Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults.

BACKGROUND: Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population. METHODS: We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI ≥ 35 kg/m2) and non-obese healthy controls (n = 8, 18.5 ≤ BMI < 30.0 kg/m2). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3. RESULTS: A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0-174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%-98.4%. With increasing total bodyweight, both higher CL and Vd were found. Sex also significantly impacted Vd, being 27% larger in male compared with female participants. CONCLUSIONS: In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed.

The association of polypharmacy with functional decline in elderly patients undergoing cardiac surgery.

AIMS: Identifying preoperative risk factors in older patients becomes more important to reduce adverse functional outcome. This study investigated the association between preoperative medication use and functional decline in elderly cardiac surgery patients and compared polypharmacy as a preoperative screening tool to a clinical frailty assessment. METHODS: This sub-study of the Anaesthesia Geriatric Evaluation study included 518 patients aged ≥70 years undergoing elective cardiac surgery. The primary outcome was functional decline, defined as a worse health-related quality of life or disability 1 year after surgery. The association between polypharmacy (i.e. ≥5 prescriptions and <10 prescriptions) or excessive polypharmacy (i.e. ≥10 prescriptions) and functional decline was investigated using multivariable Poisson regression. Discrimination, calibration and reclassification indices were used to compare preoperative screening tools for patient selection. RESULTS: Functional decline was reported in 284 patients (55%) and preoperative polypharmacy and excessive polypharmacy showed higher risks (adjusted relative risk 1.57, 95% confidence interval [CI] 1.23-1.98 and 1.93, 95% CI 1.48-2.50, respectively). Besides cardiovascular medication, proton-pump inhibitors and central nervous system medication were significantly associated with functional decline. Discrimination between models with polypharmacy or frailty was similar (area under the curve 0.67, 95% CI 0.61-0.72). The net reclassification index improved when including polypharmacy to the basic model (17%, 95% CI 0.06-0.27). CONCLUSION: Polypharmacy is associated with functional decline in elderly cardiac surgery patients. A preoperative medication review is easily performed and could be used as screening tool to identify patients at risk for adverse outcome after cardiac surgery.

Preoperative frailty and chronic pain after cardiac surgery: a prospective observational study.

BACKGROUND: Chronic pain after cardiac surgery, whether or not related to the operation, is common and has negative impact on health related quality of life (HRQL). Frailty is a risk factor for adverse surgical outcomes, but its relationship with chronic pain after cardiac surgery is unknown. This study aimed to address the association between frailty and chronic pain following cardiac surgery. METHODS: This sub-study of the Anesthesia Geriatric Evaluation study included 518 patients ≥ 70 years undergoing elective cardiac surgery. Pain was evaluated with the Short-Form 36 questionnaire prior to and one year after surgery. Associations between chronic postoperative pain and frailty domains, including medication use, nutritional status, mobility, physical functioning, cognition, HRQL, living situation and educational level, were investigated with multivariable regression analysis. RESULTS: Chronic pain one year after cardiac surgery was reported in 182 patients (35%). Medication use, living situation, mobility, gait speed, Nagi's physical functioning and preoperative HRQL were frailty domains associated with chronic pain after surgery. For patients with chronic pain physical HRQL after one year was worse compared to patients without chronic pain (ß -10.37, 99% CI -12.57 - -8.17). CONCLUSIONS: Preoperative polypharmacy, living alone, physical frailty and lower mental HRQL are associated with chronic pain following cardiac surgery. Chronic postoperative pain is related to worse physical HRQL one year after cardiac surgery. These findings may guide future preoperative interventions to reduce chronic pain and poor HRQL after cardiac surgery in older patients. TRIAL REGISTRATION: This trial has been registered before initiation under number NCT02535728 at clinicaltrials.gov.

External Validation of the ACTA-PORT Transfusion Risk Score in Older Cardiac Surgery Patients at Risk of Frailty.

