High “on treatment” platelet reactivity in the Intensive Care Unit

Es gibt kaum Daten über die Effekte und die Pharmakokinetik von Thrombozytenaggregationshemmern bei kritisch kranken Patienten. HTPR beschreibt eine residuale Thrombozytenreaktivität trotz Einnahme hemmender Therapie. Auf Grund der speziellen Eigenschaften dieser Patienten, welche sich durch Infektionen, systemische Entzündungsreaktionen, Organversagen und veränderter Pharmakokinetik definieren, nahmen wir an, dass HTPR besonders häufig vorkommt. Diese Dissertation untersucht die Effekte und die Pharmako-kinetik von Azetylsalizylsäure (ASA), Clopidogrel und Prasugrel in kritisch kranken Patienten. Tatsächlich ist die Prävalenz von HTPR in kritisch kranken Patienten deutlich höher als in Referenzpopulationen: Laut Vollblutaggregometrie sprachen (i) 85% (95% Konfidenzintervall (CI): 74-93%) der mit ASA, (ii) 74% (95% CI: 59-87%) der mit Clopidogrel und (iii) 65% (95% CI: 43-84%) der mit Prasugrel therapierten Patienten unzureichend auf die Therapie an. Die Analyse der Plasmakonzentrationen zeigte eine höchst variable Resorption dieser peroraler Medikamente. Die Plasmakonzentrationen des aktiven Metaboliten von Clopidogrel übersteigen normalerweise die der Prodrug um das 30-fache. Kritisch kranke Patienten können Clopidogrel nicht aktivieren und die Konzentrationen der Prodrug lagen sogar über jenen des aktiven Metaboliten. Wir nahmen an, dass eine reduzierte Aktivität von Enzymen des Cytochromsystems dafür verantwortlich ist und untersuchten die Halbwertszeit des ähnlich metabolisierten Pantoprazols. Diese war 5-fach höher als in Referenzpopulationen, was unsere Annahme bestätigte. Bei mit Prasugrel behandelten kritisch kranken Patienten unterschied sich die Prävalenz von HTPR bei ADP- und P2Y12-Rezeptor spezifischer Tests deutlich (Median: 65% vs. 26%), was auf eine zunehmende Bedeutung von P2Y12-Rezeptor unabhängigen Mechanismen hinweisen könnte. Zusammenfassend spricht ein Großteil der mit Thrombozytenaggregationshemmer behandelten, kritisch kranken Patienten nur unzureichend auf die Therapie an. Intravenöse Verabreichungsformen, alternative Dosierungen und Cytochrom-unabhängige Medikamente könnten die Therapie dieser Menschen verbessern.There are only limited data on the effects or on the plasma concentrations of platelet inhibitory drugs in critically ill patients. High “on treatment” platelet reactivity (HTPR) describes an insufficient platelet inhibition in spite of anti-platelet treatment. Based on the specific properties of this population, which typically feature infections, inflammatory responses, organ failure and altered pharmacokinetics, we hypothesized that HTPR may occur frequently. This thesis comprises three clinical trials that investigated the effects and drug concentrations of acetylsalicylic acid (ASA), clopidogrel and prasugrel in critically ill patients. The prevalence of HTPR was substantially higher in critically ill patients compared to reference populations: according to whole blood aggregometry (i) 85% (95% confidence intervals (CI): 74-93%) of ASA treated patients, (ii) 74% (95% CI: 59-87%) of clopidogrel treated patients, and (iii) 65% (95% CI: 43-84%) of prasugrel treated patients responded poorly to treatment. Plasma concentrations revealed highly variable absorption after intake of these drugs. Plasma concentrations of the active metabolite of clopidogrel usually exceed those of the prodrug 30-fold, while critically ill patients failed to metabolize clopidogrel and levels of the prodrug were even slightly higher than those of the active metabolite. We hypothesized that an inflammation-induced downregulation of cytochrome enzyme activity may be the underlying mechanism and measured pharmacokinetics of the similarly metabolized pantoprazole. The half-life of pantoprazole was 5-fold increased compared to reference populations, which independently confirmed our hypothesis. In prasugrel treated patients the HTPR rate differed relevantly between ADP- and P2Y12 receptor specific platelet function tests (median 65% vs. 26%). Possibly, during critical illness P2Y12 receptor independent pathways may gain importance for ADP-induced platelet activation. In conclusion, these three trials show that the majority of critically ill patients are insufficiently treated with antiplatelet drugs. Intravenous formulations, alternative dosing regimens and use of cytochrome independent drugs may improve treatment.submitted by Christian SchörgenhoferAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Dissertation, 2017OeBB(VLID)251546

