Blood purification with a cytokine adsorber for the elimination of myoglobin in critically ill patients with severe rhabdomyolysis

BACKGROUND Rhabdomyolysis is frequently occurring in critically ill patients, resulting in a high risk of acute kidney injury (AKI) and potentially permanent kidney damage due to increased myoglobin levels. The extracorporeal elimination of myoglobin might be an approach to prevent AKI, but its molecular weight of 17~kDa complicates an elimination with conventional dialysis membranes. Question of interest is, if myoglobin can be successfully eliminated with the cytokine adsorber Cytosorb® (CS) integrated in a high-flux dialysis system. METHODS Patients were included between 10/2014 and 05/2020 in the study population if they had an anuric renal failure with the need of renal replacement therapy, if CS therapy was longer than 90~min and if myoglobin level was > 5.000~ng/ml before treatment. The measurement times of the laboratory values were: d-1 = 24-36~h before CS, d0 = shortly before starting CS and d1 = 12-24~h after starting CS treatment. Statistical analysis were performed with Spearman's correlation coefficient, Wilcoxon test with associated samples and linear regression analysis. RESULTS Forty-three patients were included in the evaluation (median age: 56~years, 77% male patients, 32.6% ECMO therapy, median SAPS II: 80 points and in-hospital mortality: 67%). There was a significant equilateral correlation between creatine kinase (CK) and myoglobin at all measurement points. Furthermore, there was a significant reduction of myoglobin (p = 0.03, 95% confidence interval (CI): - 9030, - 908~ng/ml) during CS treatment, with a median relative reduction of 29%. A higher median reduction of 38% was seen in patients without ongoing rhabdomyolysis (CK decreased during CS treatment, n = 21). In contrast, myoglobin levels did not relevantly change in patients with increasing CK and therefore ongoing rhabdomyolysis (n = 22, median relative reduction 4%). Moreover, there was no significant difference in myoglobin elimination in patients with and without ECMO therapy. CONCLUSION Blood purification with Cytosorb® during high-flux dialysis led to a significant reduction of myoglobin in patients with severe rhabdomyolysis. The effect might be obscured by sustained rhabdomyolysis, which was seen in patients with rising CK during treatment. Prospective clinical trials would be useful in investigating its benefits in avoiding permanent kidney damage

Can the cytokine adsorber CytoSorb® help to mitigate cytokine storm and reduce mortality in critically ill patients? A propensity score matching analysis

BACKGROUND A cytokine storm is life threatening for critically ill patients and is mainly caused by sepsis or severe trauma. In combination with supportive therapy, the cytokine adsorber Cytosorb® (CS) is increasingly used for the treatment of cytokine storm. However, it is questionable whether its use is actually beneficial in these patients. METHODS Patients with an interleukin-6 (IL-6) > 10,000~pg/ml were retrospectively included between October 2014 and May 2020 and were divided into two groups (group 1: CS therapy; group 2: no CS therapy). Inclusion criteria were a regularly measured IL-6 and, for patients allocated to group 1, CS therapy for at least 90~min. A propensity score (PS) matching analysis with significant baseline differences as predictors (Simplified Acute Physiology Score (SAPS) II, extracorporeal membrane oxygenation, renal replacement therapy, IL-6, lactate and norepinephrine demand) was performed to compare both groups (adjustment tolerance: < 0.05; standardization tolerance: < 10%). U-test and Fisher's-test were used for independent variables and the Wilcoxon test was used for dependent variables. RESULTS In total, 143 patients were included in the initial evaluation (group 1: 38; group 2: 105). Nineteen comparable pairings could be formed (mean initial IL-6: 58,385 vs. 59,812~pg/ml; mean SAPS II: 77 vs. 75). There was a significant reduction in IL-6 in patients with (p < 0.001) and without CS treatment (p = 0.005). However, there was no significant difference (p = 0.708) in the median relative reduction in both groups (89% vs. 80%). Furthermore, there was no significant difference in the relative change in C-reactive protein, lactate, or norepinephrine demand in either group and the in-hospital mortality was similar between groups (73.7%). CONCLUSION Our study showed no difference in IL-6 reduction, hemodynamic stabilization, or mortality in patients with Cytosorb® treatment compared to a matched patient population

Digestive enzymes of fungal origin as a relevant cause of false positive Aspergillus antigen testing in intensive care unit patients

