Pharmacokinetics of tranexamic acid after intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in healthy volunteers.

BACKGROUND: In response to the World Health Organization call for research on alternative routes for tranexamic acid (TXA) administration in women with postpartum haemorrhage, we examined the pharmacokinetics of TXA after i.v., i.m., or oral administration. METHODS: We conducted a randomised, open-label, crossover trial in 15 healthy volunteers who received i.v. TXA 1 g, i.m. TXA 1 g, or oral TXA solution 2 g. Blood samples were drawn up to 24 h after administration. Tranexamic acid concentration was measured with liquid chromatography-mass spectrometry, and the parameters of the pharmacokinetic models were estimated using population pharmacokinetics. RESULTS: The median time to reach a concentration of 10 mg L-1 was 3.5 min for the i.m. route and 66 min for the oral route, although with the oral route the target concentration was reached in only 11 patients. Median peak concentrations were 57.5, 34.4, and 12.8 mg L-1 for i.v., i.m., and oral routes, respectively. A two-compartment open model with body weight as the main covariate best fitted the data. For a 70 kg volunteer, the population estimates were 10.1 L h-1 for elimination clearance, 15.6 L h-1 for intercompartmental clearance, 7.7 L for the volume of central compartment, and 10.8 L for the volume of the peripheral compartment. Intramuscular and oral bioavailabilities were 1.0 and 0.47, respectively, showing that i.m. absorption is fast and complete. Adverse events were mild and transient, mainly local reactions and low-intensity pain. CONCLUSIONS: The i.m. (but not oral) route appears to be an efficient alternative to i.v. tranexamic acid. Studies in pregnant women are needed to examine the impact of pregnancy on the pharmacokinetics. CLINICAL TRIAL REGISTRATION: EudraCT 2019-000285-38; NCT03777488.

Simulation Analysis of Flow Rate Variability During Microinfusions: The Effect of Vertical Displacement and Multidrug Infusion in Conventional Infusion Pumps Versus New Cylinder-Type Infusion Pumps.

BACKGROUND: Medication dosing errors can occur during microinfusions when there is vertical pump displacement or multidrug infusion through a single intravenous path. We compared flow rate variability between new-generation cylinder-type infusion pumps and conventional infusion pumps under simulated conditions. METHODS: We evaluated the flow rates during microinfusions using different infusion pumps (syringe pump with 10/30/50-mL syringes, peristaltic pump, and cylinder pump). Two visible dyes were used as model drugs. The study samples were quantified using spectrophotometry. For vertical displacement, the infusion pumps were moved up and down by 60 cm during microinfusions at 0.5 mL·h-1 and 2 mL·h-1. In the multi-infusion study, the second drug flow was added through 4 linearly connected stopcocks either upstream or downstream of the first drug. We compared the total error dose between the cylinder pump and the syringe pump with a Mann-Whitney U test and additionally estimated the effects of the infusion pumps on total error doses by linear regression analysis. RESULTS: There were repetitive patterns of temporary flow increases when the pump was displaced upward and flow decreases when the pump was displaced downward in all settings. However, the amount of flow irregularities was more pronounced at the lower infusion rate and in the syringe-type pump using larger volume syringes. The total error dose increased in the syringe pump loaded with a 50-mL syringe compared to that of the new cylinder pump (regression coefficient [ß] = 4.66 [95% confidence interval {CI}, 1.60-7.72]; P = .008). The initiation and cessation of a new drug during multidrug microinfusion in the same intravenous path affected the lower rate first drug leading to a transient flow rate increase and decrease, respectively. The change in flow rate was observed regardless of the port selected for addition of the second drug, and the total error dose of the first drug did not significantly vary when an upstream or a downstream port was selected. CONCLUSIONS: In the microinfusion settings, attention must be paid to the use of the syringe pump loaded with large-volume syringes. The novel cylinder pump could be considered as a practical alternative to syringe pumps with small syringes given its flow stability without the need for frequent drug replacement.

