Angela Jerath

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 24u2003h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High‐dose tranexamic acid involved a bolus of 30u2003mg.kg−1 infused over 15u2003min followed by a 16u2003mg.kg−1.h−1 infusion until chest closure with a 2u2003mg.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.

Tranexamic acid: a clinical review

Blood loss and subsequent transfusions are associated with major morbidity and mortality. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, liver surgery and solid organ transplantation, obstetrics and gynecology, neurosurgery and non-surgical diseases. The evidence of their efficacy has been mounting for years. Tranexamic acid (TXA), a synthetic lysine-analogue antifibrinolytic, was first patented in 1957 and its use has been increasing in contrast to aprotinin, a serine protease inhibitor antifibrinolytic. This review aims to help acute care physicians navigate through the clinical evidence available for TXA therapy, develop appropriate dose regimens whilst minimizing harm, as well as understand its broadening scope of applications. Many questions remain unanswered regarding other clinical effects of TXA such as anti-inflammatory response to cardiopulmonary bypass, the risk of thromboembolic events, adverse neurological effects such as seizures, and its morbidity and mortality, all of which necessitate further clinical trials on its usage and safety in various clinical settings.

An interactive online 3D model of the heart assists in learning standard transesophageal echocardiography views

PurposeTransesophageal echocardiography (TEE) is becoming a standard imaging tool during cardiac surgery as well as an important diagnostic tool in cardiology and in intensive care, resulting in an increasing demand for TEE training. To address the problem of limited time for learning during TEE studies, we have developed a novel online application that allows users to visualize each of the 20 standard diagnostic TEE views in conjunction with a three-dimensional (3D) heart model that can be rotated and “cut away” above the echo plane to reveal the internal cardiac structures. This study is an evaluation of the educational benefit of this application.MethodsThe application was evaluated using a pre-test/post-test design assessing the improvement of subjects’ test scores following three days of access to the application. The subjects were postgraduate fellows in anesthesia, cardiology, and cardiac surgery.ResultsTen subjects showed a significant increase (31%) in their test scores after an average of 130xa0min of access to the application over a three-day period (Pxa0<xa00.001, effect sizexa0=xa01.9). Using five-point Likert scales, the users indicated that the application was a useful addition to their training (4.7), they would recommend the application to their colleagues (4.9), and they found the application easy to use (4.4).ConclusionThe large improvement in test scores during a short period of study and the high level of satisfaction across all of the disciplines indicates that the application is a useful adjunctive tool for learning TEE. It is now being used in TEE training worldwide.RésuméObjectifxa0L’échocardiographie transœsophagienne (ÉTO) est en passe de devenir un outil d’imagerie standard pendant la chirurgie cardiaque ainsi qu’un outil diagnostique important en cardiologie et aux soins intensifs. Par conséquent, la demande de formation en ÉTO augmente. Afin de pallier le problème du manque de temps d’apprentissage pendant les examens d’ÉTO, nous avons mis au point une nouvelle application en ligne qui permet aux utilisateurs de visionner chacune des 20 coupes diagnostiques standard de l’ÉTO en conjonction à un modèle de cœur tridimensionnel (3D) qui peut être tourné etxa0«xa0découpéxa0»xa0au-dessus de la coupe échocardiographique pour révéler les structures internes du cœur. Notre étude a évalué les avantages éducationnels de cette application.Méthodexa0L’application a été évaluée à l’aide d’une méthode de test avant / après examinant l’amélioration des notes des sujets à l’examen après avoir eu accès à l’application pendant trois jours. Les participants à l’étude étaient des stagaires post-universitaires en anesthésie, en cardiologie et en chirurgie cardiaque.Résultatsxa0On a observé une augmentation significative (31xa0%) des notes à l’examen chez 10 participants après qu’ils eurent passé une moyenne de 130 minutes à accéder à l’application sur une période de trois jours (Pxa0<xa00,001, taille de l’effetxa0=xa01,9). À l’aide d’une échelle de Likert en cinq points, les utilisateurs ont indiqué que l’application était un ajout utile à leur formation (4,7), qu’ils recommanderaient l’application à leurs collègues (4,9), et qu’ils ont trouvé que l’application était facile à utiliser (4,4).Conclusionxa0L’amélioration considérable des notes à l’examen en l’espace d’une courte période d’étude et le niveau élevé de satisfaction, indépendamment de la spécialité, indiquent que l’application est un outil supplémentaire utile pour apprendre l’ÉTO. Il est désormais utilisé dans la formation en ÉTO partout dans le monde.

