Correlation of bilirubin and toxic bile acids in critically ill patients with cholestatic liver dysfunction and adsorber application.

Bilirubin is one of the most frequently used laboratory values to monitor critically ill patients with cholestatic liver dysfunction. Besides bilirubin, toxic bile acids (TBAs), which may cause severe organ damage, are typically elevated. A correlation between both parameters seems plausible, but data are lacking. The aim was to investigate whether there is a correlation between bilirubin and TBAs in patients' blood and whether a compareable reduction can be observed during the use of the adsorber CytoSorb (CS). As part of the Cyto-SOLVE study (NCT04913298), 16 critically ill patients with cholestatic liver dysfunction, bilirubin concentration > 10 mg/dl, continuous kidney replacement therapy and CS-application were investigated. Bilirubin and TBA concentrations were measured from arterial blood at defined time points (before start, after 6 and 12 h). Relative reduction (RR) was calculated using the formula[Formula: see text]. A moderate to high correlation between bilirubin and TBA concentration at all defined timepoints (rstart=0.64, p = 0.008; r6h = 0.85, p < 0.001, r12h = 0.72, p = 0.002) was observed. In the first six hours of CS-application, a significant elimination of TBA (median TBA: 30.8→20.1µmol/l, p < 0.001) and bilirubin (median bilirubin: 17.1→11.9 mg/dl, p < 0.001) was observed. The median RR after 6 h was 26.1% and 39.8% for bilirubin and TBA, respectively. No further reduction was observed after 12 h (RRbilirubin: - 0.6%, RRTBA: 1.8%). There was an at least moderate correlation between bilirubin and TBA in patients with cholestatic liver dysfunction. Therefore, bilirubin seems to be a suitable surrogate parameter for TBA elimination during CytoSorb application.

Extracorporeal Elimination of Pro- and Anti-inflammatory Modulators by the Cytokine Adsorber CytoSorb® in Patients with Hyperinflammation: A Prospective Study.

INTRODUCTION: The release of pro-inflammatory cytokines in critically ill patients with sepsis leads to endothelial dysfunction resulting in cardiocirculatory insufficiency. Their extracorporeal elimination using the cytokine adsorber CytoSorb® (CS) (adsorption of especially hydrophobic molecules < 60 kDa) might be promising, but data about the adsorption capacity as well as a potential harmful adsorption of anti-inflammatory cytokines are missing so far. METHODS: The prospective Cyto-SOLVE-study included 15 patients with sepsis or other hyperinflammatory conditions (interleukin 6 > 500 pg/ml), continuous kidney replacement therapy, and the application of CS. Various cytokines and chemokines were measured pre- and post-CS as well as in patients' blood at predefined timepoints. Significant changes in the concentrations were detected with the Wilcoxon test with associated samples. Clearance of the adsorber (ml/min) was calculated with: b l o o d f l o w ∗ c o n c e n t r a t i o n p r e - p o s t c o n c e n t r a t i o n pre . RESULTS: Most of the inflammatory mediators showed a high initial extracorporeal clearance of 70-100 ml/min after CS installation, which dropped quickly to 10-30 ml/min after 6 h of treatment. No difference in clearance was observed between pro- and anti-inflammatory cytokines. Despite extracorporeal adsorption, a significant (p < 0.05) decrease in the blood concentration after 6 h was only observed for the pro-inflammatory cytokines tumor necrosis factorα (TNF-α) (median 284 vs. 230 pg/ml), vascular endothelial growth factor (VEGF) (median 294 vs. 252 pg/ml), macrophage inflammatory protein 1a (MIP-1a) (median 11.1 vs. 9.0 pg/ml), and regulated upon activation, normal T cell expressed and secreted (RANTES) (median 811 vs. 487 pg/ml) as well as the anti-inflammatory cytokines interleukin 4 (median 9.3 vs. 6.4 pg/ml), interleukin 10 (median 88 vs. 56 pg/ml), and platelet-derived growth factor (PDGF) (median 177 vs. 104 pg/ml). A significant (p < 0.05) decrease in patients' blood after 12 h was only detected for interleukin 10. CONCLUSIONS: CS can adsorb pro- as well as anti-inflammatory mediators with no relevant difference regarding the adsorption rate. A fast saturation of the adsorber resulted in a rapid decrease of the clearance. The potential clinical benefit or harm of this unspecific cytokine adsorption needs to be evaluated in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04913298, registration date June 4, 2021.

