Low and Highly Variable Exposure to Prophylactic LMWH Nadroparin in Critically Ill Patients: Back to the Drawing Board for Prophylactic Dosing?

BACKGROUND AND OBJECTIVE: Low-molecular-weight heparins are routinely administered to patients in the intensive care unit to prevent venous thromboembolisms. There is considerable evidence that low-molecular-weight heparin doses should be personalised based on anti-Xa levels, but pharmacokinetic data in intensive care unit patients are lacking. This study aimed to characterise the pharmacokinetics and associated variability of the low-molecular-weight heparin nadroparin in critically ill patients. METHODS: Critically ill adult patients who were admitted to the intensive care unit and received nadroparin for prophylaxis of venous thromboembolism were included in a study. Population pharmacokinetic analysis was performed by means of parametric non-linear mixed-effects modelling (NONMEM). RESULTS: A total of 30 patients were enrolled with 12 patients undergoing continuous veno-venous hemodialysis and 18 patients not undergoing continuous veno-venous hemodialysis. Very high variability in pharmacokinetics was observed with an inter-individual variability in the volume of distribution of 63.7% (95% confidence interval 46.5-90.6), clearance of 166% (95% confidence interval 84.7-280) and relative bioavailability of 40.2% (95% confidence interval 29.5-52.6). We found that standard doses of 2850 IE and 5700 IE of nadroparin resulted in sub-prophylactic exposure in critically ill patients. CONCLUSIONS: Low exposure and highly variable pharmacokinetics of nadroparin were observed in intensive care unit patients treated with a prophylactic dose. It can be debated whether nadroparin is currently dosed optimally in intensive care unit patients and our findings encourage the investigation of higher and tailored dosing of nadroparin in the critically ill.

Optimising the Nadroparin Dose for Thromboprophylaxis During Hemodialysis by Developing a Population Pharmacodynamic Model Using Anti-Xa Levels.

INTRODUCTION: The optimal nadroparin dose in patients undergoing hemodialysis is difficult to determine in clinical practice. Anti-Xa levels ≥ 0.4 IU/mL and < 2.0 IU/mL are suggested to prevent thrombus formation within the extracorporeal circuit whilst minimizing bleeding risk. We aimed to characterize the variability in the association between dose and anti-Xa levels, identify patient and dialysis characteristics that explained this variability, and optimize nadroparin dosing based on the identified characteristics. METHODS: Anti-Xa samples were collected in patients who received intravenous nadroparin as thromboprophylaxis during routine dialysis sessions. A population pharmacodynamic model was developed using non-linear mixed-effects modelling. The percentage of patients ≥ 0.4 IU/mL (efficacy) and < 2.0 IU/mL (safety) was simulated for different doses, patient and dialysis characteristics. RESULTS: Patients (n = 137) were predominantly receiving standard hemodialysis (84.7% vs. hemodiafiltration 15.3%) and had a mean bodyweight of 76.3 kg (± 16.9). Lean body mass (LBM), mode of dialysis, and dialyzer partially explained between-subject variability in anti-Xa levels. Patients on hemodiafiltration and those receiving hemodialysis with a high LBM (≥ 80 kg) had a low probability (< 29%) of anti-Xa levels ≥ 0.4 IU/mL during the entire dialysis session. All patients, except hemodialysis patients with a low LBM (< 50 kg), had a high probability (> 70%) of peak anti-Xa levels < 2.0 IU/mL. CONCLUSION: Mainly patients receiving hemodiafiltration and those receiving hemodialysis with a high LBM can benefit from a higher nadroparin dose than currently used in clinical practice, while having anti-Xa levels < 2.0 IU/mL.

Effect of antithrombotic stewardship on the efficacy and safety of antithrombotic therapy during and after hospitalization.

BACKGROUND: Although the benefits of antithrombotic drugs are indisputable to reduce thrombotic events, they carry a high risk of compromising patient safety. No previous studies investigated the implementation and (cost-) effectiveness of a hospital-based multidisciplinary antithrombotic team on bleeding and thrombotic outcomes. The primary aim of this study was to compare the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization. METHODS AND FINDINGS: A prospective, multicenter before-after intervention study was conducted in two Dutch hospitals. Adult patients hospitalized between October 2015 and December 2017 treated with anticoagulant therapy were included. The primary aim was to estimate the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization. The intervention was the implementation of a multidisciplinary antithrombotic team focusing on education, medication reviews by pharmacists, implementing of local anticoagulant therapy guidelines based on national guidelines, patient counselling and medication reconciliation at admission and discharge. The primary endpoint was analysed using segmented linear regression. We obtained data for 1,886 patients: 941 patients were included in the usual care period and 945 patients in the intervention period. The S-team study showed that implementation of a multidisciplinary antithrombotic team over time significantly reduced the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs (-1.83% (-2.58% to -1.08%) per 2 month period). CONCLUSIONS: This study shows that implementation of a multidisciplinary antithrombotic team over time significantly reduces the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs. TRIAL REGISTRATION: Trialregister.nl NTR4887.