OBJECTIVES: Accurate preoperative transfusion risk stratification may serve to better manage older patients undergoing cardiac surgery. Therefore, the aim of the present study was to externally validate the existing Association of Cardiothoracic Anesthetists perioperative risk of blood transfusion (ACTA-PORT) score in a population ≥70 years of age scheduled for cardiac surgery. Furthermore, the study authors investigated the additional prognostic value of individual frailty variables to this transfusion risk score. DESIGN: A retrospective analysis. SETTING: At a tertiary-care hospital. PARTICIPANTS: Five hundred seven patients aged ≥70 years undergoing elective cardiac surgery from July 2015 to August 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the administration of a perioperative blood transfusion. Frailty domains were assessed in a preanesthesia geriatric assessment, and a priori selection of biomarkers derived from blood was determined. The original ACTA-PORT score resulted in a c-statistic of 0.78 (95% confidence interval 0.74-0.82), with moderate calibration in predicting perioperative allogeneic transfusion in older patients undergoing cardiac surgery. Model updating, using the closed testing procedure, resulted in model revision with a higher discriminatory performance (c-statistic of 0.83, 95% confidence interval 0.79-0.86) and corrected calibration slope. Iron deficiency, impaired nutritional status, and physical impairment were associated with perioperative transfusions. The addition of individual frailty variables to the updated ACTA-PORT model did not result in improved predictive performance. CONCLUSIONS: External validation of the original ACTA-PORT score showed good discrimination and moderate calibration in older patients at risk of frailty undergoing cardiac surgery. Updating the original ACTA-PORT improved the predictive performance. Careful evaluation of additional frailty domains did not add prognostic value to the ACTA-PORT score.

Associations Between Preoperative Biomarkers and Cardiac Surgery-Associated Acute Kidney Injury in Elderly Patients: A Cohort Study.

BACKGROUND: Acute kidney injury (AKI) is associated with mortality after cardiac surgery. Novel risk factors may improve identification of patients at risk for renal injury. The authors evaluated the association between preoperative biomarkers that reflect cardiac, inflammatory, renal, and metabolic disorders and cardiac surgery-associated AKI (CSA-AKI) in elderly patients. METHODS: This was a secondary analysis of the 2-center prospective cohort study "Anesthesia Geriatric Evaluation." Twelve biomarkers were determined preoperatively in 539 patients. Primary outcome was CSA-AKI. The association between biomarkers and CSA-AKI was investigated with multivariable logistic regression analysis. Secondary outcomes were 1-year mortality and patient-reported disability and were assessed with relative risks (RR) between patients with and without CSA-AKI. RESULTS: CSA-AKI occurred in 88 (16.3%) patients and was associated with increased risk of mortality (RR, 6.70 [95% confidence interval {CI}, 3.38-13.30]) and disability (RR, 2.13 [95% CI, 1.53-2.95]). Preoperative concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitive C-reactive protein (hs-CRP), hemoglobin, and magnesium had the strongest association with CSA-AKI. Identification of patients with CSA-AKI improved when a biomarker panel was used (area under the curve [AUC] 0.75 [95% CI, 0.69-0.80]) compared to when only clinical risk factors were used (European System for Cardiac Operative Risk Evaluation [EuroSCORE II] AUC 0.67 [95% CI, 0.62-0.73]). CONCLUSIONS: Preoperative cardiac, inflammatory, renal, and metabolic biomarkers are associated with CSA-AKI and may improve identification of patients at risk.

Predicting Unacceptable Pain in Cardiac Surgery Patients Receiving Morphine Maintenance and Rescue Doses: A Model-Based Pharmacokinetic-Pharmacodynamic Analysis.

BACKGROUND: Optimal analgesic treatment following cardiac surgery is crucial for both patient comfort and successful postoperative recovery. While knowledge of both the pharmacokinetics and pharmacodynamics of analgesics is required to predict optimal drug dosing, models quantifying the pharmacodynamics are scarce. Here, we quantify the pharmacodynamics of morphine by modeling the need for rescue morphine to treat unacceptable pain in 118 patients after cardiac surgery. METHODS: The rescue morphine event data were analyzed with repeated time-to-event (RTTE) modeling using NONMEM. Postoperative pain titration protocol consisted of continuous morphine infusions (median duration 20.5 hours) with paracetamol 4 times daily and rescue morphine in case of unacceptable pain (numerical rating scale ≥4). RESULTS: Patients had a median age of 73 years (interquartile range [IQR]: 63-77) and median bodyweight of 80 kg (IQR: 72-90 kg). Most patients (55%) required at least 1 rescue morphine dose. The hazard for rescue morphine following cardiac surgery was found to be significantly influenced by time after surgery, a day/night cycle with a peak at 23:00 (95% confidence interval [CI], 19:35-02:03) each day, and an effect of morphine concentration with 50% hazard reduction at 9.3 ng·mL-1 (95% CI, 6.7-16). CONCLUSIONS: The pharmacodynamics of morphine after cardiac surgery was successfully quantified using RTTE modeling. Future studies can be used to expand the model to better predict morphine's pharmacodynamics on the individual level and to include the pharmacodynamics of other analgesics so that improved postoperative pain treatment protocols can be developed.

