Tranexamic acid dose-response relationship for antifibrinolysis in postpartum haemorrhage during Caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre, dose-ranging biomarker study.

BACKGROUND: The optimal dose of tranexamic acid to inhibit hyperfibrinolysis in postpartum haemorrhage is unclear. Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Cesarean Delivery (TRACES) was a double-blind, placebo-controlled, randomised, multicentre dose-ranging study to determine the dose-effect relationship for two regimens of intravenous tranexamic acid vs placebo. METHODS: Women experiencing postpartum haemorrhage during Caesarean delivery were randomised to receive placebo (n=60), tranexamic acid 0.5 g (n=57), or tranexamic acid 1 g i.v. (n=58). Biomarkers of fibrinolytic activation were assayed at five time points, with inhibition of hyperfibrinolysis defined as reductions in the increase over baseline in D-dimer and plasmin-antiplasmin levels and in the plasmin peak time. RESULTS: In the placebo group, hyperfibrinolysis was evidenced by a mean increase over baseline [95% confidence interval] of 93% [68-118] for D-dimer level at 120 min and 56% [25-87] for the plasmin-antiplasmin level at 30 min. A dose of tranexamic acid 1 g was associated with smaller increases over baseline (D-dimers: 38% [13-63] [P=0.003 vs placebo]; plasmin-antiplasmin: -2% [-32 to 28] [P=0.009 vs placebo]). A dose of tranexamic acid 0.5 g was less potent, with non-significant reductions (D-dimers: 58% [32-84] [P=0.06 vs placebo]; plasmin-antiplasmin: 13% [18-43] [P=0.051]). Although both tranexamic acid doses reduced the plasmin peak, reduction in plasmin peak time was significant only for the 1 g dose of tranexamic acid. CONCLUSIONS: Fibrinolytic activation was significantly inhibited by a dose of intravenous tranexamic acid 1 g but not 0.5 g. Pharmacokinetic-pharmacodynamic modelling of these data might identify the best pharmacodynamic monitoring criteria and the optimal tranexamic acid dosing regimen for treatment of postpartum haemorrhage. CLINICAL TRIAL REGISTRATION: NCT02797119.

Case report: risk of skin necrosis related to injectable vancomycin in critically ill newborn infants.

BACKGROUND: Vancomycin is commonly used as part of empiric antibiotic therapy in the preterm infants who develop signs and symptoms of infection. Although skin necrosis has been noted to occur following injection of vancomycin into a peripheral vein in an adult patient, this complication has not been previously described in a preterm infant. CASE PRESENTATION: We report the case of a very low birthweight male infant born at 30 weeks gestational age who developed skin necrosis, most likely as a complication of vancomycin administration via a peripheral venous catheter. The immature skin and endothelial cells of this preterm infant may have increased the risk of drugs related venous and skin toxicity. In this case, assumption of a cumulative toxicity with other drugs administered concomitantly via the same catheter can't be excluded. CONCLUSIONS: To prevent the risk of skin damage, we advocate that in newborn infants, the administration of vancomycin should be limited to a concentration of < 2.5 mg/mL via a peripheral intravenous catheter if a central venous catheter is not available.

Long-term stability of 10 mg/mL dobutamine injectable solutions in 5% dextrose and normal saline solution stored in polypropylene syringes and cyclic-oleofin-copolymer vials.

OBJECTIVE: Dobutamine is an inotropic agent given to patients with low cardiac output or undergoing cardiac surgery in intensive care units. Routine clinical care protocols recommend a target dilution concentration of 10 mg/mL dobutamine from the 250 mg/20 mL commercial solution.This study aimed to assess the 1-year stability of ready-to-use 10 mg/mL diluted dobutamine solutions. Two types of 50 mL conditioning, polypropylene (PP) syringes or cyclic-oleofin-copolymer (COC) vials and two diluents (5% dextrose (D5W) and normal saline (NS)) were tested. METHODS: Reversed-phase liquid chromatography coupled with an ultraviolet detection stability-indicating method was developed for dobutamine and validated according to selectivity, linearity, sensitivity, accuracy and precision. Chemical stability was considered to have been maintained if the measured concentrations were >90% of the initial concentration with no colour change. Physical stability was assessed through sterility tests, pH and osmolality monitoring, and subvisible particle counting. Containers were stored at -20±5°C, +5±3°C and +25±2°C with 60%±5% relative humidity in a dark, closed environment. RESULTS: According to this study, the physicochemical stability of 10 mg/mL dobutamine solutions prepared with D5W or NS is constant throughout a 365-day period when stored in COC vials, at all the aforementioned temperatures, whereas solutions in PP syringes required a refrigerated temperature and should not be administered after 21 days or 3 months when prepared with D5W or NS, respectively, or after 1 month at ambient temperature whatever the diluent. CONCLUSION: Our results argue in favour of adopting the compounding of ready-to-use 10 mg/mL dobutamine solutions in COC vials in centralised intravenous additive services.