The effect of hospital-based antithrombotic stewardship on adherence to anticoagulant guidelines.

Background Anticoagulant therapy is associated with a high risk of complications. Adherence to anticoagulant therapy protocols may lower this risk but adherence is often suboptimal. The introduction of a multidisciplinary antithrombotic team may improve adherence to anticoagulant guidelines among physicians. Objective To determine the effect of hospital-based multidisciplinary antithrombotic stewardship on adherence to anticoagulant guidelines among prescribing physicians. Setting This prospective non-randomised before-and-after study was conducted in patients hospitalized between October 2015 and December 2017 and treated with anticoagulant therapy. Method A multidisciplinary antithrombotic team focusing on education, medication reviews, drafting of local anticoagulant therapy protocols, patient counseling and medication reconciliation at admission and discharge was implemented in two Dutch hospitals. Main outcome measure Primary outcome was the proportion of the admitted patients in which the prescribing physician did adhere to the anticoagulant guidelines. Results The study comprised 1886 patients, of which 941 patients were included in the usual care period and 945 patients in the intervention period. Multivariable logistic regression analysis indicated that adherence was observed significantly more often during the intervention period (adjusted odds ratio [ORadj] 1.58, 95% confidence interval [95% CI] 1.21-2.05). Detailed analysis identified that the significantly higher overall adherence in the intervention period was attributed to dosing of LMWHs (odds ratio [OR] 1.58, 95% CI 1.16-2.14). Conclusion This study shows that introduction of a multidisciplinary antithrombotic stewardship leads to a significantly higher overall adherence to anticoagulant guidelines among prescribing physicians, mainly based on the improvement of dosing of low-molecular-weight-heparins.

Risk of bleeding in hospitalized patients on anticoagulant therapy: Prevalence and potential risk factors.

INTRODUCTION: Bleeding is the most important complication of treatment with anticoagulant therapy. Although several studies have identified risk factors of bleeding in outpatients, no studies have been performed that evaluated prevalence and potential risk factors of bleeding in hospitalized patients treated with anticoagulant therapy. METHODS: The primary objective of this study was to determine the prevalence of bleeding in anticoagulant users during hospitalization. The secondary objective was to identify potential risk factors of bleeding in hospitalized patients on anticoagulant therapy. A prospective, observational cohort study was conducted in two Dutch hospitals. Adult patients hospitalized between October 2015 and October 2016 treated with anticoagulant therapy were included. Bleeding was defined as a composite endpoint of major bleeding and non-major bleeding according to the International Society on Thrombosis and Heamostasis (ISTH) criteria. Data analysis was performed by multivariate logistic regression. RESULTS: The prevalence of in-hospital bleeding in patients using anticoagulant therapy was 7.2%; 95% confidence interval [95% CI] 5.5-9.1 (65 out of 906 patients). Multivariate logistic regression analysis indicated that female gender (adjusted odds ratio [ORadj] 2.1; 95% CI 1.2-3.7), high-bleeding-risk surgical procedure (ORadj 5.3; 95% CI 2.7-10.2), low-bleeding-risk surgical procedure (ORadj 4.9; 95% CI 1.9-12.6), and non-surgical interventions (ORadj 6.2; 95% CI 3.0-12.6) were associated with bleeding events in hospitalized patients treated with anticoagulants. CONCLUSIONS: The prevalence of bleeding in anticoagulant users during hospitalization was 7.2%. This study detected potential risk factors that can help to identify patients on anticoagulants who have an increased risk of bleeding during hospitalization.

Anticoagulant medication errors in hospitals and primary care: a cross-sectional study.