Fixed Dosing of Liposomal Amphotericin B in Morbidly Obese Individuals.

In this prospective study, we examined the pharmacokinetics of 1 and 2 mg/kg liposomal amphotericin B in 16 morbidly obese individuals (104-177 kg). Body size had no effect on clearance. We recommend a fixed dose in patients ≥100 kg (ie, 300 or 500 mg rather than the current dose of 3 and 5 mg/kg, respectively). Clinical Trials Registration NCT02320604.

Dose recommendations for gentamicin in the real-world obese population with varying body weight and renal (dys)function.

BACKGROUND: The impact of weight on pharmacokinetics of gentamicin was recently elucidated for (morbidly) obese individuals with normal renal function. OBJECTIVES: To characterize the pharmacokinetics of gentamicin in real-world obese patients, ultimately to develop dose recommendations applicable across the entire obese population. METHODS: In two large Dutch hospitals, all admitted patients with BMI ≥25 kg/m2 with at least one gentamicin administration, at least one gentamicin and at least one creatinine serum concentration measurement were included. Data from one hospital, obtained from electronic health records, combined with prospective data of non-obese and morbidly obese people with normal renal function, served as the training dataset, and data from the second hospital served as the external validation dataset. RESULTS: In the training dataset [1187 observations from 542 individuals, total body weight (TBW) 52-221 kg and renal function (CKD-EPI) 5.1-141.7 mL/min/1.73 m2], TBW was identified as a covariate on distribution volume, and de-indexed CKD-EPI and ICU stay on clearance (all P < 0.001). Clearance was 3.53 L/h and decreased by 0.48 L/h with each 10 mL/min reduction in de-indexed CKD-EPI. The results were confirmed in the external validation (321 observations from 208 individuals, TBW 69-180 kg, CKD-EPI 5.3-130.0 mL/min/1.73 m2). CONCLUSIONS: Based on the study, we propose specific mg/kg dose reductions with decreasing CKD-EPI values for the obese population, and extension of the dosing interval beyond 24 h when CKD-EPI drops below 50 mL/min/1.73 m2. In ICU patients, a 25% dose reduction could be considered. These guidelines can be used to guide safe and effective dosing of gentamicin across the real-world obese population.

Implications for IV posaconazole dosing in the era of obesity.

BACKGROUND: The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients. METHODS: We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. ClinicalTrials.gov Identifier: NCT03246386. RESULTS: Total body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of ≥90% in individuals up to 140 kg, after which both twice daily loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg. CONCLUSIONS: Body size has a significant impact on posaconazole CL and V, resulting in a lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring.

Frailty and functional outcomes after open and endovascular procedures for patients with peripheral arterial disease: A systematic review.

BACKGROUND: Frailty has been associated with postoperative complications and mortality across surgical specialties, including vascular surgery. However, the influence of frailty on postoperative functional outcomes is unclear. We sought to determine the influence of frailty on functional outcomes after open or endovascular vascular procedures in patients with peripheral arterial disease. METHODS: This systematic review was conducted according to the PRISMA guidelines. Eligible articles were identified through database searches of Pubmed and EMBASE in April 2017. Studies reporting on frailty and functional outcomes after vascular interventions for peripheral artery disease (PAD) were included. Outcomes of interest were dependency in activities of daily living (ADL), dependent mobility, discharge destination, disability-free survival, and quality of life. Individual studies were assessed for quality and risk of bias using the Quality in Prognosis Studies tool. RESULTS: Eight studies met the eligibility criteria and were included. The risk of bias was low in two studies, intermediate in three studies, and high in three studies. Methods for frailty assessment were different for each study. Frailty was a predictor for discharge to a higher level of care, dependent mobility, and dependency in ADL after vascular procedures for PAD. Both frailty models and individual frailty characteristics seem to be associated with these adverse functional outcomes. CONCLUSIONS: Despite a limited amount of literature and an overall intermediate quality of the included studies, this systematic review shows an association between frailty and adverse functional outcomes after peripheral arterial procedures for PAD, including discharge to a care facility, dependent mobility, and a decline in ADL functioning.