Intravenous abciximab as a rescue therapy for immediate reocclusion after successful mechanical thrombectomy in acute ischemic stroke patients.

Immediate reocclusion after mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is a rare but devastating condition associated with poor functional outcome. The aim of this study was to gain insights into the mechanisms underlying immediate reocclusion, and to evaluate the efficacy and safety of the glycoprotein IIb/IIIa antagonist abciximab, for its treatment. Clinical data were collected from April 2015 to April 2019 in a monocentric prospective registry of AIS patients treated by MT. All patients with immediate reocclusion were retrospectively selected and subdivided into 2 groups according to abciximab treatment status. In vitro, the separate and combined effects of abciximab and alteplase on clot formation in whole blood under flow conditions were further investigated in microfluidic chambers. From 929 MT-treated patients, 21 had post-MT immediate reocclusion. Abciximab treatment in reocclusion patients (n = 10) led to higher rate of final recanalization (p < .001) while it did not increase bleeding complications. Flow chamber experiments revealed that, in contrast to alteplase, abciximab efficiently limits thrombus accretion from flowing blood by blocking platelet aggregation. Our results underscore a key role for platelet aggregation and the potential of Glycoprotein IIb/IIIa antagonists as a rescue therapy in post-MT immediate reocclusion.

Impact of parylene coating on heating performance of intravenous fluid warmer: a bench study.

BACKGROUND: Perioperative hypothermia is a common occurrence, particularly with the elderly and pediatric age groups. Hypothermia is associated with an increased risk of perioperative complications. One method of preventing hypothermia is warming the infused fluids given during surgery. The enFlow™ intravenous fluid warmer has recently been reintroduced with a parylene coating on its heating blocks. In this paper, we evaluated the impact of the parylene coating on the new enFlow's fluid warming capacity. METHODS: Six coated and six uncoated enFlow cartridges were used. A solution of 10% propylene glycol and 90% distilled H2O was infused into each heating cartridge at flow rates of 2, 10, 50, 150, and 200 ml/min. The infused fluid temperature was set at 4 °C, 20 °C, and 37 °C. Output temperature was recorded at each level. Data for analysis was derived from 18 runs at each flow rate (six cartridges at three temperatures). RESULTS: The parylene coated fluid warming cartridge delivered very stable output of 40 °C temperatures at flow rates of 2, 10, and 50 ml/min regardless of the temperature of the infusate. At higher flow rates, the cartridges were not able to achieve the target temperature with the colder fluid. Both cartridges performed with similar efficacy across all flow rates at all temperatures. CONCLUSIONS: At low flow rates, the parylene coated enFlow cartridges was comparable to the original uncoated cartridges. At higher flow rates, the coated and uncoated cartridges were not able to achieve the target temperature. The parylene coating on the aluminum heating blocks of the new enFlow intravenous fluid warmer does not negatively affect its performance compared to the uncoated model.

Criticality of Surface Characteristics of Intravenous Iron-Carbohydrate Nanoparticle Complexes: Implications for Pharmacokinetics and Pharmacodynamics.

Un-complexed polynuclear ferric oxyhydroxide cannot be administered safely or effectively to patients. When polynuclear iron cores are formed with carbohydrates of various structures, stable complexes with surface carbohydrates driven by multiple interacting sites and forces are formed. These complexes deliver iron in a usable form to the body while avoiding the serious adverse effects of un-complexed forms of iron, such as polynuclear ferric oxyhydroxide. The rate and extent of plasma clearance and tissue biodistribution is variable among the commercially available iron-carbohydrate complexes and is driven principally by the surface characteristics of the complexes which dictate macrophage opsonization. The surface chemistry differences between the iron-carbohydrate complexes results in significant differences in in vivo pharmacokinetic and pharmacodynamic profiles as well as adverse event profiles, demonstrating that the entire iron-carbohydrate complex furnishes the pharmacologic action for these complex products. Currently available physicochemical characterization methods have limitations in biorelevant matrices resulting in challenges in defining critical quality attributes for surface characteristics for this class of complex nanomedicines.

