Untargeted metabolomics profiling of skeletal muscle samples from malignant hyperthermia susceptible patients.

PURPOSE: Malignant hyperthermia (MH) is a potentially fatal hypermetabolic condition triggered by certain anesthetics and caused by defective calcium homeostasis in skeletal muscle cells. Recent evidence has revealed impairment of various biochemical pathways in MH-susceptible patients in the absence of anesthetics. We hypothesized that clinical differences between MH-susceptible and control individuals are reflected in measurable differences in myoplasmic metabolites. METHODS: We performed metabolomic profiling of skeletal muscle samples from MH-negative (control) individuals and MH-susceptible patients undergoing muscle biopsy for diagnosis of MH susceptibility. Cellular metabolites were extracted from 33 fresh and 87 frozen human muscle samples using solid phase microextraction and Metabolon® untargeted biochemical profiling platforms, respectively. Ultra-performance liquid chromatography-high resolution mass spectrometry was used for metabolite identification and validation, followed by analysis of differences in metabolites between the MH-susceptible and MH-negative groups. RESULTS: Significant fold-change differences between the MH-susceptible and control groups in metabolites from various pathways were found (P value range: 0.009 to < 0.001). These included accumulation of long chain acylcarnitines, diacylglycerols, phosphoenolpyruvate, histidine pathway metabolites, lysophosphatidylcholine, oxidative stress markers, and phosphoinositols, as well as decreased levels of monoacylglycerols. The results from both analytical platforms were in agreement. CONCLUSION: This metabolomics study indicates a shift from utilization of carbohydrates towards lipids for energy production in MH-susceptible individuals. This shift may result in inefficiency of beta-oxidation, and increased muscle protein turnover, oxidative stress, and/or lysophosphatidylcholine levels.

RéSUMé: OBJECTIF : L'hyperthermie maligne (HM) est une condition hypermétabolique potentiellement mortelle déclenchée par certains agents anesthésiques et causée par une homéostasie calcique perturbée des cellules musculaires squelettiques. Des données probantes récentes ont mis en lumière une atteinte de diverses voies biochimiques chez les patients susceptibles à l'HM en l'absence d'anesthésiques. Nous avons émis l'hypothèse que les différences cliniques entre les individus susceptibles à l'HM et des témoins se refléteraient dans des différences mesurables de métabolites myoplasmiques. MéTHODE : Nous avons réalisé un profilage métabolomique d'échantillons de muscles squelettiques provenant de personnes négatives à l'HM (témoins) et de patients susceptibles à l'HM subissant une biopsie musculaire dans le but de poser un diagnostic de susceptibilité à l'HM. Les métabolites cellulaires ont été extraits de 33 échantillons de muscles humains frais et de 87 échantillons congelés à l'aide d'une microextraction en phase solide et des plateformes de profilage biochimique non ciblées Metabolon®, respectivement. La chromatographie en phase liquide à haute performance et la spectrométrie de masse à haute résolution ont été utilisées pour l'identification et la validation des métabolites, puis suivies d'une analyse des différences dans les métabolites entre les groupes susceptibles à l'HM et les groupes négatifs à l'HM. RéSULTATS : Des différences significatives ont été observées entre les groupes susceptibles à l'HM et les groupes témoins dans les métabolites issus de diverses voies (P : de 0,009 à < 0,001). Ces différences comprenaient l'accumulation d'acylcarnitines à longue chaîne, de diacylglycérols, de phosphoénolpyruvate, de métabolites de la voie d'histidine, de lysophosphatidylcholine, de marqueurs de stress oxydatif, et de phosphoinositols, aussi bien que des taux réduits de monoacylglycérols. Les résultats des deux plateformes analytiques concordaient. CONCLUSION : Cette étude métabolomique indique un changement de l'utilisation des glucides vers les lipides pour la production d'énergie chez les personnes susceptibles à l'HM. Ce changement pourrait entraîner une inefficacité de la bêta-oxydation, ainsi qu'une augmentation du renouvellement des protéines musculaires, du stress oxydatif, et/ou des taux de lysophosphatidylcholine.

Current Evidence and Future Directions of Tranexamic Acid Use, Efficacy, and Dosing for Major Surgical Procedures.

Tranexamic acid reduces blood loss and transfusion requirements with no significant thrombotic adverse effects. Postoperative seizures have been seen in cardiac surgical patients in association with patient (advanced age, underlying neurologic disease, chronic kidney disease); surgical (open cardiac procedures, long bypass times); and drug (high tranexamic acid dose) risk factors. Tranexamic acid dosing regimens should be decreased in patients with chronic kidney dysfunction secondary to reduced clearance and drug accumulation. Optimal dosing for cardiac surgical patients has been recommended. Additional research is required to determine dosing regimens in major noncardiac surgery and plasma concentration levels associated with inducing seizures.