Lower serum cholesterol levels as a risk factor for critical illness polyneuropathy: a matched case–control study

Abstract Critical illness polyneuropathy (CIP) is a frequent and underdiagnosed phenomenon among intensive care unit patients. The lipophilic nature of neuronal synapses may result in the association of low serum cholesterol levels with a higher rate of CIP development. We aimed to investigate this issue in critically ill patients. All cases diagnosed with CIP in our tertiary care hospital between 2013 and 2017 were 1:1 matched with controls without the condition by age, sex, and ICD diagnoses. The main risk factors examined were the differences in change between initial and minimum serum total cholesterol levels, and minimum serum total cholesterol levels between matched pairs. Other predictors were serum markers of acute inflammation. We included 67 cases and 67 controls (134 critically ill patients, 49% female, 46% medical). Serum total cholesterol levels decreased more profoundly in cases than controls (median: −74 (IQR −115 to −24) vs. −39 (IQR −82 to −4), median difference: −28, 95% CI [−51, −5]), mg/dl). Minimum serum total cholesterol levels were lower in the cases (median difference: −24, 95% CI [−39, −9], mg/dl). We found significant median differences across matched pairs in maximum serum C-reactive protein (8.9, 95% CI [4.6, 13.2], mg/dl), minimum albumin (−4.2, 95% CI [−6.7, −1.7], g/l), decrease in albumin (−3.9, 95% CI [−7.6, −0.2], g/l), and lowest cholinesterase levels (−0.72, 95% CI [−1.05, −0.39], U/l). Subsequently, more pronounced decreases in serum total cholesterol levels and lower minimum total cholesterol levels during critical care unit hospitalizations may be a risk factor for CIP

High Platelet Reactivity after Transition from Cangrelor to Ticagrelor in Hypothermic Cardiac Arrest Survivors with ST-Segment Elevation Myocardial Infarction

Transition from cangrelor to oral P2Y12 inhibitors after PCI carries the risk of platelet function recovery and acute stent thrombosis. Whether the recommended transition regimen is appropriate for hypothermic cardiac arrest survivors is unknown. We assessed the rate of high platelet reactivity (HPR) after transition from cangrelor to ticagrelor in hypothermic cardiac arrest survivors. Adult survivors of out-of-hospital cardiac arrest with ST-segment elevation myocardial infarction (STEMI), who were treated for hypothermia (33 °C ± 1) and received intravenous cangrelor during PCI and subsequent oral loading with 180mg ticagrelor were enrolled in this prospective observational cohort study. Platelet function was assessed using whole blood aggregometry. HPR was defined as AUC > 46U. The primary endpoint was the rate of HPR (%) at predefined time points during the first 24 h after cangrelor cessation. Poisson regression was used to estimate the relationship between the overlap time of cangrelor and ticagrelor co-administration and the number of subsequent HPR episodes, expressed as incidence rate ratio (IRR) with 95% confidence interval (95%CI). Between December 2017 and October 2019 16 patients (81% male, 58 years) were enrolled. On average, ticagrelor was administered 39 min (IQR 5–50) before the end of cangrelor infusion. The rate of HPR was highest 90 min after cangrelor cessation and was present in 44% (7/16) of patients. The number of HPR episodes increased significantly with decreasing overlap time of cangrelor and ticagrelor co-administration (IRR 1.03, 95%CI 1.01–1.05; p = 0.005). In this selected cohort of hypothermic cardiac arrest survivors who received cangrelor during PCI, ticagrelor loading within the recommended time frame before cangrelor cessation resulted in a substantial amount of patients with HPR

Influence of tedizolid on the cytokine response to the endotoxin challenge in healthy volunteers: a cross-over trial