Volatile-based Short-term Sedation in Cardiac Surgical Patients: A Prospective Randomized Controlled Trial

Objective: To evaluate the differences in extubation times in a group of cardiac surgical patients who were anesthetized and sedated with either IV propofol or inhaled volatile anesthetic agents. Design: This was a prospective randomized controlled trial performed between September 2009 and August 2011. Setting: Cardiovascular ICU within a tertiary referral university-affiliated teaching hospital. Patients: One hundred forty-one patients undergoing coronary artery bypass graft surgery with normal or mildly reduced left ventricular systolic function. Intervention: Participants were randomly assigned to receive anesthesia and postoperative sedation using IV propofol (n = 74) or inhaled volatile (isoflurane or sevoflurane) anesthetic agent (n = 67). Measurements and Main Results: Patients sedated using inhaled volatile agent displayed faster readiness to extubation time at 135 minutes (95–200 min) compared with those receiving IV propofol at 215 minutes (150–280 min) (p < 0.001). Extubation times were faster within the volatile group at 182 minutes (140–255 min) in comparison with propofol group at 291 minutes (210–420 min) (p < 0.001). The volatile group showed a higher prevalence of vasodilatation with hypotension and higher cardiac outputs necessitating greater use of vasoconstrictors. There was no difference in postoperative pain scores, opioid consumption, sedation score, ICU or hospital length of stay, or patient mortality. Conclusions: Inhaled volatile anesthesia and sedation facilitates faster extubation times in comparison with IV propofol for patient undergoing coronary artery bypass graft surgery.

The scavenging of volatile anesthetic agents in the cardiovascular intensive care unit environment: a technical report

PurposeThe use of volatile-based sedation within critical care environments has been limited by difficulties of drug administration and safety concerns over environment pollution and staff exposure in an intensive care unit (ICU) with no scavenging. The aim of this study was to develop a simple scavenging system to be used with the Anesthesia Conserving Device (AnaConDa®) and to determine whether or not ambient concentrations of residual anesthetic are within current acceptable limits.Technical featuresThe scavenging system consists of two Deltasorb® canisters attached to the ICU ventilator in series. AnaConDa is a miniature vaporizer designed to provide volatile-based sedation within an ICU. The first ten patients recruited into a larger randomized trial assessing outcomes after elective coronary graft bypass surgery were sedated within the cardiac ICU using either isoflurane or sevoflurane. Sedation was guided by the Sedation Agitation Scale, resulting in an end-tidal minimum anesthetic concentration of volatile agent ranging from 0.1-0.3. At one hour post ICU admission, infrared photometric analysis was used to assess environmental contamination at four points along the ventilator circuit and scavenging system and around the patient’s head. All measurements taken within the patient’s room were below 1 part per million, which satisfies criteria for occupational exposure.ConclusionsThis study shows that volatile agents can be administered safely within critical care settings using a simple scavenging system. Our scavenging system used in conjunction with the AnaConDa device reduced the concentration of environmental contamination to a level that is acceptable to Canadian standards and standards in most Western countries and thus conforms to international safety standards. The related clinical trial was registered at www.clinicaltrials.gov (NCT01151254).RésuméObjectifL’utilisation de sédation aux agents volatils dans les environnements de soins critiques a été limitée par les difficultés d’administration du médicament et des inquiétudes quant à la sécurité en matière de pollution de l’environnement et d’exposition du personnel dans une unité de soins intensifs (USI) sans système de récupération. L’objectif de cette étude était de mettre au point un système de récupération simple qui pourrait être utilisé avec le Dispositif de conservation de l’anesthésie (AnaConDa®) et de déterminer si oui ou non les concentrations ambiantes d’anesthésique résiduel se situaient dans des limites actuellement acceptables.Éléments techniquesLe système de récupération est composé de deux réservoirs Deltasorb® attachés en série au ventilateur de l’USI. L’AnaConDa est un vaporisateur miniature conçu pour fournir une sédation à base d’agents volatils dans une USI. Les dix premiers patients recrutés dans une étude randomisée de plus grande envergure évaluant les devenirs après une chirurgie de pontage aorto-coronarien non urgente ont été mis sous sédation dans l’USI cardiaque avec de l’isoflurane ou du sévoflurane. La sédation a été réalisée selon l’Échelle d’agitation pendant la sédation, avec pour résultat une concentration télé-expiratoire minimum d’agent volatil se situant entre 0,1 et 0,3. Une heure aprèsxa0l’admission à l’USI, une analyse photométrique infrarouge a été réalisée pour évaluer la contamination environnementale à quatre endroits le long du circuit du ventilateur et du système de récupération ainsi qu’autour de la tête du patient. Toutes les mesures prises dans la chambre du patient étaient au dessous de 1 partie par million (ppm), ce qui est conforme aux critères d’exposition professionnelle.ConclusionCette étude démontre que les agents volatils peuvent être administrés de façon sécuritaire dans un cadre de soins critiques grâce à un simple système de récupération. Notre système de récupération, utilisé en conjonction avec le dispositif AnaConDa, a réduit la concentration de contamination environnementale à un niveau acceptable selon les normes canadiennes et les normes de la plupart des pays occidentaux; ainsi, la concentration est conforme aux normes internationales de sécurité. L’étude clinique liée a été enregistrée au www.clinicaltrials.gov (NCT01151254).

