thromboxane-b2 and Critical-Illness

Despite decades of clinical use, the pharmacokinetics and the effects of acetylsalicylic acid (ASA) in critically ill patients remain ill-defined. We aimed to investigate the pharmacokinetics and the effects of different ASA formulations during critical illness.. A cross-sectional study and a randomized, parallel-group trial were performed. Critically ill patients under chronic oral ASA treatment (100 mg enteric-coated) were screened for high 'on-treatment' platelet reactivity (HTPR) according to arachidonic acid-induced whole-blood aggregometry. Thirty patients with HTPR were randomized to receive 100 mg ASA intravenously, 100 mg enteric-coated ASA bid (bis in die) or 81 mg chewable ASA (n = 10 per group). Serum thromboxane B2 (TXB2) levels, ASA and salicylic acid levels were quantified.. Of 66 patients, 85% (95% confidence intervals 74-93%) had HTPR. Compared to baseline infusion of 100 mg, ASA significantly reduced platelet aggregation after 24 h to median 80% (Quartiles: 66-84%). Intake of 81 mg chewable ASA significantly reduced platelet aggregation to 75% (54-86%) after four hours, but increased it to 117% after 24 h (81-163%). Treatment with 100 mg enteric-coated ASA bid decreased platelet aggregation after 24 h to median 56% (52-113%). Baseline TXB2 levels were median 0·35 ng/mL (0·07-0·94). Infusion of ASA or intake of 100 mg ASA bid reduced TXB2 levels to 0·07-0·18 ng/mL after 24 h, respectively. Chewable ASA reduced TXB2 levels only transiently. Pharmacokinetic analysis revealed highly variable absorption patterns of oral ASA formulations.. There is a very high prevalence of HTPR in critically ill patients on peroral ASA therapy, caused by an incomplete suppression of TXB2 and/or by impaired absorption of ASA.

Topics: Administration, Oral; Aged; Analysis of Variance; Aspirin; Critical Illness; Cross-Sectional Studies; Female; Humans; Infusions, Intravenous; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

Platelets critically contribute to atherothrombosis and worsening ischaemia in patients with peripheral arterial disease (PAD), eventually leading to critical limb ischaemia (CLI). Furthermore, persistent platelet activation despite antiplatelet therapy has been reported in this setting. The prostacyclin analogue iloprost is currently recommended in CLI patients for its effects in relieving symptoms by promoting local perfusion. In this study, we investigated the effects of iloprost infusion on urinary 11-dehydro-TXB₂ and 8-iso-PGF(₂α) excretion rate, as in vivo indexes of thromboxane-dependent platelet activation and lipid peroxidation, respectively, and on platelet-derived proinflammatory sCD40L and nitric oxide bioavailability in 44 patients with CLI while on chronic treatment with low-dose aspirin. Daily iloprost infusion for one-week significantly decreased urinary 11-dehydro-TXB₂ [499 (277-807) vs. 380 (189-560) pg/mg creatinine, p < 0.0001] and 8-iso-PGF(₂α) [533 (316-842) vs. 334 (196-540) pg/mg creatinine, p < 0.0001] as well as plasma sCD40L [1540 (1005-3015) vs. 948 (845-2030) pg/ml, p < 0.0001]. Furthermore, a significant increase in plasma nitrate plus nitrite levels has been observed [26.8 (18.8-35.9) vs. 43.7 (33.0-75.5) μM, p < 0.0001]. A significant direct correlation was also found between urinary 8-iso-PGF(₂α) and 11-dehydro-TXB2 before and after iloprost treatment (Rho = 0.695, p < 0.0001). In conclusion, we report that a short-term course of iloprost is able to significantly reduce residual thromboxane biosynthesis, oxidative stress, endothelial dysfunction and platelet-derived inflammation in low-dose aspirin treated patients with CLI.

Topics: Aged; Aged, 80 and over; Aspirin; Biomarkers; Blood Platelets; CD40 Ligand; Chi-Square Distribution; Critical Illness; Dinoprost; Drug Administration Schedule; Female; Humans; Iloprost; Inflammation Mediators; Infusions, Intravenous; Ischemia; Italy; Lipid Peroxidation; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane B2; Time Factors; Treatment Outcome

Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients.. The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the urinary levels of prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1α), thromboxane A2 (TXA2) metabolite (11-dehydro-TXB2) were determined.. Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6-OXO-PGF1α/Cr (r = 0.57, p < 0.0001) and 11-dehydro-TXB2/Cr (r = 0.47, p < 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE2/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF1α/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC-area under the curve (AUC): 0.75].. Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adult; Biomarkers; Creatinine; Critical Care; Critical Illness; Female; Humans; Japan; Male; Postoperative Complications; Predictive Value of Tests; Prospective Studies; Prostaglandins; Thromboxane B2; Treatment Outcome