Preoperative frailty and outcome in patients undergoing radical cystectomy.

OBJECTIVE: To determine the value of preoperative frailty screening in predicting postoperative severe complications and 1-year mortality in patients undergoing radical cystectomy (RC). PATIENTS AND METHODS: Prospective cohort single-centre study in patients undergoing RC from September 2016 to December 2017. Preoperative frailty screening was implemented as standard care and was used to guide shared decision-making during multidisciplinary team meetings. Frailty screening consisted of validated tools to assess physical, mental and social frailty. Patients were considered frail when having two or more frailty characteristics. The primary endpoint was the composite of a severe complication (Clavien-Dindo Grade III-V) within 30 days and 1-year all-cause mortality. The secondary endpoints included any complication (Clavien-Dindo II-V), length of stay, readmission within 30 days, and all-cause mortality. Logistic regression analysis and the concordance statistic (c-statistic) were used to describe the association and predictive value of preoperative frailty screening. RESULTS: A total of 63 patients were included; 39 (61.9%) were considered frail. Preoperative frailty was associated with a seven-fold increased risk of a severe complication or death 1 year after RC [adjusted odds ratio (OR) 7.36, 95% confidence interval (CI) 1.7-31.8; 22 patients]. Compared to the American Society of Anesthesiologists (ASA) score and Charlson Comorbidity Index, frailty showed the best model performance (Nagelkerke R2 0.20) and discriminative ability(c-statistic 0.72, P < 0.01) for the primary endpoint. After adding frailty to the conventional ASA risk score, the c-statistic improved by 11% (P < 0.01). Overall survival was significantly worse in frail patients (23.2 months, 95% CI 18.7-30.1) vs non-frail patients (32.9 months, 95% CI 30.0-35.9; P = 0.01). CONCLUSIONS: Frail patients undergoing RC are at high risk of postoperative adverse outcomes including death. Preoperative frailty screening improves preoperative risk stratification and may be used to guide patient selection for RC.

Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals.

AIMS: For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400-700 mg h L-1 ). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese. METHODS: Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese healthy volunteers (n = 8; total body weight [TBW] 60.0-234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg-1 , maximum 2500 mg; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11-13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60-230 kg) were performed using NONMEM. RESULTS: In a 3-compartment model, peripheral volume of distribution and clearance increased with TBW (both p < 0.001), which was confirmed in the external validation. A dose of 35 mg kg-1 day-1 (maximum 5500 mg/day) resulted in a > 90% target attainment (area under the curve > 400 mg h L-1 ) in individuals up to 200 kg, with corresponding trough concentrations of 5.7-14.6 mg L-1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for steady state on day 1. CONCLUSION: In this prospective, rich sampling pharmacokinetic study, vancomycin clearance was well predicted using TBW. We recommend that in obese individuals without renal impairment, vancomycin should be dosed as 35 mg kg-1 day-1 (maximized at 5500 mg/day). When given over 2 daily doses, trough concentrations of 5.7-14.6 mg L-1 correspond to the target exposure in obese individuals.

Anaesthesia geriatric evaluation to guide patient selection for preoperative multidisciplinary team care in cardiac surgery.