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.

Use of a novel technique, solid phase microextraction, to measure tranexamic acid in patients undergoing cardiac surgery.

PurposeSolid phase microextraction (SPME) is a technique widely used and accepted in the field of food technology and in environmental and biological analyses. Despite its numerous advantages over older analytical methods, it has not been studied extensively in the medical sciences. Tranexamic acid (TXA) is currently the sole antifibrinolytic agent used during cardiac surgery involving the use of cardiopulmonary bypass (CPB). The current standard method of measuring TXA in plasma is based on plasma protein precipitation (PPP), but this analytical approach is time-consuming and not practical for routine use. The aim of the current study was to compare plasma TXA levels measured with the PPP method vs those acquired with the novel, highly efficient SPME technique. We also investigated the use of automated SPME with the aim of improving the technique so it could be used efficiently for measuring plasma TXA levels.MethodsWith Research Ethics Board approval, we undertook a prospective, investigator-blinded study in ten patients undergoing cardiac surgery with CPB. An initial TXA bolus of 30xa0mg·kg−1 was infused over 15xa0min followed by a 16xa0mg·kg−1·hr−1 infusion until chest closure with a 2xa0mg·kg−1 load in the pump prime. Each blood sample was divided into two portions and assigned a random number to blind the analyzing laboratory. The blood TXA concentration was measured using both PPP and SPME. Agreement between the two tests was analyzed using the Bland-Altman plot.ResultsComparisons of plasma TXA concentrations measured with the two methods (PPP and SPME) showed good agreement. Absolute recovery of TXA for PPP was 64.9-78.2%; its precision, as a percentage of the relative standard deviation (RSD) was < 10% [with the exception of the lower limit of quantification (LLOQ), where the RSD was 18%]; and its accuracy, as the bias against the nominal concentration, was < 7% (for LLOQ it was 15%). Thus, extraction with SPME compared favourably with the PPP technique.ConclusionsSolid phase microextraction is a relatively simple, rapid extraction technique that can facilitate future pharmacokinetic studies analyzing TXA drug concentrations and drug dosing in various clinical settings.RésuméObjectifLa microextraction en phase solide (SPME) est une technique largement utilisée et acceptée dans les domaines de la technologie alimentaire et des analyses environnementales et biologiques. En dépit de ses nombreux avantages par rapport aux méthodes d’analyse plus anciennes, elle n’a pas été étudiée de façon approfondie dans le cadre des sciences médicales. L’acide tranexamique (TXA) est actuellement le seul antifibrinolytique utilisé au cours de la chirurgie cardiaque impliquant l’utilisation d’une circulation extracorporelle (CEC). La méthode de référence actuelle du dosage de la TXA plasmatique repose sur la précipitation des protéines plasmatiques (PPP), mais cette approche analytique prend du temps et n’est pas adaptée à une utilisation en routine. Le but de la présente étude était de comparer les niveaux plasmatiques de TXA dosés par la méthode PPP à ceux obtenus avec la nouvelle technique, très efficace, de SPME. Nous nous sommes également intéressés à l’utilisation de la SPME automatisée dans le but d’améliorer la technique afin de pouvoir l’utiliser efficacement pour le dosage de la TXA plasmatique.MéthodeNous avons entrepris, avec l’accord du Comité d’éthique de la recherche, une étude prospective à l’insu de l’investigateur chez dix patients subissant une chirurgie cardiaque avec CEC. Un bolus initial de 30xa0mg·kg−1 a été perfusé en 15xa0min suivi d’une perfusion de 16xa0mg·kg−1·h−1 jusqu’à la fermeture de la paroi thoracique avec une dose de charge de 2xa0mg·kg−1 dans l’amorçage de la pompe. Chaque échantillon de sang a été divisé en deux spécimens auxquels ont été attribués un numéro aléatoire pour assurer l’insu du laboratoire d’analyse. La concentration sanguine de TXA a été dosée par les deux méthodes de PPP et de SPME. La correspondance entre les deux tests a été analysée par la méthode de Bland-Altman.RésultatsLa comparaison des concentrations plasmatiques de TXA dosées par les deux méthodes (PPP et SPME) a fait apparaître une concordance satisfaisante. Le taux de récupération absolue de la TXA par la méthode PPP a été compris entre 64,9xa0% et 78,2 %; sa précision, exprimée en pourcentage de l’écart-type relatif (ETR), était <xa010xa0% (à l’exception du seuil de détection [LLOQ] pour lequel l’ETR était de 18xa0%); et son exactitude, exprimée par l’écart par rapport à la concentration nominale, était < 7xa0% (15xa0% pour le LLOQ). Ainsi, la technique d’extraction par SPME se comparait favorablement à la technique PPP.ConclusionsLa microextraction en phase solide est une technique d’extraction relativement simple et rapide susceptible de faciliter les études pharmacocinétiques futures analysant les concentrations de TXA et sa posologie dans différents contextes cliniques.