Venoarterial extracorporeal membrane oxygenation as mechanical circulatory support in adult septic shock: a systematic review and meta-analysis with individual participant data meta-regression analysis.

BACKGROUND: While recommended by international societal guidelines in the paediatric population, the use of venoarterial extracorporeal membrane oxygenation (VA ECMO) as mechanical circulatory support for refractory septic shock in adults is controversial. We aimed to characterise the outcomes of adults with septic shock requiring VA ECMO, and identify factors associated with survival. METHODS: We searched Pubmed, Embase, Scopus and Cochrane databases from inception until 1st June 2021, and included all relevant publications reporting on > 5 adult patients requiring VA ECMO for septic shock. Study quality and certainty in evidence were assessed using the appropriate Joanna Briggs Institute checklist, and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, respectively. The primary outcome was survival to hospital discharge, and secondary outcomes included intensive care unit length of stay, duration of ECMO support, complications while on ECMO, and sources of sepsis. Random-effects meta-analysis (DerSimonian and Laird) were conducted. DATA SYNTHESIS: We included 14 observational studies with 468 patients in the meta-analysis. Pooled survival was 36.4% (95% confidence interval [CI]: 23.6%-50.1%). Survival among patients with left ventricular ejection fraction (LVEF) < 20% (62.0%, 95%-CI: 51.6%-72.0%) was significantly higher than those with LVEF > 35% (32.1%, 95%-CI: 8.69%-60.7%, p = 0.05). Survival reported in studies from Asia (19.5%, 95%-CI: 13.0%-26.8%) was notably lower than those from Europe (61.0%, 95%-CI: 48.4%-73.0%) and North America (45.5%, 95%-CI: 16.7%-75.8%). GRADE assessment indicated high certainty of evidence for pooled survival. CONCLUSIONS: When treated with VA ECMO, the majority of patients with septic shock and severe sepsis-induced myocardial depression survive. However, VA ECMO has poor outcomes in adults with septic shock without severe left ventricular depression. VA ECMO may be a viable treatment option in carefully selected adult patients with refractory septic shock.

Mortality in septic patients treated with vitamin C: a systematic meta-analysis.

BACKGROUND: Supplementation of vitamin C in septic patients remains controversial despite eight large clinical trials published only in 2020. We aimed to evaluate the evidence on potential effects of vitamin C treatment on mortality in adult septic patients. METHODS: Data search included PubMed, Web of Science, and the Cochrane Library. A meta-analysis of eligible peer-reviewed studies was performed in accordance with the PRISMA statement. Only studies with valid classifications of sepsis and intravenous vitamin C treatment (alone or combined with hydrocortisone/thiamine) were included. RESULTS: A total of 17 studies including 3133 patients fulfilled the predefined criteria and were analyzed. Pooled analysis indicated no mortality reduction in patients treated with vitamin C when compared to reference (risk difference - 0.05 [95% CI - 0.11 to - 0.01]; p = 0.08; p for Cochran Q = 0.002; I2 = 56%). Notably, subgroup analyses revealed an improved survival, if vitamin C treatment was applied for 3-4 days (risk difference, - 0.10 [95% CI - 0.19 to - 0.02]; p = 0.02) when compared to patients treated for 1-2 or > 5 days. Also, timing of the pooled mortality assessment indicated a reduction concerning short-term mortality (< 30 days; risk difference, - 0.08 [95% CI - 0.15 to - 0.01]; p = 0.02; p for Cochran Q = 0.02; I2 = 63%). Presence of statistical heterogeneity was noted with no sign of significant publication bias. CONCLUSION: Although vitamin C administration did not reduce pooled mortality, patients may profit if vitamin C is administered over 3 to 4 days. Consequently, further research is needed to identify patient subgroups that might benefit from intravenous supplementation of vitamin C.

Impact of treating iron deficiency, diagnosed according to hepcidin quantification, on outcomes after a prolonged ICU stay compared to standard care: a multicenter, randomized, single-blinded trial.