BACKGROUND: A multidisciplinary approach to improve postoperative outcomes in frail elderly patients is gaining interest. Multidisciplinary team care should be targeted at complex patients at high risk for adverse postoperative outcome to limit the strain on available resources and to prevent an unnecessary increase in patient burden. This study aimed to improve patient selection for multidisciplinary care by identifying risk factors for disability after cardiac surgery in elderly patients. METHODS: This was a two-centre prospective cohort study of 537 patients aged ≥70 yr undergoing elective cardiac surgery. Before surgery, 11 frailty characteristics were investigated. Outcome was disability at 3 months defined as World Health Organization Disability Assessment Schedule 2.0 ≥25%. Multivariable modelling using logistic regression, concordance statistic (c-statistic), and net reclassification index was used to identify factors contributing to patient selection. RESULTS: Disability occurred in 91 (17%) patients. Ten out of 11 frailty characteristics were associated with disability. A multivariable model, including the European System for Cardiac Operative Risk Evaluation II and preoperative haemoglobin, yielded a c-statistic of 0.71 (95% confidence interval [CI]: 0.66-0.77). After adding pre-specified frailty characteristics (polypharmacy, gait speed, physical disability, preoperative health-related quality of life, and living alone) to this model, the c-statistic improved to 0.78 (95% CI: 0.73-0.83). The net reclassification index was 0.32 (P<0.001), showing improved discrimination for patients at risk for disability at 3 months. CONCLUSIONS: The addition of preoperative frailty characteristics to a multivariable model improved discrimination between elderly patients with and without disability at 3 months after cardiac surgery, and can be used to guide patient selection for preoperative multidisciplinary team care. CLINICAL TRIAL REGISTRATION: NCT02535728.

Pharmacokinetics and probability of target attainment for micafungin in normal-weight and morbidly obese adults.

OBJECTIVES: The rising pandemic of obesity means an increasing number of obese patients who require antimicrobial therapy for serious infections. Micafungin is an echinocandin drug frequently used as therapy or prophylaxis for fungal infections, predominantly with Candida species. In order to maximize the efficacy of micafungin in obese patients, the dose that corresponds to optimal exposure for each obese individual needs to be identified. METHODS: We performed a prospective study in 16 obese and 8 normal-weight healthy subjects with a weight ranging from 61.5-184 kg (ClinicalTrials.gov Identifier: NCT03102658). A population pharmacokinetic model was developed and used to simulate several dosing regimens to evaluate the PTA for relevant MICs to define the optimal dose using the pharmacokinetic/pharmacodynamic target of an AUC/MIC ratio above 5000. RESULTS: Total body weight was found to be most predictive for CL and V. Simulations showed that a 100 mg dose results in a PTA of >90% in patients weighing ≤125 kg infected with a Candida species having an MIC of 0.016 mg/L. The maintenance dose should be increased to 200 mg in patients >125 kg infected with a Candida species with an MIC of 0.016 mg/L. For an MIC of 0.032 mg/L, a 300 mg maintenance dose is recommended above 125 kg weight. Furthermore, we demonstrate that patients can benefit from a loading dose (i.e. twice the maintenance dose). CONCLUSIONS: We present easy-to-use dose recommendations for obese patients, based on both weight and target MIC, that result in adequate exposure in patients with body weight up to 190 kg.

Perioperative point of care platelet function testing and postoperative blood loss in high-risk cardiac surgery patients.

Postoperative coagulopathic bleeding is common in cardiac surgery and associated with increased morbidity and mortality. Platelet function is affected by multiple factors, including patient and procedural characteristics. Point-of-care (POC) multiple electrode aggregometry (MEA) can rapidly detect and quantify platelet dysfunction and could contribute to optimal patient blood management. In patients undergoing CABG and heart valve surgery platelet function was assessed using POC MEA at four different perioperative timepoints in response to stimulation with four specific receptor agonists (ADP, AA, COL, TRAP). Postoperative bleeding was recorded during 24 h after surgery. Regression analyses were performed to establish associations between perioperative platelet function and postoperative blood loss. Ninety-nine patients were included in the study. Fifty-nine patients (60%) were on antiplatelet therapy (APT) at time of surgery. ADP- and AA-induced platelet aggregation declined during CPB and after decannulation from CPB, with a maximum decrease of 55% for ADP (35 vs. 77 AU at baseline; P < 0.001) and 78% for ASPI (14 vs. 64 AU at baseline; P < 0.001). A linear relationship was present between ADP-induced platelet aggregometry at baseline and postoperative blood loss (r = -0.249; P = 0.015). In aspirin users, the maximum decline in platelet function between baseline and CPB decannulation was related to postoperative blood loss (r = 0.308; P = 0.037). In multivariate analysis, a reduced ADP platelet function prior to surgery remained associated with postoperative blood loss (r = -0.239; P = 0.012). Reduced ADP-induced platelet aggregation at baseline is associated with increased postoperative blood loss in high-risk cardiac surgery patients.

Intra-operative red blood cell transfusion and mortality after cardiac surgery.