OBJECTIVE: To assess the proportion of all medication error reports in hospitals and primary care that involved an anticoagulant. Secondary objectives were the anticoagulant involved, phase of the medication process in which the error occurred, causes and consequences of 1000 anticoagulant medication errors. Additional secondary objectives were the total number of anticoagulant medication error reports per month, divided by the total number of medication error reports per month and the proportion of causes of 1000 anticoagulant medication errors (comparing the pre- and post-guideline phase). DESIGN: A cross-sectional study. SETTING: Medication errors reported to the Central Medication incidents Registration reporting system. PARTICIPANTS: Between December 2012 and May 2015, 42 962 medication errors were reported to the CMR. INTERVENTION: N/A. MAIN OUTCOME MEASURE: Proportion of all medication error reports that involved an anticoagulant. Phase of the medication process in which the error occurred, causes and consequences of 1000 anticoagulant medication errors. The total number of anticoagulant medication error reports per month, divided by the total number of medication error reports per month (comparing the pre- and post-guideline phase) and the total number of causes of 1000 anticoagulant medication errors before and after introduction of the LSKA 2.0 guideline. RESULTS: Anticoagulants were involved in 8.3% of the medication error reports. A random selection of 1000 anticoagulant medication error reports revealed that low-molecular weight heparins were most often involved in the error reports (56.2%). Most reports concerned the prescribing phase of the medication process (37.1%) and human factors were the leading cause of medication errors mentioned in the reports (53.4%). Publication of the national guideline on integrated antithrombotic care had no effect on the proportion of anticoagulant medication error reports. Human factors were the leading cause of medication errors before and after publication of the guideline. CONCLUSIONS: Anticoagulant medication errors occurred in 8.3% of all medication errors. Most error reports concerned the prescribing phase of the medication process. Leading cause was human factors. The publication of the guideline had no effect on the proportion of anticoagulant medication errors.

Development of a clinical prediction model for an international normalised ratio ≥ 4·5 in hospitalised patients using vitamin K antagonists.

Vitamin K antagonists (VKAs) used for the prevention and treatment of thromboembolic disease, increase the risk of bleeding complications. We developed and validated a model to predict the risk of an international normalised ratio (INR) ≥ 4·5 during a hospital stay. Adult patients admitted to a tertiary hospital and treated with VKAs between 2006 and 2010 were analysed. Bleeding risk was operationalised as an INR value ≥4·5. Multivariable logistic regression analysis was used to assess the association between potential predictors and an INR ≥ 4·5 and validated in an independent cohort of patients from the same hospital between 2011 and 2014. We identified 8996 admissions of patients treated with VKAs, of which 1507 (17%) involved an INR ≥ 4·5. The final model included the following predictors: gender, age, concomitant medication and several biochemical parameters. Temporal validation showed a c statistic of 0·71. We developed and validated a clinical prediction model for an INR ≥ 4·5 in VKA-treated patients admitted to our hospital. The model includes factors that are collected during routine care and are extractable from electronic patient records, enabling easy use of this model to predict an increased bleeding risk in clinical practice.

Influence of CYP2C8 polymorphisms on imatinib steady-state trough level in chronic myeloid leukemia and gastrointestinal stromal tumor patients.

Imatinib trough levels have been associated with its clinical effects. During chronic use of imatinib, CYP2C8 becomes an important metabolizing enzyme because of cytochrome P450 3A4 (CYP3A4) autoinhibition. Single nucleotide polymorphisms (SNPs) in CYP2C8 may affect imatinib trough levels. This study investigates the effect of common CYP2C8 polymorphisms [*1B (rs7909236), *1C (rs17110453), *3 (rs11572080 and rs10509681), and *4 (rs1058930)] on steady-state trough levels imatinib during chronic imatinib use in 43 patients with chronic myeloid leukemia or gastrointestinal stromal tumors. Standardized imatinib trough levels did not show a significant difference between wild-type and variant groups for any of the tested SNPs, but an association with age was found, with older patients having higher trough levels. This suggests that common CYP2C8 SNPs have no effect on the pharmacokinetics of imatinib.

Antithrombotic stewardship: a multidisciplinary team approach towards improving antithrombotic therapy outcomes during and after hospitalisation: a study protocol.

INTRODUCTION: Antithrombotic therapy carries high risks for patient safety. Antithrombotics belong to the top 5 medications involved in potentially preventable hospital admissions related to medication. To provide a standard for antithrombotic therapy and stress the importance of providing optimal care to patients on antithrombotic therapy, the Landelijke Standaard Ketenzorg Antistolling (LSKA; Dutch guideline on integrated antithrombotic care) was drafted. However, the mere publication of this guideline does not guarantee its implementation. This may require a multidisciplinary team effort. Therefore, we designed a study aiming to determine the influence of hospital-based antithrombotic stewardship on the effect and safety of antithrombotic therapy outcomes during and after hospitalisation. METHODS AND ANALYSIS: In this study, the effect of the implementation of a multidisciplinary antithrombotic team is compared with usual care using a pre-post study design. The study is performed at the Erasmus University Medical Center Rotterdam and the Reinier de Graaf Hospital Delft. Patients who are or will be treated with antithrombotics are included in the study. We aim to include 1900 patients, 950 in each hospital. Primary outcome is the proportion of patients with a composite end point consisting of ≥1 bleeding or ≥1 thrombotic event from the beginning of antithrombotic therapy (or hospitalisation) until 3 months after hospitalisation. Bleeding is defined according to the International Society of Thrombosis and Haemostasis (ISTH) classification. A thrombotic event is defined as any objectively confirmed arterial or venous thrombosis, including acute myocardial infarction or stroke for arterial thrombosis and deep venous thrombosis or pulmonary embolism or venous thrombosis. An economic evaluation is performed to determine whether the implementation of the multidisciplinary antithrombotic team will be cost-effective. ETHICS AND DISSEMINATION: This protocol was approved by the Medical Ethical Committee of the Erasmus University Medical Center. The findings of the study will be disseminated through peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION NUMBER: NTR4887; pre-results.