BACKGROUND: Anemia is a significant problem in patients on ICU. Its commonest cause, iron deficiency (ID), is difficult to diagnose in the context of inflammation. Hepcidin is a new marker of ID. We aimed to assess whether hepcidin levels would accurately guide treatment of ID in critically ill anemic patients after a prolonged ICU stay and affect the post-ICU outcomes. METHODS: In a controlled, single-blinded, multicenter study, anemic (WHO definition) critically ill patients with an ICU stay ≥ 5 days were randomized when discharge was expected to either intervention by hepcidin treatment protocol or control. In the intervention arm, patients were treated with intravenous iron (1 g of ferric carboxymaltose) when hepcidin was < 20 µg/l and with intravenous iron and erythropoietin for 20 ≤ hepcidin < 41 µg/l. Control patients were treated according to standard care (hepcidin quantification remained blinded). Primary endpoint was the number of days spent in hospital 90 days after ICU discharge (post-ICU LOS). Secondary endpoints were day 15 anemia, day 30 fatigue, day 90 mortality and 1-year survival. RESULTS: Of 405 randomized patients, 399 were analyzed (201 in intervention and 198 in control arm). A total of 220 patients (55%) had ID at discharge (i.e., a hepcidin < 41 µg/l). Primary endpoint was not different (medians (IQR) post-ICU LOS 33(13;90) vs. 33(11;90) days for intervention and control, respectively, median difference - 1(- 3;1) days, p = 0.78). D90 mortality was significantly lower in intervention arm (16(8%) vs 33(16.6%) deaths, absolute risk difference - 8.7 (- 15.1 to - 2.3)%, p = 0.008, OR 95% IC, 0.46, 0.22-0.94, p = 0.035), and one-year survival was improved (p = 0.04). CONCLUSION: Treatment of ID diagnosed according to hepcidin levels did not reduce the post-ICU LOS, but was associated with a significant reduction in D90 mortality and with improved 1-year survival in critically ill patients about to be discharged after a prolonged stay. TRIAL REGISTRATION: www.clinicaltrial.gov NCT02276690 (October 28, 2014; retrospectively registered).

Transient Inhibition of PI3Kδ Enhances the Therapeutic Effect of Intravenous Delivery of Oncolytic Vaccinia Virus.

Tumor-targeting oncolytic viruses such as vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and disseminated tumor cells. In the present study we have identified transient pharmacological inhibition of the leukocyte-enriched phosphoinositide 3-kinase δ (PI3Kδ) as a novel mechanism to potentiate intravenous delivery of oncolytic VV to tumors. Pre-treatment of immunocompetent mice with the PI3Kδ-selective inhibitor IC87114 or the clinically approved idelalisib (CAL-101), prior to intravenous delivery of a tumor-tropic VV, dramatically improved viral delivery to tumors. This occurred via an inhibition of viral attachment to, but not internalization by, systemic macrophages through perturbation of signaling pathways involving RhoA/ROCK, AKT, and Rac. Pre-treatment using PI3Kδ-selective inhibitors prior to intravenous delivery of VV resulted in enhanced anti-tumor efficacy and significantly prolonged survival compared to delivery without PI3Kδ inhibition. These results indicate that effective intravenous delivery of oncolytic VV may be clinically achievable and could be useful in improving anti-tumor efficacy of oncolytic virotherapy.

Intravenous push versus intravenous piggyback beta-lactams for the empiric management of gram-negative bacteremia.