BACKGROUND: Anemia in cardiac surgery patients has been associated with poor outcomes. Transfusion of red blood cells during surgery is common practice for perioperative anemia, but may come with risks. Little is known about the association between intra-operative transfusion and mortality in patients undergoing cardiac surgery. METHODS: Single centre historical cohort study in 2933 adult patients undergoing coronary surgery with or without aortic valve replacement from June 2011 until September 2014. To estimate the odds ratio for mortality in patients receiving intra-operative transfusion, a propensity score based logistic regression analysis was performed. RESULTS: Intra-operative transfusion was associated with a more than three-fold increased risk of 30-day mortality. Patients in the highest quartile of probability of transfusion were older (age 75 vs 66; P <  0.001), had a higher EuroSCORE (6 vs 3; P <  0.001), had lower preoperative hemoglobin levels (7.6 vs 8.9 mmol/l; P < 0.001), had combined surgery more often (CABG + AVR in 33.4% of cases vs 6.6% (P < 0.001) and a longer duration of surgery (224 vs 188 min; P < 0.001). The association between intra-operative transfusion and mortality persisted after adjustment for these risk factors (adjusted OR 2.6; P = 0.007). CONCLUSIONS: Intra-operative transfusion of red blood cells was found to be associated with increased mortality in adults undergoing coronary surgery. Preoperative patient optimization may improve perioperative outcomes by reducing the likelihood of requiring transfusion and thus its associated risk.

Short- and long-term impact of remifentanil on thermal detection and pain thresholds after cardiac surgery: A randomised controlled trial.

BACKGROUND: The clinical relevance of the suggested hyperalgesic effects of remifentanil is still unclear, especially in the long term. OBJECTIVE: The current study evaluated the impact of remifentanil on thermal thresholds 3 days and 12 months after surgery, measured with Quantitative Sensory Testing. DESIGN: A single-blind, randomised controlled trial. SETTING: A tertiary care teaching hospital in The Netherlands, from 2014 to 2016. PATIENTS: A total of 126 patients aged between 18 and 85 years, undergoing cardiothoracic surgery via sternotomy (coronary artery bypass grafts and/or valve replacement) were included. Exclusion criteria were BMI above 35 kg m, history of cardiac surgery, chronic pain conditions, neurological conditions, allergy to opioids or paracetamol, language barrier and pregnancy. INTERVENTIONS: Patients were allocated randomly to receive intra-operatively either a continuous remifentanil infusion or intermittent intra-operative fentanyl as needed in addition to standardised anaesthesia with propofol and intermittent intravenous fentanyl at predetermined time points. MAIN OUTCOME MEASURES: Warm and cold detection and pain thresholds 3 days and 12 months after surgery. In addition the use of remifentanil, presence of postoperative chronic pain, age, opioid consumption and pre-operative quality of life were tested as a predictor for altered pain sensitivity 12 months after surgery. RESULTS: Both warm and cold detection, and pain thresholds, were not significantly different between the remifentanil and fentanyl groups 3 days and 12 months after surgery (P > 0.05). No significant predictors for altered pain sensitivity were identified. CONCLUSION: Earlier reports of increased pain sensitivity 1 year after the use of remifentanil could not be confirmed in this randomised study using Quantitative Sensory Testing. This indicates that remifentanil plays a minor role in the development of chronic thoracic pain. Still, the relatively high incidence of chronic thoracic pain and its accompanying impact on quality of life remain challenging problems. TRIAL REGISTRATION: The study was registered at EudraCT (ref: 2013-000201-23) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02031016).

Pharmacokinetics of Anidulafungin in Obese and Normal-Weight Adults.

