heparin differently and reaching the anticoagulation target can be challenging. Machine learning algorithms may potentially support clinicians with improved dosing recommendations. Objective: This study evaluates a range of machine learning algorithms on their capability of predicting the patients' response to heparin treatment. In this analysis, we apply, for the first time, a model that considers time series. Methods: We extracted patient demographics, laboratory values, dialysis and extracorporeal membrane oxygenation treatments, and scores from the hospital information system. We predicted the numerical values of aPTT laboratory values 24 hours after continuous heparin infusion and evaluated 7 different machine learning models. The best-performing model was compared to recently published models on a classification task. We considered all data before and within the first 12 hours of continuous heparin infusion as features and predicted the aPTT value after 24 hours. Results: The distribution of aPTT in our cohort of 5926 hospital admissions was highly skewed. Most patients showed aPTT values below 75 s, while some outliers showed much higher aPTT values. A recurrent neural network that consumes a time series of features showed the highest performance on the test set. Conclusions: A recurrent neural network that uses time series of features instead of only static and aggregated features showed the highest performance in predicting aPTT after heparin treatment

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

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

an observational study

Background Currently there is no ARDS definition or classification system that allows optimal prediction of mortality in ARDS patients. This study aimed to examine the predictive values of the AECC and Berlin definitions, as well as clinical and respiratory parameters obtained at onset of ARDS and in the course of the first seven consecutive days. Methods The observational study was conducted at a 14-bed intensive care unit specialized on treatment of ARDS. Predictive validity of the AECC and Berlin definitions as well as PaO2/FiO2 and FiO2/PaO2*Pmean (oxygenation index) on mortality of ARDS patients was assessed and statistically compared. Results Four hundred forty two critically-ill patients admitted for ARDS were analysed. Multivariate Cox regression indicated that the oxygenation index was the most accurate parameter for mortality prediction. The third day after ARDS criteria were met at our hospital was found to represent the best compromise between earliness and accuracy of prognosis of mortality regarding the time of assessment. An oxygenation index of 15 or greater was associated with higher mortality, longer length of stay in ICU and hospital and longer duration of mechanical ventilation. In addition, non-survivors had a significantly longer length of stay and duration of mechanical ventilation in referring hospitals before admitted to the national reference centre than survivors. Conclusions The oxygenation index is suggested to be the most suitable parameter to predict mortality in ARDS, preferably assessed on day 3 after admission to a specialized centre. Patients might benefit when transferred to specialized ICU centres as soon as possible for further treatment

Predictors of survival in critically ill patients with acute respiratory distress syndrome (ARDS): an observational study

Number of patients receiving extracorporeal lung assist devices (ELAD) on each day. (DOC 26 kb

Pleural effusions are associated with adverse outcomes after cardiac surgery: a propensity-matched analysis

Background: Pleural effusions commonly occur in patients recovering from cardiac surgery; however, the impact on outcomes is not well characterized. The purpose of this study is to characterize the clinical outcomes of cardiac surgery patients with pleural effusion. Methods: All patients undergoing cardiac surgery between 2006 and 2019 at a tertiary care university hospital were included in this observational, cross-sectional analysis using propensity matching. Results: Of 11,037 patients that underwent cardiac surgery during the study period, 6461 (58.5%) had no pleural effusion (Group 0), 3322 (30.1%) had pleural effusion only (Group 1), and 1254 (11.4%) required at least one secondary drainage procedure after the index operation (Group 2). After propensity matching, the mortality of patients who underwent secondary drainage procedures was 6.1% higher than in Group 1 (p < 0.001). Intensive care unit (ICU) stay was longer for those with pleural effusions (18 [IQR 9-32] days in Group 2, 10 [IQR 6-17] days for Group 1, and 7 [IQR 4-11] days for Group 0, p < 0.001). Patients with pleural effusions had a higher incidence of hemodialysis (246 [20.0%] in Group 2, 137 [11.1%] in Group 1, 98 [7.98%] in Group 0), and a longer ventilation time in the ICU (57 [IQR 21.0-224.0] hours in Group 2, 25.0 [IQR 14.0-58.0] hours in Group 1, 16.0 [IQR 10.0-29.0] hours in Group 0). Conclusion: Pleural effusions, especially those that require a secondary drainage procedure during recovery, are associated with significantly worse outcomes including increased mortality, longer length of stay, and higher complication rates. These insights may be of great interest to scientists, clinicians, and industry leaders alike to foster research into innovative methods for preventing and treating pleural effusions with the aim of improving outcomes for patients recovering from cardiac surgery

COVID-19 Patients Require Prolonged Extracorporeal Membrane Oxygenation Support for Survival Compared With Non-COVID-19 Patients

OBJECTIVES: To investigate the ICU survival of venovenous extracorporeal membrane oxygenation (ECMO) patients suffering from COVID-19–related acute respiratory distress syndrome (ARDS) versus ECMO patients without COVID-19 (non-COVID-19)–related ARDS. DESIGN: Preliminary analysis of data from two prospective ECMO trials and retrospective analysis of a cohort of ARDS ECMO patients. SETTING: Single-center ICU. PATIENTS: Adult ARDS ECMO patients, 16 COVID-19 versus 23 non-COVID-19 patients. Analysis of retrospective data from 346 adult ARDS ECMO patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: COVID-19 and non-COVID-19 ARDS patients did not differ with respect to preexisting disease or body mass index. ICU survival rate was 62% for COVID-19 ECMO patients and 70% for non-COVID-19 ECMO patients. COVID-19 ECMO survivors were supported with ECMO for a median of 43 days (interquartile range [IQR], 18–58 d) versus 16 days (IQR, 19–39 d; p = 0.03) for non-COVID-19 patients. The median duration of ECMO therapy for all ARDS patients between 2007 and 2018 was 15 days (IQR, 6–28 d). The subgroup of patients suffering from any viral pneumonia received ECMO support for a median of 16 days (IQR, 9–27 d), survivors of influenza pneumonia received ECMO support for 13 days (IQR, 7–25 d). CONCLUSIONS: COVID-19 patients required significant longer ECMO support compared with patients without COVID-19 to achieve successful ECMO weaning and ICU survival

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 [= 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