WHAT IS KNOWN AND OBJECTIVE: Nationwide shortages of small-volume parenteral solutions (SVPS) compelled hospitals to develop strategies including the use of intravenous push (IVP) administration of antibiotics to reserve SVPS for absolute necessities. It is unknown if administration of beta-lactam antibiotics (BL) via IVP results in worse clinical outcomes compared to intravenous piggyback (IVPB) due to the potential inability to achieve pharmacodynamic targets. METHODS: Our health-system implemented a mandatory IVP action plan for BL from October 2017 to September 2018. This was a retrospective study of adult patients with GNB who received empiric therapy with IVPB (30 minutes) or IVP (5 minutes) cefepime (FEP) or meropenem (MEM) for at least 2 days. Endpoints included clinical response, microbiological clearance and mortality. All data are presented as n (%) or median (interquartile range). RESULTS: The final cohort included 213 patients (IVPB n = 105, IVP n = 108). The primary source of bacteremia was urinary, with Escherichia coli being the primary pathogen. Escalation of therapy was similar between groups (15 [14%] vs 11 [10%], P = .36) at a median of 3 days (P = .68). No significant differences were observed in any secondary endpoints including microbiological clearance, bacteremia recurrence, time to defervescence, WBC normalization, vasopressor duration or in-hospital mortality. WHAT IS NEW AND CONCLUSION: Our findings suggest no differences in clinical response with the use of IVP compared to IVPB FEP and MEM for treatment of GNB. This form of administration may be considered as a fluid conservation strategy in times of shortage.

Therapeutic Strategies for IVD Regeneration through Hyaluronan/SDF-1-Based Hydrogel and Intravenous Administration of MSCs.

Intervertebral disc (IVD) degeneration involves a complex cascade of events, including degradation of the native extracellular matrix, loss of water content, and decreased cell numbers. Cell recruitment strategies for the IVD have been increasingly explored, aiming to recruit either endogenous or transplanted cells. This study evaluates the IVD therapeutic potential of a chemoattractant delivery system (HAPSDF5) that combines a hyaluronan-based thermoreversible hydrogel (HAP) and the chemokine stromal cell derived factor-1 (SDF-1). HAPSDF5 was injected into the IVD and was combined with an intravenous injection of mesenchymal stem/stromal cells (MSCs) in a pre-clinical in vivo IVD lesion model. The local and systemic effects were evaluated two weeks after treatment. The hydrogel by itself (HAP) did not elicit any adverse effect, showing potential to be administrated by intradiscal injection. HAPSDF5 induced higher cell numbers, but no evidence of IVD regeneration was observed. MSCs systemic injection seemed to exert a role in IVD regeneration to some extent through a paracrine effect, but no synergies were observed when HAPSDF5 was combined with MSCs. Overall, this study shows that although the injection of chemoattractant hydrogels and MSC recruitment are feasible approaches for IVD, IVD regeneration using this strategy needs to be further explored before successful clinical translation.

Intravenous supplementation type and volume are associated with 1-year outcome and major complications in patients with chronic intestinal failure.

BACKGROUND AND AIM: No marker to categorise the severity of chronic intestinal failure (CIF) has been developed. A 1-year international survey was carried out to investigate whether the European Society for Clinical Nutrition and Metabolism clinical classification of CIF, based on the type and volume of the intravenous supplementation (IVS), could be an indicator of CIF severity. METHODS: At baseline, participating home parenteral nutrition (HPN) centres enrolled all adults with ongoing CIF due to non-malignant disease; demographic data, body mass index, CIF mechanism, underlying disease, HPN duration and IVS category were recorded for each patient. The type of IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorised as <1, 1-2, 2-3 and >3 L/day. The severity of CIF was determined by patient outcome (still on HPN, weaned from HPN, deceased) and the occurrence of major HPN/CIF-related complications: intestinal failure-associated liver disease (IFALD), catheter-related venous thrombosis and catheter-related bloodstream infection (CRBSI). RESULTS: Fifty-one HPN centres included 2194 patients. The analysis showed that both IVS type and volume were independently associated with the odds of weaning from HPN (significantly higher for PN <1 L/day than for FE and all PN >1 L/day), patients' death (lower for FE, p=0.079), presence of IFALD cholestasis/liver failure and occurrence of CRBSI (significantly higher for PN 2-3 and PN >3 L/day). CONCLUSIONS: The type and volume of IVS required by patients with CIF could be indicators to categorise the severity of CIF in both clinical practice and research protocols.