In 2025, approximately one out of five adults will be obese. Physiological changes associated with obesity have been shown to influence the pharmacokinetics of drugs. Anidulafungin is frequently used in critically ill patients, and to achieve optimal efficacy, it is essential that its dose is appropriate for each patient's characteristics. We combined data from obese subjects with data from normal-weight subjects and determined an optimal dosing regimen for obese patients by population pharmacokinetic modeling. Twenty adults, 12 of which were normal-weight healthy subjects (median weight, 67.7 kg; range, 61.5 to 93.6 kg) and 8 of which were morbidly obese subjects (median weight, 149.7 kg; range, 124.1 to 166.5 kg) were included in the analysis. Subjects received a single dose of 100 mg anidulafungin intravenously over 90 min, upon which blood samples were obtained. Monte Carlo simulations were performed to optimize dosing in obesity. A three-compartment model and equal volumes of distribution described the data best. Total body weight was identified as a descriptor for both clearance and the volume of distribution, but the effect of weight on these parameters was limited. Simulations showed that with the licensed 100-mg dose, more than 97% of subjects with a weight above 140 kg will have an area under the concentration-time curve from 0 to 24 h of less than 99 mg · h/liter (the reference value for normal-weight individuals). We found that in obese and normal-weight subjects, weight influenced both of the anidulafungin pharmacokinetic parameters clearance and volume of distribution, implying a lower exposure to anidulafungin in (morbidly) obese individuals. Consequently, a 25% increase in the loading and maintenance doses could be considered in patients weighing more than 140 kg.

Long-term outcome and quality of life after ruptured abdominal aortic aneurysm repair.

Objectives To evaluate long-term outcome and quality of life after open and endovascular repair of ruptured abdominal aortic aneurysms. Methods All consecutive ruptured abdominal aortic aneurysm patients at the St. Antonius Hospital treated for ruptured abdominal aortic aneurysm between January 2005 and January 2015 were included. Mortality, morbidity, and re-interventions within 30 days and during follow-up were registered. Quality of life was measured with Short Form-36 questionnaire among survivors. Additional subgroup analysis between open repair and endovascular repair was performed. Results A total of 192 patients with ruptured abdominal aortic aneurysm were included: 76.6% (147/192) underwent open repair and 23.4% (45/192) endovascular repair. All-cause 30-day mortality rate was 31.3% (60/192), and 30-day morbidity rate was 70.3% (135/192). Median stay at the intensive care unit was two days for endovascular repair and four days for open repair ( p = 0.002). No other statistically significant differences between endovascular repair and open repair were observed. After a mean follow-up period of 62 months (range 9-126), 72.4% (76/105) of the responders had equivalent Short Form-36 scores as compared to the age-matched general Dutch population, and 84.2% (64/76) of the responders would choose surgery again if they would have a ruptured abdominal aortic aneurysm. Conclusions Survivors of ruptured abdominal aortic aneurysm have similar long-term quality of life scores compared to the age-matched general population. The majority of all survivors would choose to undergo acute abdominal aortic aneurysm repair again.

Randomized Controlled Trial on the Influence of Intraoperative Remifentanil versus Fentanyl on Acute and Chronic Pain after Cardiac Surgery.

BACKGROUND: Remifentanil has been associated with increased acute and potentially chronic postoperative pain. The objective of this prospective randomized controlled trial was to investigate the influence of intraoperative remifentanil on acute and chronic postoperative pain after cardiac surgery. METHODS: Patients (N = 126) receiving standardized anesthesia with propofol and intermittent intravenous fentanyl at predetermined times for cardiac surgery were randomized to intraoperatively receive either a continuous remifentanil infusion or additional intermittent intraoperative fentanyl as needed. The primary endpoint was chronic thoracic pain at 12 months after surgery. Secondary endpoints were pain at 3 and 6 months after surgery and analgesic requirements and pain levels in the first 72 hours. RESULTS: There was no significant difference in incidence of chronic thoracic pain between the remifentanil and fentanyl groups, respectively (20% vs. 18%; P = 0.817). At 3 months, however, significantly more patients in the remifentanil group reported chronic thoracic pain (51% vs. 33%; P = 0.047). This effect was more pronounced in younger patients and in patients receiving a higher dose of remifentanil (both P < 0.05). The first 24 and 48 hours postoperatively, morphine consumption in the remifentanil group was significantly higher than in the fentanyl group (34.3 mg [interquartile range (IQR) 25.3 to 48.2] vs. 30.2 mg [IQR 19.2 to 38.1], P = 0.028; and 46.8 mg [IQR 33.8 to 59.2] vs. 39.0 mg [IQR 6.2 to 51.4], P = 0.047, respectively). CONCLUSIONS: Intraoperative use of remifentanil during cardiac surgery does not impact chronic postoperative pain 1 year after surgery. Nevertheless, remifentanil increases analgesic requirements and thoracic pain until 3 months after surgery, and its use is therefore less favorable during cardiac surgery.