Stability of 1-unit/mL insulin aspart solution in cyclic olefin copolymer vials and polypropylene syringes.

PURPOSE: This study evaluated the stability of diluted insulin aspart solutions (containing insulin aspart and preservatives) at their most commonly used concentration in intensive care units (1 unit/mL), in 2 container types: cyclic olefin copolymer (COC) vials and polypropylene (PP) syringes. METHODS: Insulin aspart solution (1 unit/mL, diluted in 0.9% sodium chloride injection) was stored for 365 days in COC vials with gray stoppers and PP syringes at refrigerated (5°C ± 3°C) and ambient temperatures (25°C ± 2°C at 60% ± 5% relative humidity and protected from light). Chemical testing was conducted monthly using a validated high-performance liquid chromatography method (quantification of insulin aspart, phenol, and metacresol). Physical stability was evaluated monthly via pH measurements, visible and subvisible particle counts, and osmolality measurements. Sterility testing was also performed to validate the sterile preparation process and the maintenance of sterility throughout the study. RESULTS: The limit of stability was set at 90% of the initial concentrations of insulin aspart, phenol, and metacresol. The physicochemical stability of 1-unit/mL insulin solutions stored refrigerated and protected from light, was unchanged in COC vials for the 365-day period and for 1 month in PP syringes. At ambient temperature, subvisible particulate contamination as well as the chemical stability of insulin and metacresol were acceptable for only 1 month's storage in PP syringes, while insulin chemical stability was maintained for only 3 months' storage in COC vials. CONCLUSION: According to our results, it is not recommended to administer 1-unit/mL pharmacy-diluted insulin solutions after 3 months' storage in COC vials at ambient temperature or after 1 month in PP syringes at ambient temperature. The findings support storage of 1-unit/mL insulin aspart solution in COC vials at refrigerated temperature as the best option over the long term. Sterility was maintained in every condition. Both sterility and physicochemical stability are essential to authorize the administration of a parenteral insulin solution.

Pharmacokinetics of Curative Tranexamic Acid in Parturients Undergoing Cesarean Delivery.

The aim of this study was to evaluate the population pharmacokinetics of tranexamic acid (TXA) administered intravenously at a single dose of 0.5 or 1 g in parturients undergoing active hemorrhagic cesarean delivery and to evaluate the influence of patient variables on TXA pharmacokinetics. Subjects from three recruiting centers were included in this PK sub-study if randomized in the experimental group (i.v TXA 0.5 g or 1 g over one minute) of the TRACES study. Blood samples and two urinary samples were collected within 6 h after TXA injection. Parametric non-linear mixed-effect modeling (Monolix v2020R1) was computed. The final covariate model building used 315 blood and 117 urinary concentrations from seventy-nine patients. A two-compartment model with a double first-order elimination from the central compartment best described the data. The population estimates of clearance (CL), central volume of distribution (V1), and half-life for a typical 70 kg patient with an estimated renal clearance of 150 mL/min (Cockroft-Gault) were 0.14 L/h, 9.25 L, and 1.8 h. A correlation between estimated creatinine clearance and CL, body weight before pregnancy, and V1 was found and partly explained the PK variability. The final model was internally validated using a 500-run bootstrap. The first population pharmacokinetic model of TXA in active hemorrhagic caesarean section was successfully developed and internally validated.

The role of tranexamic acid in the management of postpartum haemorrhage.