Emergency Medicine Physicians Accurately Select Acute Stroke Patients for Tissue-Type Plasminogen Activator Treatment Using a Checklist.

Background and Purpose- There is uncertainty among many emergency medicine physicians about the decision to give intravenous tPA (tissue-type plasminogen activator), which limits its use. A checklist approach has been suggested as a solution. We compared agreement on tPA treatment in suspected acute ischemic stroke patients between emergency medicine residents (EMRs) using a checklist and vascular neurology fellows (VNFs). Methods- Every suspected acute stroke patient brought to our comprehensive stroke center emergency room within 4.5 hours from symptom onset was prospectively evaluated simultaneously and independently by VNFs and EMRs. The latter used a tPA screening checklist, which included guideline exclusion criteria to help with their treatment decision. Agreement was determined using kappa (k) statistics. Results- Over 6 months, 60 patients were enrolled; 10% large vessel atherosclerosis, 18% cardioembolism, 12% small vessel, 12% cryptogenic, and 47% mimic. Forty-two percent were deemed tPA eligible by the EMR, 30% by the VNF, and 37% by the vascular neurology faculty. There were no complications in any tPA-treated patients. Agreement was substantial between EMR and VNF (κ=0.68 [95% CI, 0.49-0.87]) and between EMR and vascular neurology faculty (κ=0.69 [95% CI, 0.50-0.87]). Stroke mimics were the main cause of disagreement between EMR and VNF (κ=0.24 [95% CI, -0.15 to 0.63]) and between EMR and vascular neurology faculty (κ=0.35 [95% CI, -0.08 to 0.78]). Conclusions- Our data suggest that with the aid of a checklist, EMRs can accurately treat stroke patients with tPA. Areas for improvement include recognition of stroke mimics. Further studies are warranted to evaluate checklist-enhanced tPA treatment to allay emergency medicine physician uncertainty and expand the use of tPA.

Sampling Site Has a Critical Impact on Physiologically Based Pharmacokinetic Modeling.

It has been shown that arterial (central) and venous (peripheral) plasma drug concentrations can be very different. While pharmacokinetic studies typically measure drug concentrations from the peripheral vein such as the arm vein, physiologically based pharmacokinetic (PBPK) models generally output simulated concentrations from the central venous compartment that physiologically represents the right atrium, a merge of the superior and inferior vena cava. In this study, a physiologically based peripheral forearm sampling site model was developed and verified using nicotine, ketamine, lidocaine, and fentanyl as model drugs. This verified model allows output of simulated peripheral venous concentrations that can be meaningfully compared with observed pharmacokinetic data from the arm vein. The generalized effect of PBPK model sampling site on simulation output was investigated. Drugs and metabolites with large volumes of distribution showed considerable concentration discrepancy between the simulated central venous compartment and the peripheral arm vein after intravenous or oral administration, resulting in significant differences in values for C max and time taken to reach C max (t max ) In addition, the simulated central venous metabolite profile showed an unexpected profile that was not observed in the peripheral arm vein. Using fentanyl as a model compound, we show that using the wrong sampling site in PBPK models can lead to biased model evaluation and subsequent erroneous model parameter optimization. Such an error in model parameters along with the discrepant sampling site could dramatically mislead the pharmacokinetic prediction in unstudied clinical scenarios, affecting the assessment of drug safety and efficacy. Overall, this study shows that PBPK model publications should specify the model sampling sites and match them with those employed in clinical studies. SIGNIFICANCE STATEMENT: Our study shows that sampling from the central venous compartment (right atrium) during physiologically based pharmacokinetic model development gives rise to biased model evaluation and erroneous model parameterization when observed data are collected from the peripheral arm vein. This can lead to a clinically significant error in predictions of plasma concentration-time profiles in unstudied scenarios. To address this error, we developed and verified a novel peripheral sampling site model to simulate arm vein drug concentrations that can be applied to different drug dosing scenarios.

Does Circadian Rhythm Affect the Pharmacokinetics of Once-Daily Tobramycin in Adults With Cystic Fibrosis?