Myoglobin adsorption and saturation kinetics of the cytokine adsorber Cytosorb® in patients with severe rhabdomyolysis: a prospective trial.

BACKGROUND: Rhabdomyolysis is a serious condition that can lead to acute kidney injury with the need of renal replacement therapy (RRT). The cytokine adsorber Cytosorb® (CS) can be used for extracorporeal myoglobin elimination in patients with rhabdomyolysis. However, data on adsorption capacity and saturation kinetics are still missing. METHODS: The prospective Cyto-SOLVE study (NCT04913298) included 20 intensive care unit patients with severe rhabdomyolysis (plasma myoglobin > 5000 ng/ml), RRT due to acute kidney injury and the use of CS for myoglobin elimination. Myoglobin and creatine kinase (CK) were measured in the patient´s blood and pre- and post-CS at defined time points (ten minutes, one, three, six, and twelve hours after initiation). We calculated Relative Change (RC, %) with: [Formula: see text]. Myoglobin plasma clearances (ml/min) were calculated with: [Formula: see text] RESULTS: There was a significant decrease of the myoglobin plasma concentration six hours after installation of CS (median (IQR) 56,894 ng/ml (11,544; 102,737 ng/ml) vs. 40,125 ng/ml (7879; 75,638 ng/ml) (p < 0.001). No significant change was observed after twelve hours. Significant extracorporeal adsorption of myoglobin can be seen at all time points (p < 0.05) (ten minutes, one, three, six, and twelve hours after initiation). The median (IQR) RC of myoglobin at the above-mentioned time points was - 79.2% (-85.1; -47.1%), -34.7% (-42.7;-18.4%), -16.1% (-22.1; -9.4%), -8.3% (-7.5; -1.3%), and - 3.9% (-3.9; -1.3%), respectively. The median myoglobin plasma clearance ten minutes after starting CS treatment was 64.0 ml/min (58.6; 73.5 ml/min), decreasing rapidly to 29.1 ml/min (26.5; 36.1 ml/min), 16.1 ml/min (11.9; 22.5 ml/min), 7.9 ml/min (5.5; 12.5 ml/min), and 3.7 ml/min (2.4; 6.4 ml/min) after one, three, six, and twelve hours, respectively. CONCLUSION: The Cytosorb® adsorber effectively eliminates myoglobin. However, the adsorption capacity decreased rapidly after about three hours, resulting in reduced effectiveness. Early change of the adsorber in patients with severe rhabdomyolysis might increase the efficacy. The clinical benefit should be investigated in further clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04913298. Registered 07 May 2021, https//clinicaltrials.gov/study/NCT04913298.

Tricuspid valve annuloplasty and mitral valve replacement are associated with bradyarrhythmia after mitral valve surgery.

INTRODUCTION: Mitral valve surgery has developed into a strong subspecialty of cardiac surgery with operative techniques and outcomes constantly improving. The development of bradyarrhythmias after mitral valve surgery is not completely understood. METHODS: We investigated a cohort of 797 patients requiring mitral valve surgery with and without concomitant procedures. Incidences and predictors of pacemaker requirement as well as survival were analyzed. RESULTS: In the complete follow-up period (median follow-up time: 6.09 years [95% confidence interval [CI]: 5.94-6.22 years, maximum 8.77 years) 80 patients (10% of the complete cohort) required pacemaker implantation for bradyarrhythmia. The cumulative rate of pacemaker implantation was 6.4% at 50 days (48 patients) with most (54.2%) requiring pacing for atrioventricular block. Mitral valve replacement (odds ratio [OR]: 1.905; 95% CI: 1.206-3.536; p = .041) and tricuspid ring annuloplasty (OR: 2.348; 95% CI: 1.165-4.730, p = .017) were identified as operative risk factors of pacemaker requirement after mitral valve surgery. Insulin-dependent diabetes mellitus was also identified as a predictor of pacemaker requirement (OR: 4.665; 95% CI: 1.975-11.02; p = .001). There was no difference in survival in the paced and unpaced groups. CONCLUSIONS: After mitral valve surgery, a relevant subgroup of patients requires pacemaker implantation-most for atrioventricular block. We identified mitral valve replacement and tricuspid ring annuloplasty as significant operative risk factors and insulin-dependent diabetes mellitus as a demographic risk factor. While anatomic relationships help explain the operative risk factors the role of diabetes mellitus is not completely understood.