In the last decades, tranexamic acid (TXA) has emerged as an essential tool in blood loss management in obstetrics. TXA prophylaxis for postpartum haemorrhage (PPH) has been studied in double-blind, placebo-controlled, randomized clinical trials (RCTs). Given the small observed preventive effect, the systematic use of TXA for vaginal and/or caesarean deliveries remains controversial. The result of a pharmacokinetic modelling suggests that relative to intravenous administration, intramuscular administration may be an equally effective alternative route for preventing PPH and may enable access to this drug in low-resource countries. Prophylaxis is currently studied in high-risk populations, such as women with prepartum anaemia or placenta previa. TXA effectively reduces blood loss and PPH-related morbidity and mortality during active PPH, as demonstrated by high-grade evidence from large RCTs. The drug has a good safety profile: in most cases, only mild gastrointestinal or visual adverse events may be observed. TXA use does not increase the risk of serious adverse events, such as venous or arterial thromboembolism, seizures, or acute kidney injury. The TRACES in vivo analysis of biomarkers of TXA's antifibrinolytic effect have suggested that a dose of at least 1 g is required for the treatment of PPH. The TRACES pharmacokinetic model suggests that because TXA can be lost in the haemorrhaged blood, a second dose should be administered if the PPH continues or if severe coagulopathy occurs. Future pharmacodynamic analyses will focus on the appropriateness of TXA dosing regimens with regard to the intensity of fibrinolysis in catastrophic obstetric events.

Factors influencing accuracy when preparing injectable drug concentrations in appliance with clinical practice: a norepinephrine case study.

Errors in injectable preparations with high-risk drugs can be fatal. This study aimed to identify the factors influencing the accuracy of high-risk injectable drug concentrations in appliances used for intensive care unit preparation practices. Norepinephrine (NE) was chosen as an example of a high-risk medication drug. The concentration (0.2 and 0.5 mg/mL), the diluent (sodium chloride 0.9% and 5% dextrose), and the container type (prefilled- and empty-infusion bag and syringe) were tested as potential variability factors. An ultraviolet spectrophotometric method was used for NE dosage. 108 NE solutions were prepared by five individuals (pharmacists or laboratory technicians) with clinical experience as well as experience in the aseptic preparation of solutions. The container type was found to be the only factor influencing the accuracy of NE concentration. NE solutions in syringes proved to be the most accurate while preparations in prefilled bags tended to underdose NE.

Case Report: Persistent Pulmonary Hypertension of the Newborn and Narrowing of the Ductus Arteriosus After Topical Use of Non-Steroidal Anti-Inflammatory During Pregnancy.

Background: The use of non-steroidal anti-inflammatory drugs (NSAIDs) during the third trimester of pregnancy can cause premature constriction of the ductus arteriosus. This report describes a case of in utero narrowing of the ductus arteriosus (DA) diagnosed postnatally in a baby with Persistent Pulmonary Hypertension of the Newborn (PPHN), after maternal use of Diclofenac-Epolamine 140 mg patch during the second and third trimester. Case Presentation: A fetal ultrasounds revealed an enlarged hypertrophic right ventricle at 32 weeks of gestation. Detailed questioning of the mother highlighted that topical Diclofenac (FLECTOR®) had been used at 26 and at 31 weeks of gestation. An echocardiography performed 8 h postnatally showed supra-systemic pulmonary hypertension, a restrictive ductus arteriosus and a dilated right ventricle. The newborn was treated by inhaled nitric oxide and oral Sildenafil and was discharged from hospital on day 24. He had a complete normalization of his pulmonary vascular resistance on day 48. Conclusion: This case illustrates the potential fetal and neonatal complications associated with maternal topical Diclofenac medication during pregnancy resulting in antenatal closure of the DA.

Long-term stability of ready-to-use 1-mg/mL midazolam solution.

PURPOSE: Midazolam is a benzodiazepine derivative commonly used in intensive care units to control sedation. Its use requires dilution of a 5-mg/mL commercial solution to a target concentration of 1 mg/mL. A study was conducted to evaluate the stability of diluted ready-to-use 1-mg/mL midazolam solutions over 365 days when stored in cyclic olefin copolymer vials or polypropylene syringes. METHODS: A specific stability-indicating high-performance liquid chromatography coupled with UV detection method was developed for midazolam hydrochloride and validated for selectivity, linearity, sensitivity, precision, and accuracy. Three storage conditions were tested: -20°C ± 5°C, 5°C ± 3°C, and 25°C ± 2°C at 60% ± 5% relative humidity. Half of the vials were stored upside down to test for the absence of interaction between midazolam and the stopper. Particle contamination, sterility, and pH were assessed. RESULTS: The limit of stability was set at 90% of the initial concentration. After 1 year's storage at -20°C and 5°C, concentrations remained superior to 90% under all storage conditions. At 25°C, stability was maintained up to day 90 in syringes (mean [SD], 92.71% [1.43%]) and to day 180 in upright and upside-down vials (92.12% [0.15%] and 91.57% [0.15%], respectively). No degradation products were apparent, no variations in pH values were detected, and containers retained their sterility and conformity with regard to any specific contamination during the study. CONCLUSION: The evaluated 1-mg/mL midazolam solution was stable over a 1-year period when stored at a refrigerated (5°C) or frozen (-20°C) temperature in both vials and syringes; with storage at 25°C, the stability duration was lower. The preparation of ready-to-use midazolam solutions by a hospital pharmacy is compatible with clinical practice and could help to decrease risks inherent in dilution in care units.