BACKGROUND: In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of the time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated. METHODS: In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 hours. Pharmacokinetic and kidney function parameters were compared between the 2 groups. RESULTS: Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 versus 1.43 mL/h*kg (P = 0.50) and mean volumes of distribution were 0.25 versus 0.27 L/kg (P = 0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group, indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 versus 0.2 mmol/L, P = 0.015). CONCLUSIONS: The time of administration (8:00 versus 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

Intravenous Cetirizine Versus Intravenous Diphenhydramine for the Treatment of Acute Urticaria: A Phase III Randomized Controlled Noninferiority Trial.

STUDY OBJECTIVE: Acute urticaria is a frequent presentation in emergency departments (EDs), urgent care centers, and other clinical arenas. Treatment options are limited if diphenhydramine is the only intravenous antihistamine offered because of its short duration of action and well-known adverse effects. We evaluate cetirizine injection, the first second-generation injectable antihistamine, for acute urticaria in this multicenter, randomized, noninferiority, phase 3 clinical trial. METHODS: Adult patients presenting to EDs and urgent care centers with acute urticaria requiring an intravenous antihistamine were randomized to either intravenous cetirizine 10 mg or intravenous diphenhydramine 50 mg. The primary endpoint was the 2-hour pruritus score change from baseline, with time spent in treatment center and rate of return to treatment centers as key secondary endpoints. Frequency of sedation and anticholinergic adverse effects were also recorded. RESULTS: Among 262 enrolled patients, the 2-hour pruritus score change from baseline for intravenous cetirizine was statistically noninferior to that for intravenous diphenhydramine (-1.6 versus -1.5; 95% confidence interval -0.1 to 0.3), and in favor of cetirizine. Treatment differences also favored cetirizine for mean time spent in treatment center (1.7 versus 2.1 hours; P=.005), return to treatment center (5.5% versus 14.1%; P=.02), lower change from baseline sedation score at 2 hours (0.1 versus 0.5; P=.03), and adverse event rate (3.9% versus 13.3%). CONCLUSION: Intravenous cetirizine is an effective alternative to intravenous diphenhydramine for treating acute urticaria, with benefits of less sedation, fewer adverse events, shorter time spent in treatment center, and lower rates of revisit to treatment center.

Iodinated contrast medium: Is there a re(n)al problem? A clinical vignette-based review.

As we were taught, for decades, that iodinated contrast-induced acute kidney injury should be dreaded, considerable efforts were made to find out effective measures in mitigating the renal risk of iodinated contrast media. Imaging procedures were frequently either downgraded (unenhanced imaging) or deferred as clinicians felt that the renal risk pertaining to contrast administration outweighed the benefits of an enhanced imaging. However, could we have missed the point? Among the abundant literature about iodinated contrast-associated acute kidney injury, recent meaningful advances may help sort out facts from false beliefs. Hence, there is increasing evidence that the nephrotoxicity directly attributable to modern iodinated CM has been exaggerated. Failure to demonstrate a clear benefit from most of the tested prophylactic measures might be an indirect consequence. However, the toxic potential of iodinated contrast media is well established experimentally and should not be overlooked completely when making clinical decisions. We herein review these advances in disease and pathophysiologic understanding and the associated clinical crossroads through a typical case vignette in the critical care setting.

Prehospital administration of tranexamic acid in trauma patients: A 1:1 matched comparative study from a level 1 trauma center.