BACKGROUND Galactomannan antigen (GM) testing is widely used in the diagnosis of invasive aspergillosis (IA). Digestive enzymes play an important role in enzyme substitution therapy in exocrine pancreatic insufficiency. As digestive enzymes of fungal origin like Nortase contain enzymes from Aspergillus, a false-positive result of the test might be possible because of cross-reacting antigens of the cell wall of the producing fungi. We, therefore, asked whether the administration of fungal enzymes is a relevant cause of false-positive GM antigen test results. METHODS Patients with a positive GM antigen test between January 2016 and April 2020 were included in the evaluation and divided into two groups: group 1—Nortase-therapy, group 2—no Nortase-therapy. In addition, dissolved Nortase samples were analyzed in vitro for GM and β-1,3-D-glucan. For statistical analysis, the chi-squared and Mann‒Whitney U tests were used. RESULTS Sixty-five patients were included in this evaluation (30 patients receiving Nortase and 35 patients not receiving Nortase). The overall false positivity rate of GM testing was 43.1%. Notably, false-positive results were detected significantly more often in the Nortase group (73.3%) than in the control group (17.1%, p < 0.001). While the positive predictive value of GM testing was 0.83 in the control group, there was a dramatic decline to 0.27 in the Nortase group. In vitro analysis proved that the Nortase enzyme preparation was highly positive for the fungal antigens GM and β-1,3-D-glucan. CONCLUSIONS Our data demonstrate that the administration of digestive enzymes of fungal origin like Nortase leads to a significantly higher rate of false-positive GM test results compared to that in patients without digestive enzyme treatment

Systematic Evaluation of Voriconazole Pharmacokinetic Models without Pharmacogenetic Information for Bayesian Forecasting in Critically Ill Patients

Voriconazole (VRC) is used as first line antifungal agent against invasive aspergillosis. Model-based approaches might optimize VRC therapy. This study aimed to investigate the predictive performance of pharmacokinetic models of VRC without pharmacogenetic information for their suitability for model-informed precision dosing. Seven PopPK models were selected from a systematic literature review. A total of 66 measured VRC plasma concentrations from 33 critically ill patients was employed for analysis. The second measurement per patient was used to calculate relative Bias (rBias), mean error (ME), relative root mean squared error (rRMSE) and mean absolute error (MAE) (i) only based on patient characteristics and dosing history (a priori) and (ii) integrating the first measured concentration to predict the second concentration (Bayesian forecasting). The a priori rBias/ME and rRMSE/MAE varied substantially between the models, ranging from -15.4 to 124.6%/-0.70 to 8.01 mg/L and from 89.3 to 139.1%/1.45 to 8.11 mg/L, respectively. The integration of the first TDM sample improved the predictive performance of all models, with the model by Chen (85.0%) showing the best predictive performance (rRMSE: 85.0%;rBias: 4.0%). Our study revealed a certain degree of imprecision for all investigated models, so their sole use is not recommendable. Models with a higher performance would be necessary for clinical use

Letter to the editor regarding Extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis

10.1186/s13054-021-03702-6CRITICAL CARE25

High prevalence of falsely declaring nicotine abstinence in lung transplant candidates

Tobacco use after lung transplantation is associated with adverse outcome. Therefore, active smoking is regarded as a contraindication for lung transplantation and should be excluded prior to placement on the waiting list. The aim of the study was to compare self-reporting with a systematic cotinine based screening approach to identify patients with active nicotine abuse. Nicotine use was systematically assessed by interviews and cotinine test in all lung transplant candidates at every visit in our center. Patients were classified according to the stage prior to transplantation and cotinine test results were compared to self-reports and retrospectively analyzed until June 2019. Of 620 lung transplant candidates, 92 patients (14.8%) had at least one positive cotinine test. COPD as underlying disease (OR 2.102, CI 1.110-3.981;p = 0.023), number of pack years (OR 1.014, CI 1.000-1.028;p = 0.047) and a time of cessation less than one year (OR 2.413, CI 1.410-4.128;p = 0.001) were associated with a positive cotinine test in multivariable regression analysis. The majority of non-COPD patients (n = 13, 72.2%) with a positive test had a cessation time of less than one year. 78 patients (84.7%) falsely declared not consuming any nicotine-based products prior to the test. Finally, all never smokers were test negative. In conclusion, our data demonstrate that active nicotine use is prevalent in transplant candidates with a high prevalence of falsely declaring nicotine abstinence. COPD was the main diagnosis in affected patients. Short cessation time and a high number of pack years are risk factors for continued nicotine abuse

Charakteristika und Outcome von 70 beatmeten COVID-19-Patienten : Bilanz nach der ersten Welle an einem universitären Zentrum