Intraoperative and Early Postoperative Management of Heart Transplantation: Anesthetic Implications.

The gold standard treatment for end-stage heart failure, with 50% mortality within 5 years of diagnosis, is considered heart transplantation. Despite the improvements in immunosuppression, the period of highest mortality risk in the heart transplantation population is during the first year post-transplantation, with primary graft dysfunction being the leading cause of mortality. After adequate preoperative assessment of the recipient, including patients on mechanical support, the intraoperative care of heart transplantation patients requires extensive monitoring followed by proficient management of anesthesia induction and maintenance, ventilation, and fluid therapy. The focus on weaning from cardiopulmonary bypass should be on preventing right ventricular failure and high pulmonary vascular resistances, with protocolized blood conservation strategies and transfusion protocols. The early postoperative care of a heart transplantation patient is focused on the post-cardiopulmonary bypass and transplantation status, with particular attention to the presence of primary graft dysfunction, right ventricular performance, pulmonary pressures, and vasoplegia. The aim is early extubation, inotropic and chronotropic support weaning, and chest tube removal to facilitate discharge of the patient from the intensive care unit. The increased complexity of heart transplantation recipients, including the incremental use of pre- transplantation mechanical circulatory support and extended criteria donor hearts, requires extensive and sophisticated preparation of the cardiac anesthesiologist. This article aims to provide an overview of the intraoperative and early postoperative anesthesia management of heart transplantation patients.

Recent advances in nonoperating room anesthesia for cardiac procedures.

PURPOSE OF REVIEW: The number of complex procedures performed in the cardiac catheterization laboratory (CCL) is rapidly increasing. Because of their complexity, they frequently require the assistance of an anesthesiologist. The CCL is primarily designed to facilitate a percutaneous cardiac intervention; therefore, it might be a challenging workplace for an anesthesiologist. The aim of this review is to briefly present tasks and challenges of providing anesthesia in the CCL and to provide a concise description of common cardiac procedures performed there. RECENT FINDINGS: Recent literature indicates that many complicated cardiac procedures can be performed in CCL under monitored anesthesia care. At the same time several of them (e.g. transcatheter aortic valve replacement) are quickly becoming a viable alternative for surgical valve replacement. The most recent expansion of CCL procedures is related to rapidly growing population of grown-ups with congenital heart disease. All aforementioned developments present new challenges to an anesthesiologist. SUMMARY: New and fast development of percutaneous cardiac interventions has created a new working place for the anesthesiologist - the CCL. Our expertise in complex cardiac pathophysiology allows conduct of complicated procedures outside of the operating theater. For the same reasons, there is ongoing discussion whether anesthesia support in CCL should be provided by a general or cardiac anesthesiologist.

Intubation outside of the operating room: new challenges and opportunities in COVID-19 era.

PURPOSE OF REVIEW: Airway management in patients outside the operating room is associated with increased difficulties and risks, and the setting of the COVID-19 global pandemic adds another layer of complexity. Therefore, endotracheal intubation (ETT) of a patient who is presumptive COVID-19 or COVID-19 positive presents an additional challenge to an anesthesiologist. The aim of this review is to summarize the important principles of airway management outside of the operating room during the COVID-19 pandemic. RECENT FINDINGS: Several professional societies have formulated guidelines on airway management COVID-19 suspect and proven patients. Additionally, anesthesiologists working in hospitals treating many infected patients have developed specialized teams responsible for airway management outside the operating room. These documents and protocols focus on the importance of wearing personal protective equipment and the skills of the providers responsible for securing the airway. Staff safety is always a priority when performing ETT outside operating room. SUMMARY: The COVID-19 pandemic redefined the management of patients requiring aerosol generating procedures (droplet and airborne precautions). ETT is one of them and anesthesiologists are experts in performing airway management. Although the operating room is a highly controlled environment, airway management outside of this setting is not always the easiest task.

Predictor parameters of liver viability during porcine normothermic ex situ liver perfusion in a model of liver transplantation with marginal grafts.