Atrioventricular Block after Tricuspid Valve Surgery.

Tricuspid valve (TV) surgery is associated with a high risk of postoperative pacemaker requirement. We set out to identify the incidence of atrioventricular block (AVB) after TV surgery and determine whether atrioventricular conduction recovers within time.We investigated pre/intra- and postoperative predictors of AVB in patients who underwent tricuspid valve surgery (not only isolated TV surgery) at our institution between 2004 and 2017. Patients who had pacemakers prior to surgery were excluded.One year after surgery, 5.8% of the surviving cohort had received a pacemaker due to AVB. In the complete follow-up time, 33 out of 505 patients required pacemaker implantation because of AVB. Of the 37 patients who presented to the intensive care unit postoperatively with AVB III, 14 (38%) underwent pacemaker implantation for AVB, and 20 (54%) did not require a pacemaker. AVB III at ICU admission was identified as a predictor of pacemaker implantation (OR: 9.7, CI: 3.8-24.5, P < 0.001). TV endocarditis was also identified as a predictor (OR: 12.4, CI: 3.3-46.3, P < 0.001). Eleven out of 32 patients (34%) with tricuspid endocarditis required a pacemaker for AVB. The mean ventricular pacing burden within the first 5 years after pacemaker implantation was 79%.The issue of AVB after TV surgery is significant. Both the initial rhythm after surgery and etiology of the tricuspid disease can help predict pacemaker requirement. Within the first 5 years after surgery, the ventricular pacing burden remains high without relevant rhythm recovery.

Etiology of tricuspid valve disease is a predictor of bradyarrhythmia after tricuspid valve surgery.

AIMS: The tricuspid valve is situated in close proximity to cardiac conduction tissue and damage to this tissue can affect postoperative rhythm. The aim of this study was to quantify the incidence of pacemaker requirement after tricuspid valve surgery and investigate predictors. METHODS: Data were collected via our operative data collection system and patient files. All patients who underwent surgical procedures of the tricuspid valve from 2004 until 2017 and lacked a pacemaker preoperatively were included in the study. RESULTS: In our cohort of 505 patients 54 required a pacemaker in the first 50 days after surgery. We calculated a 17.5% (95% confidence interval [CI], 13.5-21.3) risk of pacemaker implantation at 4 years postoperatively. Multivariate analysis identified preoperative active endocarditis (odds ratio 3.17; CI, 1.32-7.65; P = 0.010) and "inadequate pacemaker dependent rhythm" (defined as any intrinsic heart rate below 45 per minute requiring pacing) upon admission to the intensive care unit after surgery (odds ratio 5.924; CI, 2.82-12.44; P = 0.001) as predictors for pacemaker requirement in the first 50 days after surgery. Twenty-six pacemakers (48%) were implanted for atrioventricular block, 16 (30%) for sinus node dysfunction and 12 (22%) for atrial fibrillation. Kaplan-Meier analysis showed no difference in survival between the pacemaker and no pacemaker group. CONCLUSION: Surgery of the tricuspid valve has a high burden of postoperative pacemaker requirement. Preoperative active endocarditis and the initial postoperative rhythm are predictors. Understanding this allows for better decision-making regarding further medical/device therapy.