Background: Preclinical data suggested anti-inflammatory properties of tedizolid. Objectives: To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid. Methods: In this cross-over trial, 14 male healthy volunteers underwent two treatment periods: (A) 200 mg of tedizolid phosphate once daily for 6 days (3 days orally and 3 days intravenously), followed by an intravenous bolus of 2 ng/kg body weight of LPS on the last treatment day; and (B) intravenous bolus of LPS (2 ng/kg body weight) without concomitant tedizolid treatment. Participants underwent first period A or B, separated by at least 6 weeks. Plasma was sampled to assess cytokines and the pharmacokinetics of tedizolid. Results: Following the endotoxin challenge, the peak plasma concentration (median [IQR]; 280 [155-502] versus 287 [132-541] pg/mL; P = 0.875) and AUC0-24 (979 [676-1319] versus 1000 [647-1632] pg·h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC0-24 of TNF-α remained also unchanged with and without tedizolid (47 [31-61] versus 54 [27-69] pg/mL; P = 0.73 and 197 [163-268] versus 234 [146-280] pg·h/mL; P = 0.875, respectively). The total maximum concentration (mean ± SD; 2.94 ± 0.69 versus 2.96 ± 0.62 mg/L), total AUC0-24 (22.3 ± 3.8 versus 21.1 ± 3.6 mg·h/L) and protein binding (21.4% ± 1.7% versus 21.6% ± 1.9%) of tedizolid were similar with and without the endotoxin challenge. Conclusions: Tedizolid did not attenuate the LPS-induced cytokine response in healthy volunteers. Furthermore, endotoxaemia did not influence the plasma pharmacokinetics of tedizolid

Age Related Differences in Monocyte Subsets and Cytokine Pattern during Acute COVID-19—A Prospective Observational Longitudinal Study

The COVID-19 pandemic drastically highlighted the vulnerability of the elderly population towards viral and other infectious threats, illustrating that aging is accompanied by dysregulated immune responses currently summarized in terms like inflammaging and immunoparalysis. To gain a better understanding on the underlying mechanisms of the age-associated risk of adverse outcome in individuals experiencing a SARS-CoV-2 infection, we analyzed the impact of age on circulating monocyte phenotypes, activation markers and inflammatory cytokines including interleukin 6 (IL-6), IL-8 and tumor necrosis factor (TNF) in the context of COVID-19 disease progression and outcome in 110 patients. Our data indicate no age-associated differences in peripheral monocyte counts or subset composition. However, age and outcome are associated with differences in monocyte activation status. Moreover, a distinct cytokine pattern of IL-6, IL-8 and TNF in elderly survivors versus non-survivors, which consolidates over the time of hospitalization, suggests that older patients with adverse outcomes experience an inappropriate immune response, reminiscent of an inflammaging driven immunoparalysis. Our study underscores the value, necessity and importance of longitudinal monitoring in elderly COVID-19 patients, as dynamic changes after symptom onset can be observed, which allow for a differentiated insight into confounding factors that impact the complex pathogenesis following an infection with SARS-CoV-2

Adverse outcome in COVID-19 is associated with an aggravating hypo-responsive platelet phenotype

Thromboembolic complications are frequently observed in Coronavirus disease 2019 (COVID-19). While COVID-19 is linked to platelet dysregulation, the association between disease outcome and platelet function is less clear. We prospectively monitored platelet activation and reactivity in 97 patients during the first week of hospitalization and determined plasma markers of platelet degranulation and inflammation. Adverse outcome in COVID-19 was associated with increased basal platelet activation and diminished platelet responses, which aggravated over time. Especially GPIIb/IIIa responses were abrogated, pointing toward impeded platelet aggregation. Moreover, platelet-leukocyte aggregate formation was diminished, pointing toward abrogated platelet-mediated immune responses in COVID-19. No general increase in plasma levels of platelet-derived granule components could be detected, arguing against platelet exhaustion. However, studies on platelets from healthy donors showed that plasma components in COVID-19 patients with unfavorable outcome were at least partly responsible for diminished platelet responses. Taken together this study shows that unfavorable outcome in COVID-19 is associated with a hypo-responsive platelet phenotype that aggravates with disease progression and may impact platelet-mediated immunoregulation