Pharmacosimulation of delays and interruptions during administration of tirofiban: a systematic comparison between EU and US dosage regimens.

Tirofiban is a glycoproteine (GP) IIb/IIIa receptor antagonist, which inhibits platelet-platelet aggregation and is a potential adjunctive antithrombotic treatment in patients with acute coronary syndromes (ACS) or high-risk percutaneous coronary interventions (PCI). It is administered intravenously as a bolus followed by continuous infusion. However, the dosage recommendations in the United States (US) and European Union (EU) differ considerably. Furthermore, in routine clinical practice, deviations from the recommendations may occur. The objective of the present study was to investigate the impact of different alterations on tirofiban plasma concentrations in US and EU administration regimens and to give suggestions for delay management in clinical practice. We therefore mathematically simulated the effects of different bolus-infusion delays and infusion interruptions in different scenarios according to the renal function. Here, we provide a systematic assessment of concentration patterns of tirofiban in the US versus EU dosage regimens. We show that differences between the two regimens have important effects on plasma drug levels. Furthermore, we demonstrate that deviations from the proper administration mode affect the concentration of tirofiban. Additionally, we calculated the optimal dosage of a second bolus to rapidly restore the initial concentration without causing overdosage. In conclusion, differences in tirofiban dosing regimens between the U.S and EU and potential infusion interruptions have important effects on drug levels that may impact on degrees of platelet inhibition and thus antithrombotic effects. Thus, the findings of our modelling studies may help to explain differences in clinical outcomes observed in previous clinical trials on tirofiban.

[Oro- and nasopharyngeal swab for detection of SARS-CoV-2 - step-by-step approach]. / Oro- und nasopharyngealer Abstrich ­ Schritt für Schritt.

Oro- and nasopharyngeal swab specimens by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) to detect SARS-CoV-2 is currently the main diagnostic tool during the ongoing COVID-19 pandemia. Accurate performance of the procedure to avoid false negative results, adequate personal protective equipment and material sparing algorithms are mandatory while obtaining swab specimens. In the current stey-by-step review a feasible approach will be presented.

Comprehensive Analysis of Macrocirculation and Microcirculation in Microgravity During Parabolic Flights.

BACKGROUND: Profound knowledge about cardiovascular physiology in the setting of microgravity can help in the course of preparations for human space missions. So far, influences of microgravity on the cardiovascular system have been demonstrated, particularly pertaining to venous fluid shifts. Yet, little is known about the mechanisms of these adaptations on continuous macrocirculatory level and regarding the microcirculation. METHODS: Twelve healthy volunteers were subjected to alternating microgravity and hypergravity in the course of parabolic flight maneuvers. Under these conditions, as well as in normal gravity, the sublingual microcirculation was assessed by intravital sidestream dark field microscopy. Furthermore, hemodynamic parameters such as heart rate, blood pressure, and cardiac output were recorded by beat-to-beat analysis. In these settings, data acquisition was performed in seated and in supine postures. RESULTS: Systolic [median 116 mmHg (102; 129) interquartile range (IQR) vs. 125 mmHg (109; 136) IQR, p = 0.01] as well as diastolic [median 72 mmHg (61; 79) IQR vs. 80 mmHg (69; 89) IQR, p = 0.003] blood pressure was reduced, and cardiac output [median 6.9 l/min (6.5; 8.8) IQR vs. 6.8 l/min (6.2; 8.5) IQR, p = 0.0002] increased in weightlessness compared to normal gravitation phases in the seated but not in the supine posture. However, microcirculation represented by perfused proportion of vessels and by total vessel density was unaffected in acute weightlessness. CONCLUSION: Profound changes of the macrocirculation were found in seated postures, but not in supine postures. However, microcirculation remained stable in all postures.

Lipid lowering therapy in cardiovascular disease: From myth to molecular reality.