BACKGROUND In a pandemic situation the overall mortality rate is of considerable interest; however, these data must always be seen in relation to the given healthcare system and the availability of local level of care. A recently published German data evaluation of more than 10,000 COVID-19 patients treated in 920 hospitals showed a high mortality rate of 22% in hospitalized patients and of more than 50% in patients requiring invasive ventilation. Because of the high infection rates in Bavaria, a large number of COVID-19 patients with considerable severity of disease were treated at the intensive care units of the LMU hospital. The LMU hospital is a university hospital and a specialized referral center for the treatment of patients with acute respiratory distress syndrome (ARDS). OBJECTIVE Data of LMU intensive care unit (ICU) patients were systematically evaluated and compared with the recently published German data. METHODS Data of all COVID-19 patients with invasive and noninvasive ventilation and with completed admission at the ICU of the LMU hospital until 31 July 2020 were collected. Data were processed using descriptive statistics. RESULTS In total 70 critically ill patients were included in the data evaluation. The median SAPS II on admission to the ICU was 62~points. The median age was 66 years and 81% of the patients were male. More than 90% were diagnosed with ARDS and received invasive ventilation. Treatment with extracorporeal membrane oxygenation (ECMO) was necessary in 10% of the patients. The median duration of ventilation was 16 days, whereby 34.3% of patients required a tracheostomy. Of the patients 27.1% were transferred to the LMU hospital from external hospitals with reference to our ARDS/ECMO program. Patients from external hospitals had ARDS of higher severity than the total study population. In total, nine different substances were used for virus-specific treatment of COVID-19. The most frequently used substances were hydroxychloroquine and azithromycin. Immunomodulatory treatment, such as Cytosorb® (18.6%) and methylprednisolone (25.7%) were also frequently used. The overall in-hospital mortality rate of ICU patients requiring ventilation was 28.6%. The mortality rates of patients from external hospitals, patients with renal replacement therapy and patients with ECMO therapy were 47.4%, 56.7% and 85.7%, respectively. CONCLUSION The mortality rate in the ventilated COVID-19 intensive care patients was considerably different from the general rate in Germany. The data showed that treatment in an ARDS referral center could result in a lower mortality rate. Low-dose administration of steroids may be another factor to improve patient outcome in a preselected patient population. In the authors' opinion, critically ill COVID-19 patients should be treated in an ARDS center provided that sufficient resources are available.ZUSAMMENFASSUNG HINTERGRUND: Eine aktuelle, deutschlandweite Datenerhebung zeigte bei beatmeten Patienten mit COVID-19 eine Letalität von über 50 %. Auch am LMU Klinikum wurde eine große Anzahl an Patienten mit COVID-19 mit teils erheblicher Erkrankungsschwere intensivmedizinisch behandelt. FRAGESTELLUNG Die Daten der am LMU-Klinikum behandelten COVID-19-Patienten wurden systematisch ausgewertet und mit den deutschlandweiten Daten verglichen. METHODIK Für die vorliegende Studie wurden die Daten aller Patienten, die bis zum 31.07.2020 am LMU-Klinikum aufgrund von COVID-19 invasiv und nichtinvasiv beatmet wurden und deren Krankenhausaufenthalt zum Zeitpunkt der Auswertung bereits abgeschlossen war, analysiert und mittels deskriptiver Statistik aufgearbeitet. ERGEBNISSE Insgesamt wurden 70 kritisch kranke, beatmete Patienten (SAPS-II-Median: 62 Punkte) analysiert (Altersmedian: 66 Jahre, 81 % männlich). Über 90 % wurden wegen eines akuten Lungenversagens (ARDS) unterschiedlicher Schweregrade behandelt. Eine Therapie mittels extrakorporaler Membranoxygenierung (ECMO) war bei 10 % erforderlich. Die Übernahme von externen Kliniken im Rahmen einer ARDS/ECMO-Anfrage erfolgte bei 27,1 % der Patienten. Häufig eingesetzte immunmodulatorische Therapien waren die Behandlung mit Cytosorb® (18,6 %) und die prolongierte Gabe von Methylprednisolon (25,7 %). Die krankenhausinterne Letalität betrug 28,6 %. FAZIT Trotz erheblicher Erkrankungsschwere lag die Letalität bei beatmeten COVID-19-Intensivpatienten im LMU-Kollektiv deutlich unter der deutschlandweit erhobenen Letalität. Ein möglicher Faktor ist die Behandlung in einem Zentrum für ARDS

Delayed intracardial shunting and hypoxemia after massive pulmonary embolism in a patient with a biventricular assist device

We describe the interdisciplinary management of a 34-year-old woman with dilated cardiomyopathy three months postpartum on a cardiac biventricular assist device (BVAD) as bridge to heart transplantation with delayed onset of intracardial shunting and subsequent hypoxemia due to massive pulmonary embolism. After emergency surgical embolectomy pulmonary function was highly compromised (PaO2/FiO2 54) requiring bifemoral veno-venous extracorporeal membrane oxygenation. Transesophageal echocardiography detected atrial level hypoxemic right-to-left shunting through a patent foramen ovale (PFO). Percutaneous closure of the PFO was achieved with a PFO occluder device. After placing the PFO occluder device oxygenation increased significantly (Δ paO2 119 Torr). The patient received heart transplantation 20 weeks after BVAD implantation and was discharged from ICU 3 weeks after transplantation