Marcin Wąsowicz

Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass

We conducted a study to assess pharmacokinetics of high‐dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High‐dose tranexamic acid involved a bolus of 30 mg.kg−1 infused over 15 min followed by a 16 mg.kg−1.h−1 infusion until chest closure with a 2 mg.kg−1 load within the pump prime. Tranexamic acid followed first‐order kinetics best described using a two‐compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra‐operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high‐dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high‐risk cardiac surgery needs to be refined.

Application of solid phase microextraction for quantitation of polyunsaturated fatty acids in biological fluids.

Development of a straightforward strategy for simultaneous quantitative analysis of nonesterified fatty acids (NEFA) species in biofluids is a challenging task because of the extreme complexity of fatty acid distribution in biological matrices. In this study, we present a direct immersion solid phase microextraction method coupled to a liquid chromatography-mass spectrometry platform (DI-SPME- HPLC-ESI -MS) for determination of unconjugated fatty acids (FA) in fish and human plasma. The proposed method was fully validated according to bioanalytical method validation guidelines. The LOD and LOQ were in the range of 0.5-2 and 5-12 ng/mL, respectively, with a linear dynamic range of 100 fold for each compound. Absolute and relative matrix effects were comprehensively evaluated and found to be in the acceptable range of 91-116%. The affinity constant (Ka) of individual FAs to protein albumin was determined to be 9.2 × 10(4) to 4.3 × 10(5) M(-1). The plasma protein binding (PPB%) was calculated and found to be in the range of 98.0-99.7% for different polyunsaturated fatty acids (PUFAs). The PUFAs under study were found at a high concentration range in fish plasma, whereas only a few were within quantification range in control human plasma. The method was successfully applied for monitoring PUFA changes during the operation in plasma samples obtained from patients undergoing cardiac surgery with the use of cardiopulmonary bypass (CPB). The most significant contribution induced by surgery was noticed in the concentration level of α-linolenic acid (18:3, ALA), arachidonic acid (20:4, AA), and docosahexanoic acid (22:6, DHA) soon after administration of CPB in all cases.

Early Complications and Immediate Postoperative Outcomes of Paravalvular Leaks After Valve Replacement Surgery

OBJECTIVES To evaluate the incidence of perivalvular leaks (PVLs) after valve replacement and assess its impact on immediate postoperative outcomes. DESIGN A retrospective review. SETTINGS A tertiary care university hospital. PARTICIPANTS Four hundred forty-two consecutive patients undergoing aortic (AVR) and/or mitral (MVR) valve replacement. MEASUREMENTS AND MAIN RESULTS All patients had comprehensive intraoperative transesophageal echocardiography. Follow-up transthoracic echocardiography was performed at 5 to 7 days and 1 year after surgery. PVLs were classified as trace, mild, moderate, and severe. Perioperative variables including demographic data, surgical characteristics including the degree of valve calcification, and postoperative outcomes were compared between patients with and without PVLs. Multivariate logistic regression analysis was used to identify the variables predictive of PVLs. PVLs were identified in a total of 53 (12%) patients, 29 (13%) after MVR and 24 (11%) after AVR. At the 1-year transthoracic echocardiographic follow-up, 2 (7%) of 27 patients had residual PVLs after MVR and none after AVR. The duration of cardiopulmonary bypass (CPB) was predictive of PVLs. The presence of PVLs was associated with postoperative sepsis. CONCLUSIONS The incidence of PVLs was similar after MVR and AVR. Bioprosthetic MVR and mechanical AVR were associated with higher-incidence PVLs when compared with controls. Mitral annular calcification was a potential risk factor for PVLs with bioprosthetic valves. The prolonged CPB time was predictive of PVLs. After adjusting for covariates, the overall presence of PVLs was associated with an increased risk of sepsis after surgery.

Development of SPME method for concomitant sample preparation of rocuronium bromide and tranexamic acid in plasma

A high-throughput method using solid-phase microextraction coupled to liquid chromatography-tandem mass spectrometry (SPME-LC-MS/MS) for determination of tranexamic acid and rocuronium bromide in human plasma was developed and validated. Standard analytical approaches employ acidification of the sample due to the instability of rocuronium bromide in collected plasma samples. However, acidification affects the binding equilibrium of the drug and consequently no information on the free/bound concentration can be obtained. Contrary to these protocols, the proposed method requires minimum sample handling and no ion pairing and/or derivatization procedure. A weak cation exchange coating was chosen as the best extracting phase for selected drugs, guaranteed a good recovery, minimum carry-over, reusability and reproducibility. SPME procedure met all Food and Drug Administration acceptance criteria for bioanalytical assays at three concentration levels, for both selected drugs. Post-extraction addition experiments showed that matrix effect was less than ±3%. Here, a weak cation exchange thin-film solid-phase microextraction (WCX TF-SPME) approach is presented, offering effective cleanup procedure and full quantitation of the drugs in plasma, undoubtedly one the most challenging matrices with regards to its complexity. In addition, the 96-well plate format of WCX TF-SPME system provides considerable advantages, such as high throughput analysis for up to 96 samples in 35min (22s/sample), requirement of small amounts of plasma samples (0.8mL), and a simple sample preparation protocol, all of which shows a promise for possible on-site application in hospitals to monitor concentrations of the drugs in close to real time.