Lipid-lowering therapy is one major cornerstone of medical treatment of cardiovascular disease in order to modulate atherosclerosis. Statins, ezetimibe and novel PCSK9-inhibitors are already recommended in current guidelines and were shown to improve lipid profiles and have positive effects on the rate of ischemic events and cardiovascular mortality. Recent studies suggest that the concept of "The lower the better" might be valid at least regarding low density lipoproteins. In addition, lowering lipoprotein (a) still displays a major challenge in lipid therapy. Furthermore, also lowering triglycerides seems to improve cardiovascular outcome. Regarding triglycerides, icosapent ethyl, a polyunsaturated fatty acid recently attracted attention showing cardiovascular risk reduction due to triglyceride lowering. Therefore, new therapeutic strategies and drug classes are eagerly awaited. Targeting LDL, bempedoic acid and the siRNA inclisiran provide promising results. Moreover, regarding TG a monoclonal antibody called evinacumab and an antisense-oligonucleotide against ANGPTL3 showed effective TG-lowering. At least, using antisense-oligonucleotides against ApoC-III and Lp(a) resulted in promising outcomes. In this review, current and future options for lipid management are presented depending on different drug classes.

Clinical Frailty Scale (CFS) reliably stratifies octogenarians in German ICUs: a multicentre prospective cohort study.

BACKGROUND: In intensive care units (ICU) octogenarians become a routine patients group with aggravated therapeutic and diagnostic decision-making. Due to increased mortality and a reduced quality of life in this high-risk population, medical decision-making a fortiori requires an optimum of risk stratification. Recently, the VIP-1 trial prospectively observed that the clinical frailty scale (CFS) performed well in ICU patients in overall-survival and short-term outcome prediction. However, it is known that healthcare systems differ in the 21 countries contributing to the VIP-1 trial. Hence, our main focus was to investigate whether the CFS is usable for risk stratification in octogenarians admitted to diversified and high tech German ICUs. METHODS: This multicentre prospective cohort study analyses very old patients admitted to 20 German ICUs as a sub-analysis of the VIP-1 trial. Three hundred and eight patients of 80 years of age or older admitted consecutively to participating ICUs. CFS, cause of admission, APACHE II, SAPS II and SOFA scores, use of ICU resources and ICU- and 30-day mortality were recorded. Multivariate logistic regression analysis was used to identify factors associated with 30-day mortality. RESULTS: Patients had a median age of 84 [IQR 82-87] years and a mean CFS of 4.75 (± 1.6 standard-deviation) points. More than half of the patients (53.6%) were classified as frail (CFS ≥ 5). ICU-mortality was 17.3% and 30-day mortality was 31.2%. The cause of admission (planned vs. unplanned), (OR 5.74) and the CFS (OR 1.44 per point increase) were independent predictors of 30-day survival. CONCLUSIONS: The CFS is an easy determinable valuable tool for prediction of 30-day ICU survival in octogenarians, thus, it may facilitate decision-making for intensive care givers in Germany. TRIAL REGISTRATION: The VIP-1 study was retrospectively registered on ClinicalTrials.gov (ID: NCT03134807 ) on May 1, 2017.

Pharmacosimulation of interruptions and its solution in intravenous administration of cangrelor.

BACKGROUND: Cangrelor is an intravenous adenosine diphosphate (ADP) P2Y12 receptor antagonist, which has to be administered as a bolus followed by immediate infusion. Nevertheless, in clinical routine deviations from the correct practice, such as delayed infusion onset or interruptions during infusion, may occur. OBJECTIVE: The objective of the present study was to investigate the impact of administration delays on cangrelor concentration in a pharmacological simulation setting and to give possible solutions for the clinical practice. METHODS: We simulated the effects of different delays in administration of cangrelor in a model based on known pharmacokinetic parameters. Additionally, we calculated the optimal dosage of a second bolus. RESULTS: We demonstrate that already a short delay between the bolus and begin of infusion as well as short infusion interruptions considerably affect the serum concentration of cangrelor. Additionally, we estimate the dosage of a possible second bolus which highly depends on the duration of the delay. CONCLUSIONS: Our results emphasize that continuous administration of cangrelor is crucial to avoid the critical time frame of increased thrombosis risk. We suggest a strategy for dealing with interruptions by demonstrating that a second bolus allows to reach rapidly an effective but not excessive cangrelor serum concentration.

Acute chest pain in a triathlete: rupture of the noncoronary sinus of Valsalva into the right ventricle.