PURPOSE: The purpose of this study was to test the efficacy of prehospital administration of tranexamic acid (TXA) to injured patients on mortality, thromboembolic events and need for blood transfusion in a level 1 trauma center. METHODS: We conducted a retrospective study comparing adult trauma patients receiving or not receiving prehospital TXA between January 2017 and September 2018. Patients not receiving TXA but transfused within 4 h of admission were 1:1 matched to TXA-treated patients for age, sex, injury severity score, head abbreviated injury score, prehospital heart rate and systolic blood pressure. RESULTS: In total 204 patients were included (102 TXA and 102 control), with a mean age of 31 years. On admission, shock index (p = 0.03) and serum lactate (p = 0.001) were greater in the control group, whereas the initial base deficit, hemoglobin levels and EMS time were comparable in both groups. The odd ratio (OR) for shock index ≥0.9 after TXA administration was 0.44 (95% CI 0.23-0.84). The median amount of blood transfusion was greater in the control group [eight units (range 1-40) vs three (range 0-40), p = 0.01] as well as the use of massive blood transfusion [OR 0.35 (95% CI 0.19-0.67)]. In the TXA group, VTE was higher [OR 2.0 (95% CI 0.37-11.40)]; whereas the overall mortality was lower [OR 0.78 (95% CI 0.42-1.45)] without reaching statistical significance. CONCLUSIONS: Prehospital TXA administration is associated with less in-hospital blood transfusion and massive transfusion protocol (MTP). There is no significant increase in the thromboembolic events and mortality, however, further evaluation in larger clinical trials is needed.

Tranexamic acid attenuates inflammatory effect and modulates immune response in primary total knee arthroplasty: a randomized, placebo-controlled, pilot trial.

AIMS: To explore the effect of intravenous tranexamic acid (IV-TXA) on inflammation and immune response following primary total knee arthroplasty (TKA). METHODS: Primary TKA patients (n = 125) were randomized into the following four groups: group A to receive placebo; group B to receive a single dose of 20 mg kg-1 IV-TXA and 20 mg of intravenous dexamethasone (IV-DXM); group C to receive six doses of IV-TXA (total dosage > 6 g); and group D to receive six doses of IV-TXA combined with three doses of IV-DXM (total dosage = 40 mg). The primary outcomes were C-reactive protein (CRP) and interleukin (IL)-6 levels and the secondary outcomes were complement C3 and C4 and T-cell subset levels, which were measured preoperatively and at 24 h, 48 h, 72 h, and 2 weeks postoperatively. RESULTS: The postoperative peak CRP and IL-6 levels in group C (93.7 ± 22.2 mg L-1, 108.8 ± 41.7 pg mL-1) were lower compared with those in group A (134.7 ± 28.8 mg L-1, P < 0.01; 161.6 ± 64.4 pg mL-1, P < 0.01). Groups B and D exhibited significantly lower CRP and IL-6 levels compared with groups A and C at 24 h, 48 h, and 72 h postoperatively (P < 0.05 for all). In group C, complement C3 and C4 levels were higher compared with those in group A at 48 h (0.967 ± 0.127 g L-1 vs. 0.792 ± 0.100 g L-1, P < 0.01; 0.221 ± 0.046 g L-1 vs. 0.167 ± 0.028 g L-1, P < 0.01) and 72 h (1.050 ± 0.181 g L-1 vs. 0.860 ± 0.126 g L-1, P = 0.01; 0.240 ± 0.052 g L-1 vs. 0.182 ± 0.036 g L-1, P < 0.01) postoperatively and CD3 and CD4 subset levels were higher compared with those in group B at 24 h postoperatively (66.78 ± 9.29% vs. 56.10 ± 12.47%, P < 0.05; 36.69 ± 5.78% vs. 28.39 ± 8.89%, P < 0.05). CONCLUSION: Six doses of IV-TXA could attenuate the inflammatory effect, modulate the immune response, and reduce immunosuppression caused by DXM in patients after TKA.

2018 Infectious Diseases Society of America Clinical Practice Guideline for the Management of Outpatient Parenteral Antimicrobial Therapy.

A panel of experts was convened by the Infectious Diseases Society of America to update the 2004 clinical practice guideline on outpatient parenteral antimicrobial therapy (OPAT) [1]. This guideline is intended to provide insight for healthcare professionals who prescribe and oversee the provision of OPAT. It considers various patient features, infusion catheter issues, monitoring questions, and antimicrobial stewardship concerns. It does not offer recommendations on the treatment of specific infections. The reader is referred to disease- or organism-specific guidelines for such support.