Normothermic ex situ liver perfusion (NEsLP) offers the opportunity to assess biomarkers of graft function and injury. We investigated NEsLP parameters (biomarkers and markers) for the assessment of liver viability in a porcine transplantation model. Grafts from heart-beating donors (HBD), and from donors with 30 minutes (donation after cardiac death [DCD]30'), 70 minutes (DCD70'), and 120 minutes (DCD120') of warm ischemia were studied. The HBD, DCD30', and DCD70'-groups had 100% survival. In contrast, 70% developed primary nonfunction (PNF) and died in the DCD120'-group. Hepatocellular function during NEsLP showed low lactate (≤1.1 mmol/L) in all the groups except the DCD120'-group (>2 mmol/L) at 4 hours of perfusion (P = .04). The fold-urea increase was significantly lower in the DCD120'-group (≤0.4) compared to the other groups (≥0.65) (P = .01). As for cholangiocyte function, bile/perfusate glucose ratio was significantly lower (<0.6) in all the groups except the DCD120'-group (≥0.9) after 3 hours of perfusion (<0.01). Bile/perfusate Na+ ratio was significantly higher (≥1.2) after 3 hours of perfusion in all the groups except for the DCD120'-group (≤1) (P < .01). Three hours after transplantation, the DCD120'-group had a significantly higher international normalized ratio (>5) compared to the rest of the groups (≤1.9) (P = .02). Rocuronium levels were higher at all the time-points in the animals that developed PNF during NEsLP and after transplantation. This study demonstrates that biomarkers and markers of hepatocellular and cholangiocyte function during NEsLP correlate with the degree of ischemic injury and posttransplant function.

Solid phase microextraction coupled to mass spectrometry via a microfluidic open interface for rapid therapeutic drug monitoring.

Tranexamic acid (TXA) is an antifibrinolytic used during cardiac surgery that presents high inter-patient variability. High plasma concentrations have been associated with post-operative seizures. Due to the difficulties with maintaining acceptable concentrations of TXA during surgery, implementation of a point-of-care strategy for testing TXA plasma concentration would allow for close monitoring of its concentration during administration. This would facilitate timely corrections to the dosing schedule, and in effect tailor treatment for individual patient needs. In this work, a method for the rapid monitoring of TXA from plasma samples was subsequently carried out via biocompatible solid-phase microextraction (Bio-SPME) coupled directly to tandem mass spectrometry via a microfluidic open interface (MOI). MOI operates under the concept of a flow-isolated desorption volume and was designed with aims to directly hyphenate Bio-SPME to different detection and ionization systems. In addition, it allows the desorption of Bio-SPME fibers in small volumes while it concurrently continues feeding the ESI with a constant flow to minimize cross-talking and instabilities. The methodology was used to monitor six patients with varying degrees of renal dysfunction, at different time points during cardiac surgery. MOI proves to be a reliable and feasible tool for rapid therapeutic drug monitoring. Affording total times of analysis as low as 30 seconds per sample in its high throughput mode configuration while the single sample turn-around time was 15 minutes, including sample preparation. In addition, cross-validation against a standard thin film solid phase microextraction using liquid chromatography coupled to tandem mass spectrometry (TFME-LC-MS/MS) method was performed. Bland-Altman analysis was used to cross-validate the results obtained by the two methods. Data analysis demonstrated that 92% of the compared data pairs (n = 63) were distributed within the acceptable range. The data was also validated by the Passing Bablok regression, demonstrating good statistical agreement between these two methods. Finally, the currently presented method offers comparable results to the conventional liquid chromatography with acceptable RSDs, while only necessitating a fraction of the time. In this way, TXA concentration in plasma can be monitored in a close to real time throughput during surgery.

Tranexamic Acid Dosing for Cardiac Surgical Patients With Chronic Renal Dysfunction: A New Dosing Regimen.

BACKGROUND: Tranexamic acid (TXA) is a common antifibrinolytic agent used to minimize bleeding in cardiac surgery. Up to 50% cardiac surgical patients have chronic renal dysfunction (CRD). Optimal dosing of TXA in CRD remains poorly investigated. This is important as TXA is renally eliminated with accumulation in CRD. High TXA doses are associated with postoperative seizures. This study measures plasma TXA concentrations in CRD cardiac surgical patients for pharmacokinetic modeling and dose adjustment recommendations. METHODS: This prospective cohort study enrolled 48 patients with stages 1-5 CRD, classified by Kidney Disease Outcome Quality Initiative. Patients were separated into 2 treatment groups. A "low-risk" group underwent simple aortocoronary bypass or single-valve repair/replacement and received a 50 mg/kg TXA bolus. A "high-risk" group underwent redo, aortic, multiple valve or combination surgery and received the Blood Conservation Using Anti-fibrinolytics Trial dosing regimen (loading dose 30 mg/kg, infusion 16 mg/kg/h with 2 mg/kg in pump prime). Primary outcome identified changes in TXA clearance and distribution volume, which provided the rationale for dose adjustment. Descriptive clinical outcomes assessed postoperative seizures, blood loss, ischemic-thrombotic complications, in-hospital mortality, and length of hospital stay. RESULTS: TXA concentrations were elevated and sustained above the therapeutic threshold for approximately 12 hours in high-risk stages 3-5 groups, in accordance to CRD severity. CONCLUSIONS: Using a pharmacokinetic model, we propose a simple new TXA dosing regimen that optimizes maximal antifibrinolysis and avoids excessive drug dosing.