Sinus of Valsalva (SoV) aneurysm is a rare cardiac disease which can be congenital or acquired. A ruptured SoV aneurysm presents a clinical emergency and can lead to progressively deteriorating heart failure. Therefore, appropriate treatment requires prompt and accurate diagnosis. Most ruptured or nonruptured SoV aneurysms are diagnosed by the means of echocardiography. However, cardiovascular magnetic resonance (CMR) can provide information on precise anatomy and mechanisms due to its excellent soft tissue contrast and high resolution, and thereby allows for optimized preoperative planning of the repair strategy. In the present case, we demonstrate the benefit of CMR in emergency settings.

Randomized Control of Sympathetic Drive With Continuous Intravenous Esmolol in Patients With Acute ST-Segment Elevation Myocardial Infarction: The BEtA-Blocker Therapy in Acute Myocardial Infarction (BEAT-AMI) Trial.

OBJECTIVES: This study sought to evaluate the role of esmolol-induced tight sympathetic control in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Elevated sympathetic drive has a detrimental effect on patients with acute STEMI. The effect of beta-blocker-induced heart rate mediated sympathetic control on myocardial damage is unknown. METHODS: The authors conducted a prospective, randomized, single-blind trial involving patients with STEMI and successful percutaneous intervention (Killip class I and II). Patients were randomly allocated to heart rate control with intravenous esmolol for 24 h or placebo. The primary outcome was the maximum change in troponin T release as a prognostic surrogate marker for myocardial damage. A total of 101 patients were enrolled in the study. RESULTS: There was a significant difference between patients allocated to placebo and those who received sympathetic control with esmolol in terms of maximum change in troponin T release: the median serum troponin T concentration increased from 0.2 ng/ml (interquartile range [IQR] 0.1 to 0.7 ng/ml) to 1.3 ng/ml (IQR: 0.6 to 4.7 ng/ml) in the esmolol group and from 0.3 ng/ml (IQR: 0.1 to 1.2 ng/ml) to 3.2 ng/ml (IQR: 1.5 to 5.3 ng/ml) in the placebo group (p = 0.010). The levels of peak creatine kinase (CK), CK subunit MB (CK-MB), and n-terminal brain natriuretic peptide (NT-proBNP) were lower in the esmolol group compared with placebo (CK 619 U/l [IQR: 250-1,701 U/l] vs. 1,308 U/l [IQR: 610 to 2,324 U/l]; p = 0.013; CKMB: 73.5 U/l [IQR: 30 to 192 U/l] vs. 158.5 U/l [IQR: 74 to 281 U/l]; p = 0.005; NT-proBNP: 1,048 pg/ml (IQR: 623 to 2,062 pg/ml] vs. 1,497 pg/ml [IQR: 739 to 3,318 pg/ml]; p = 0.059). Cardiogenic shock occurred in three patients in the placebo group and in none in the esmolol group. CONCLUSIONS: Esmolol treatment statistically significantly decreased troponin T, CK, CK-MB and NT-proBNP release as surrogate markers for myocardial injury in patients with STEMI. (Heart Rate Control After Acute Myocardial Infarction; DRKS00000766).

Remote ischemic preconditioning and renoprotection: from myth to a novel therapeutic option?

There is currently no effective prophylactic regimen available to prevent contrast-induced AKI (CI-AKI), a frequent and life-threatening complication after cardiac catheterization. Therefore, novel treatment strategies are required to decrease CI-AKI incidence and to improve clinical outcomes in these patients. Remote ischemic preconditioning (rIPC), defined as transient brief episodes of ischemia at a remote site before a subsequent prolonged ischemia/reperfusion injury of the target organ, is an adaptational response that protects against ischemic and reperfusion insult. Indeed, several studies demonstrated the tissue-protective effects of rIPC in various target organs, including the kidneys. In this regard, rIPC may offer a novel noninvasive and virtually cost-free treatment strategy for decreasing CI-AKI incidence. This review evaluates the current experimental and clinical evidence for rIPC as a potential renoprotective strategy, and discusses the underlying mechanisms and key areas for future research.

Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial).

BACKGROUND: Contrast medium-induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium-induced acute kidney injury. METHODS AND RESULTS: Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL · min(-1) · 1.73 m(-2)) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium-induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium-induced kidney injury, defined as an increase in serum creatinine ≥25% or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium-induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07-0.57; P=0.002). No major adverse events were related to remote ischemic preconditioning. CONCLUSIONS: Remote ischemic preconditioning before contrast medium use prevents contrast medium-induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.germanctr.de. Unique identifier: U1111-1118-8098.