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

Early versus late tracheostomy in cardiovascular intensive care patients

BACKGROUNDnBenefits of tracheostomy have been well established. Most of the literature, refers these benefits to general intensive care population, excluding cardiac surgery or including only small number of these patients. On the other hand, there is no clear definition describing the proper time to perform the procedure and defining what are potential benefits of early compared to late tracheostomy. This retrospective cohort aims to assess the potential benefits of early tracheostomy on post-operative outcomes, length of stay and post-tracheostomy complications within cardiac surgical population.nnnMETHODSnAfter obtaining REB approval, we conducted a retrospective chart review in a single, tertiary care institution, identifying patients who underwent tracheostomy after cardiac surgery from 1999 to 2006. Time-to-tracheostomy was defined as early if < 7 days or late if ≥ 7 days post-cardiac surgery).nnnRESULTSn14,101 patients underwent cardiac surgery over the 7-year study period; from those, 147 (1.36%) received tracheostomy. 32 (22%) patients underwent early tracheostomy and 115 (78%) late tracheostomy. Incidence of atrial fibrillation (31.2% vs 61.7%; P = 0.003), kidney dysfunction (6.3% vs 27.2%; P=0.015) and kidney failure 18.8% vs 43.5%; P = 0.013) were lower in the early tracheostomy group. There were no differences on post tracheostomy infection or presence of acute respiratory distress syndrome. Both the ICU and hospital length of stay were significantly shorter in early tracheostomy group, 21.5 (ET) vs 36.9 (LT) days and 37.5 (ET) vs 57.6 (LT) days respectively. There were no differences in mortality between groups.nnnCONCLUSIONSnThere are significant benefits in reduction of postoperative morbidities with overall shorter ICU and hospital stay. These benefits may promote faster patient rehabilitation with reduced healthcare costs.

Left and Right Ventricles 3D Imaging

Quantitative assessment of LV systolic function includes estimates of stroke volume (SV) and ejection fraction (EF) by M-mode (FS), 2D (FAC and Simpson’s), and Doppler echocardiography. Accurate volume calculations using TEE are difficult as assumptions are made about symmetric LV shape and uniform global function. Load conditions may affect indices of systolic function. Technical limitations include inadequate endocardial border definition and avoidance of LV foreshortening.