Long-term stability of ready-to-use norepinephrine solution at 0.2 and 0.5 mg/mL.

Objectives: Norepinephrine is a vasopressor frequently administered after dilution to treat hypotension and shocks in intensive care units. The stability of norepinephrine is known to be highly sensitive to storage conditions. Moreover, medication errors linked to the dilution step are frequent and may be deleterious for critically-ill patients, especially in intensive care units. This study aimed to evaluate the stability of ready-to-use diluted norepinephrine solutions prepared at two target concentrations (0.2 and 0.5 mg/mL), according to the summary of product characteristics, and stored for 365 days in two containers: AT-closed cyclic olefin copolymer vials, and polypropylene syringes. Methods: A fast reversed-phase liquid chromatography method coupled with an ultra-violet detector was developed to assess the chemical stability of norepinephrine solutions. Validation was conducted according to the linearity of the calibration ranges, selectivity, sensitivity, accuracy and precision. Dosage, sub-visible particle contamination, pH monitoring and sterility assays were performed. Chemical stability was maintained if the measured concentration respected the lower limit of 90% of the initial concentration. Containers were stored at -20±5°C, +5±3°C and +25±2°C with 60±5% relative humidity in a dark closed enclosure. Results: Stability was successfully maintained for every concentration and container tested when stored at -20±5°C and +5±3°C. In these storage conditions, particle contamination, pH monitoring and sterility assay respected the required criteria. Chemical degradation and colouring of solutions appeared before the end of the 1 year study period for most norepinephrine solutions stored at room temperature. Conclusions: Ready-to-use solutions containing 0.2 and 0.5 mg/mL norepinephrine in polypropylene syringes or cyclic olefin copolymer vials must be stored at refrigerated or frozen temperatures to obtain acceptable 1 year shelf-stability. Exposure to higher temperatures significantly decreases shelf-stability. Our study protocol for compounding polypropylene syringes and cyclic olefin copolymer vials containing norepinephrine is adapted to implementation in centralised intravenous additive services.

Association of prestroke metformin use, stroke severity, and thrombolysis outcome.

OBJECTIVE: To evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis. METHODS: Data from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET. RESULTS: Of 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET-). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0-4.0] vs 3 [IQR 1.0-4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups. CONCLUSIONS: Patients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome.

Influence of on-going treatment with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker on the outcome of patients treated with intravenous rt-PA for ischemic stroke.

BACKGROUND: Many patients who receive intravenous (i.v.) recombinant tissue-plasminogen activator (rt-PA) for acute cerebral ischemia were under angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) at stroke onset. ACE-Is and ARBs have neuroprotective properties in animal models. OBJECTIVE: To evaluate whether the 3-month outcome of patients treated with i.v. rt-PA for cerebral ischemia was influenced by on-going therapy with ACE-Is or ARBs. METHOD: This study was observational, conducted in two prospective registries of stroke patients treated with i.v. rt-PA. We evaluated outcomes with the modified Rankin scale and symptomatic intracranial hemorrhages (s-ICH) according to the ECASS2 criteria. We compared outcomes between patients with and without ACE-Is/ARBs according to the modified Rankin scale (mRS) at month 3, using logistic regression analyses adjusted on propensity scores, and propensity-matched analyses. RESULTS: Of 1803 patients, 455 (25.2%) were under ACE-Is (259), ARBs (188) or both (8). At 3 months, patients under ACE-Is or ARBs were more likely to have an mRS 0-1, but did not differ for mRS 0-2, s-ICH and death. After adjustment on propensity scores, the association between ACE-Is/ARBs and mRS 0-1 disappeared. The propensity-matched analysis, performed in 397 pairs of patients, found no difference in outcomes between patients with and without ACE-Is or ARBs. CONCLUSION: In patients treated by intravenous thrombolytic therapy for ischemic stroke, on-going treatment with ACE-Is or ARBs does not influence on outcomes after adjustment on baseline characteristics and propensity scores.