Safety and Efficacy of Volatile Anesthetic Agents Compared With Standard Intravenous Midazolam/Propofol Sedation in Ventilated Critical Care Patients: A Meta-analysis and Systematic Review of Prospective Trials.

BACKGROUND: Inhalation agents are being used in place of intravenous agents to provide sedation in some intensive care units. We performed a systematic review and meta-analysis of prospective randomized controlled trials, which compared the use of volatile agents versus intravenous midazolam or propofol in critical care units. METHODS: A search was conducted using MEDLINE (1946-2015), EMBASE (1947-2015), Web of Science index (1900-2015), and Cochrane Central Register of Controlled Trials. Eligible studies included randomized controlled trials comparing inhaled volatile (desflurane, sevoflurane, and isoflurane) sedation to intravenous midazolam or propofol. Primary outcome assessed the effect of volatile-based sedation on extubation times (time between discontinuing sedation and tracheal extubation). Secondary outcomes included time to obey verbal commands, proportion of time spent in target sedation, nausea and vomiting, mortality, length of intensive care unit, and length of hospital stay. Heterogeneity was assessed using the I statistic. Outcomes were assessed using a random or fixed-effects model depending on heterogeneity. RESULTS: Eight trials with 523 patients comparing all volatile agents with intravenous midazolam or propofol showed a reduction in extubation times using volatile agents (difference in means, -52.7 minutes; 95% confidence interval [CI], -75.1 to -30.3; P < .00001). Reductions in extubation time were greater when comparing volatiles with midazolam (difference in means, -292.2 minutes; 95% CI, -384.4 to -200.1; P < .00001) than propofol (difference in means, -29.1 minutes; 95% CI, -46.7 to -11.4; P = .001). There was no significant difference in time to obey verbal commands, proportion of time spent in target sedation, adverse events, death, or length of hospital stay. CONCLUSIONS: Volatile-based sedation demonstrates a reduction in time to extubation, with no increase in short-term adverse outcomes. Marked study heterogeneity was present, and the results show marked positive publication bias. However, a reduction in extubation time was still evident after statistical correction of publication bias. Larger clinical trials are needed to further evaluate the role of these agents as sedatives for critically ill patients.

Volatile Anesthetics. Is a New Player Emerging in Critical Care Sedation?

Volatile anesthetic agent use in the intensive care unit, aided by technological advances, has become more accessible to critical care physicians. With increasing concern over adverse patient consequences associated with our current sedation practice, there is growing interest to find non-benzodiazepine-based alternative sedatives. Research has demonstrated that volatile-based sedation may provide superior awakening and extubation times in comparison with current intravenous sedation agents (propofol and benzodiazepines). Volatile agents may possess important end-organ protective properties mediated via cytoprotective and antiinflammatory mechanisms. However, like all sedatives, volatile agents are capable of deeply sedating patients, which can have respiratory depressant effects and reduce patient mobility. This review seeks to critically appraise current volatile use in critical care medicine including current research, technical consideration of their use, contraindications, areas of controversy, and proposed future research topics.

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 © 2017 John Wiley & Sons, Ltd.

Function of the Respiratory System in Elderly Patients After Aortic Valve Replacement.

OBJECTIVE: To compare the function of the respiratory system after aortic valve replacement through median sternotomy (AVR) or the minimally invasive right anterior minithoracotomy (RAT-AVR) approach among elderly (aged≥75 years) patients. DESIGN: Observational cohort study. SETTINGS: University hospital. PARTICIPANTS: The study included 65 elderly patients scheduled for RAT-AVR and 82 for standard AVR. INTERVENTIONS: Pulmonary function tests (PFT) were performed preoperatively, 1 week, 1 month, and 3 months after surgery. In addition, respiratory complications were analyzed. MEASUREMENTS AND MAIN RESULTS: Respiratory complications occurred in 12.3% of patients in the RAT-AVR group and 18.3% of patients in the AVR group (p = 0.445). Mechanical ventilation time in the intensive care unit was 7.7±3.6 hours for RAT-AVR patients and 9.7±5.4 hours for AVR patients (p = 0.003). Most PFT were worse in the AVR group than in the RAT-AVR group when performed 1 week after surgery. After 1 month, forced expiratory volume in the first second, vital capacity, and total lung capacity differed significantly in favor of the RAT-AVR group (p = 0.002, p<0.001, and p = 0.001, respectively). After 3 months, the PFT parameters still had not returned to preoperative values, but the differences were no longer significant between the RAT-AVR and AVR groups. The multivariable median regression analysis demonstrated that RAT-AVR surgery was a key factor in a patient's higher postoperative PFT parameter values. CONCLUSIONS: RAT-AVR surgery resulted in shorter postoperative mechanical ventilation time and improved the recovery of pulmonary function in elderly patients, but it did not reduce the incidence of pulmonary complications when compared with surgery performed through a median sternotomy.

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.

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.

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.