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.

Elevated Initial Serum Phosphate Levels Predict Higher Mortality and Impaired Neurological Outcome in Cardiac Arrest Patients with Return of Spontaneous Circulation.

Purpose: Although a moderate proportion of cardiac arrest (CA) patients achieve a return of spontaneous circulation (ROSC), few survive to discharge, mostly with poor neurological development. As serum phosphate levels were described as elevated after cardiopulmonary resuscitation (CPR), we asked whether these elevations would predict a higher risk of mortality and impaired neurological outcome in CA patients following ROSC. Methods: Initial serum phosphate levels, survival, and neurologic status at discharge of 488 non-traumatic CA patients treated at a single German hospital after achieving ROSC were analyzed. The cut-off value of phosphate for mortality prediction was determined using the receiver operator characteristic (ROC) curve, and patients were divided accordingly for comparison. Results were validated by analyzing phosphate levels in a multi-centric cohort containing 3299 CA patients from the eICU database of the United States. Results: In the German cohort, ROC analysis showed a 90% specificity for phosphate levels >2.7 mmol/L to predict mortality (AUC: 0.76, p < 0.0001), and phosphate level elevations were associated with higher in-hospital mortality (crude odds ratio 3.04, 95% CI 2.32 to 4.08). Patients with initial phosphate levels >2.7 mmol/L had significantly higher mortality in both analyzed collectives (p < 0.0001). Similarly, patients from the German cohort who initially had higher phosphate levels also showed a higher proportion of impaired neurological status at discharge and morphological signs of brain injury. Conclusions: In CA patients following ROSC, initial serum phosphate levels >2.7 mmol/L predict higher mortality and impaired neurological outcome. Our data suggests that phosphate determination might improve the preciseness of the overall and neurologic prognostication in patients after CPR following ROSC.

Relevance of pre-existing anaemia for patients admitted for acute coronary syndrome to an intensive care unit: a retrospective cohort analysis of 7418 patients.

Aims: Patients with acute coronary syndrome (ACS) frequently suffer from anaemia, but its role in patients admitted to an intensive care unit (ICU) is unclear. This analysis evaluates the prognostic relevance of different degrees of anaemia and their specific impact on disease severity and the outcome in critically ill ACS patients. Methods and results: and results The multi-centre electronic Intensive Care Unit Collaborative Research Database was used, and all patients admitted with ACS were included in a retrospective analysis. Anaemia and its degrees were defined according to the criteria by the World Health Organization. A multi-level logistic regression analysis was used to fit three sequential regression models for the binary primary outcome of hospital mortality. A total of 7418 patients were included; 3437 patients (46%) had anaemia on admission. Patients with anaemia were significantly older [61 (53-70) vs. 70 (61-78) years, P < 0.001], more often female (P < 0.001), and required an increased rate of vasopressor use (P < 0.001) and mechanical ventilation (P < 0.001). With the higher Sequential organ failure assessment score (1 vs. 2; P < 0.001) and Acute Physiology And Chronic Health Evaluation (35 vs. 47; P < 0.001) scores, a higher degree of anaemia was associated with prolonged ICU stay (2 vs. 5 days, P < 0.001). Even patients with mild anaemia needed significantly from more intensive treatment and suffered worse outcome. Intensive care unit and hospital mortality were inversely associated with haemoglobin levels. Conclusion: Nearly half of critically ill patients with ACS suffer from anaemia, which is associated with increased illness severity, complex ICU procedures, and mortality-even in mild anaemia. Haemoglobin on admission is an independent factor for adverse outcome.

Acidosis predicts mortality independently from hyperlactatemia in patients with sepsis.

RATIONALE AND OBJECTIVES: Acidosis and hyperlactatemia predict outcome in critically ill patients. We assessed BE and pH for risk prediction capabilities in a sub-group of septic patients in the MIMIC-III database. METHODS: Associations with mortality were assessed by logistic regression analysis in 5586 septic patients. Baseline parameters, lactate concentrations, pH, and BE were analyzed at baseline and after 6 hours. MEASUREMENTS AND MAIN RESULTS: We combined acidosis (defined as either BE ≤-6 and/or pH ≤7.3) and hyperlactatemia and split the cohort into three subgroups: low-risk (no acidosis and lactate <2.3 mmol/L; n = 2294), medium-risk (either acidosis or lactate >2.3 mmol/L; n = 2125) and high-risk (both acidosis and lactate >2.3 mmol/L; n = 1167). Mortality was 14%, 20% and 38% (p<0.001) in low-risk, medium-risk and high-risk patients, respectively. The predictiveness of this model (AUC 0.63 95%CI 0.61-0.65) was higher compared to acidosis (AUC 0.59 95%CI 0.57-0.61; p<0.001) and lactate >2.3 mmol/L (AUC 0.60 95%CI 0.58-0.62; p<0.001) alone. Hyperlactatemia alone was only moderately predictive for acidosis (AUC 0.60 95%CI 0.59-0.62). CONCLUSIONS: Acidosis and hyperlactatemia can occur independently to a certain degree. Combining acidosis and hyperlactatemia in a model yielded higher predictiveness for ICU-mortality. Septic patients with acidosis should be treated even more aggressively in the future.

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.