The Utility of Thromboelastography for Guiding Recombinant Activated Factor VII Therapy for Refractory Hemorrhage After Cardiac Surgery

OBJECTIVE Recombinant activated factor VII (rFVIIa) is being increasingly used in cardiac surgical patients with refractory hemorrhage. In this study, the authors assessed the ability of thromboelastography (TEG) in guiding rFVIIa therapy in this setting. DESIGN Retrospective study. SETTING Tertiary care university hospital. PARTICIPANTS Thirty-eight consecutive patients who received rFVIIa for refractory hemorrhage after cardiac surgery and had a complete coagulation profile including TEG within 30 minutes before and after rFVIIa. INTERVENTIONS Standard coagulation (prothrombin time, partial thromboplastin time, platelet number, and fibrinogen) and TEG measurements (r time, k time, alpha angle, and maximum amplitude) before and after rFVIIa therapy were compared between responders and nonresponders (determined retrospectively based on clinical records). MEASUREMENTS AND RESULTS Twenty-eight patients (74%) were classified as responders. There were no consistent changes in standard coagulation and TEG measurements before and after rFVIIa therapy. The number of abnormalities in pretreatment coagulation tests was related to response rates; odds of response were 11-fold (95% confidence interval [CI]) and 33-fold (95% CI) greater among patients with 0 or 1 abnormality in standard coagulation tests and TEG measures, respectively, than those with 2 or more abnormalities. CONCLUSIONS TEG may be a useful tool for predicting response to rFVIIa in the setting of refractory hemorrhage after cardiac surgery.

Pharmacokinetic modeling of tranexamic acid for patients undergoing cardiac surgery with normal renal function and model simulations for patients with renal impairment

Tranexamic acid (TXA), an effective anti‐fibrinolytic agent that is cleared by glomerular filtration, is used widely for cardiopulmonary bypass (CPB) surgery. However, an effective dosing regimen has not been fully developed in patients with renal impairment. The aims of this study were to characterize the inter‐patient variability associated with pharmacokinetic parameters and to recommend a new dosing adjustment based on the BART dosing regimen for CPB patients with chronic renal dysfunction (CRD). Recently published data on CPB patients with normal renal function (n = 15) were re‐examined with a two‐compartment model using the ADAPT5® and NONMEMVII® to identify covariates that explain inter‐patient variability and to ascertain whether sampling strategies might affect parameter estimation. A series of simulations was performed to adjust the BART dosing regimen for CPB patients with renal impairment. Based on the two‐compartmental model, the number of samples obtained after discontinuation of TXA infusion was found not to be critical in parameter estimation (p > 0.05). Both body weight and creatinine clearance were identified as significant covariates (p < 0.005). Simulations showed significantly higher than normal TXA concentrations in CRD patients who received the standard dosing regimen in the BART trial. Adjustment of the maintenance infusion rate based on the percent reduction in renal clearance resulted in predicted plasma TXA concentrations that were safe and therapeutic (~100 mg·L−1). Our proposed dosing regimen, with consideration of renal function, is predicted to maintain effective target plasma concentrations below those associated with toxicity for patients with renal failure for CPB. Copyright

Technology III: in-line vaporizer with reflector

As the clinical advantages of vapor anesthesia (VA) for sedation of patients in ICU become more apparent, the ergonomics, economy and safety issues need to be better addressed. Here we describe the use of a new commercial digital in-line anesthetic vaporizer that can be attached to the inspiratory limb of a ventilator. If used with a simple, and easily assembled secondary circuit and anesthetic reflector, the circuit remains remote from the patient, the VA consumption approaches a physical minimum, VA level is controlled and monitored, and the tidal volume size is not limited.

High volatile anaesthetic conservation with a digital in-line vaporizer and a reflector

A volatile anaesthetic (VA) reflector can reduce VA consumption (VAC) at the cost of fine control of its delivery and CO2 accumulation. A digital in‐line vaporizer and a second CO2 absorber circumvent both of these limitations. We hypothesized that the combination of a VA reflector with an in‐line vaporizer would yield substantial VA conservation, independent of fresh gas flow (FGF) in a circle circuit, and provide fine control of inspired VA concentrations.

A Case Report of Paradoxical Air Embolism Caused by Intrapulmonary Shunting During Liver Transplantation

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Comparing Early Liver Graft Function From Heart Beating and Living-Donors: A Pilot Study Aiming to Identify New Biomarkers of Liver Injury

The liver and kidney functions of recipients of liver transplantation (LT) surgery with heart beating (HBD, n = 13) or living donors (LD, n = 9) with different cold ischemia times were examined during the neohepatic phase for the elimination of rocuronium bromide (ROC, cleared by liver and kidney) and tranexamic acid (TXA, cleared by kidney). Solid phase micro‐extraction and LC–MS/MS was applied to determine the plasma concentrations of ROC and TXA, and creatinine was determined by standard laboratory methods. Metabolomics and the relative expressions of miR‐122, miR‐148a and γ‐glutamyltranspeptidase (GGT), liver injury biomarkers, were also measured. The ROC clearance for HBD was significantly lower than that for LD (0.147 ± 0.052 vs. 0.265 ± 0.148 ml·min−1·g−1 liver) after intravenous injection (0.6 mg·kg−1). The clearance of TXA, a compound cleared by glomerular filtration, given as a 1 g bolus followed by infusion (10 mg·kg−1·h−1), was similar between HBD and LD groups (~ 1 ml·min−1·kg−1). The TXA clearance in both groups was lower than the GFR, showing a small extent of hepatorenal coupling. The miR‐122 and miR‐148a expressions were similar for the HBD and LD groups, whereas GGT expression was significantly increased for HBD. The lower ROC clearance and the higher GGT levels in the HBD group of longer cold ischemia times performed worse than the LD group during the neophase. Metabololmics further showed clusters of bile acids, phospholipids and lipid ω‐oxidation products for the LD and HBD groups. In conclusion, ROC CL and GGT expression, and metabolomics could serve as sensitive indices of early graft function. Copyright