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.

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.

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).

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.

Evaluation of five different aneurysm scoring systems to predict mortality in ruptured abdominal aortic aneurysm patients.

BACKGROUND: Ruptured abdominal aortic aneurysms (RAAAs) are associated with a high overall mortality (up to 25% to 35%) ≤30 days when offered surgical treatment. Risk prediction models can provide valuable information on surgical risks, guide clinical decision making, and help identify patients who should not be operated on to prevent futile surgery. Finally, they can be used to evaluate clinical outcome. Different aneurysm scores are available. New ones (with only four parameters) are being developed, such as the Dutch Aneurysm Score (DAS). This study analyzed and compared these scoring models. METHODS: The study selected consecutive patients who presented with RAAA in two large vascular centers (Medisch Centrum Alkmaar and St. Antonius Nieuwegein) between 2005 and 2015. Variables necessary to retrospectively evaluate the scoring systems were registered in the patients' medical files. The discriminatory power and calibration were assessed using the receiver operating characteristic curve and the Hosmer-Lemeshow χ2 test. RESULTS: The study included 347 consecutive patients with RAAA. There were 298 men (85.9%), and the mean ± standard deviation age was 72.6 ± 8.1 years. The receiver operating characteristic curves were developed for the DAS, Glasgow Aneurysm Score (GAS), Edinburgh Ruptured Aneurysm Score, Vancouver Scoring System (VSS), and Hardman Index. The area under the curve was better for the VSS (0.716; 95% confidence interval [CI], 0.647-0.786) than for the other scoring systems. Areas under the curve for the DAS (0.664; 95% CI, 0.592-0.736), Hardman Index (0.664; 95% CI, 0.592-0.736), Edinburgh Ruptured Aneurysm Score (0.621; 95% CI, 0.543-0.700), and GAS (0.591; 95% CI, 0.517-0.665) were slightly smaller, although only the difference between the VSS and GAS was statistically significant. Calibration showed a good fit for all models. CONCLUSIONS: The performance of the tested models for the prediction of mortality in RAAA patients was comparable, with only a statistically significant difference between the VSS and the GAS in favor of the VSS. However, an almost perfect prediction is needed to withhold intervention, and no existing scoring system is capable of that.

Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint.

PURPOSE: In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters. METHODS: Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM. RESULTS: In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L × (LBW/60)). CONCLUSIONS: A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.