Population pharmacokinetic-pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents.

BACKGROUND: Optimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines. METHODS: A prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10. RESULTS: A three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 µg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW. CONCLUSION: This is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.

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.

Drug disposition in obesity: toward evidence-based dosing.

Obesity and morbid obesity are associated with many physiological changes affecting pharmacokinetics, such as increased blood volume, cardiac output, splanchnic blood flow, and hepatic blood flow. In obesity, drug absorption appears unaltered, although recent evidence suggests that this conclusion may be premature. Volume of distribution may vary largely, but the magnitude and direction of changes seem difficult to predict, with extrapolation on the basis of total body weight being the best approach to date. Changes in clearance may be smaller than in distribution, whereas there is growing evidence that the influence of obesity on clearance can be predicted on the basis of reported changes in the metabolic or elimination pathways involved. For obese children, we propose two methods to distinguish between developmental and obesity-related changes. Future research should focus on the characterization of physiological concepts to predict the optimal dose for each drug in the obese population.

Evaluation of propofol anesthesia in morbidly obese children and adolescents.

BACKGROUND: Poor characterization of propofol pharmacokinetics and pharmacodynamics in the morbidly obese (MO) pediatric population poses dosing challenges. This study was conducted to evaluate propofol total intravenous anesthesia (TIVA) in this population. METHODS: After IRB approval, a prospective study was conducted in 20 MO children and adolescents undergoing laparoscopic surgery under clinically titrated propofol TIVA. Propofol doses/infusion rates, hemodynamic variables, times to induction and emergence, and postoperative occurrence of respiratory adverse events (RAE) were recorded, along with intraoperative blinded Bispectral Index/BIS and postoperative Ramsay sedation scores (RSS). Study subjects completed awareness questionnaires on postoperative days 1 and 3. Propofol concentrations were obtained at predetermined intra- and post-operative time points. RESULTS: Study subjects ranged 9 - 18 years (age) and 97 - 99.9% (BMI for age percentiles). Average percentage variability of hemodynamic parameters from baseline was ≈ 20%. Patients had consistently below target BIS values (BIS < 40 for >90% of maintenance phase), delayed emergence (25.8 ± 22 minutes), increased somnolence (RSS ≥ 4) in the first 30 minutes of recovery from anesthesia and 30% incidence of postoperative RAE, the odds for which increased by 14% per unit increase in BMI (p ≤ 0.05). Mean propofol concentration was 6.2 mg/L during maintenance and 1.8 mg/L during emergence from anesthesia. CONCLUSIONS: Our findings indicate clinical overestimation of propofol requirements and highlight the challenges of clinically titrated propofol TIVA in MO adolescents. In this setting, it may be advantageous to titrate propofol to targeted BIS levels until more accurate weight-appropriate dosing regimens are developed, to minimize relative overdosing and its consequences.

Propofol clearance in morbidly obese children and adolescents: influence of age and body size.

BACKGROUND AND OBJECTIVE: Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. METHODS: A prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM(®) was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors. RESULTS: Twenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9-18 years), a mean total body weight (TBW) of 125 kg (range 70-184 kg) and a mean body mass index of 46 kg/m(2) (range 31-63 kg/m(2)) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min) = 1.70 × (TBW/70)(0.8)]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable. CONCLUSION: In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function.

Impact of obesity on drug metabolism and elimination in adults and children.

The prevalence of obesity in adults and children is rapidly increasing across the world. Several general (patho)physiological alterations associated with obesity have been described, but the specific impact of these alterations on drug metabolism and elimination and its consequences for drug dosing remains largely unknown. In order to broaden our knowledge of this area, we have reviewed and summarized clinical studies that reported clearance values of drugs in both obese and non-obese patients. Studies were classified according to their most important metabolic or elimination pathway. This resulted in a structured review of the impact of obesity on metabolic and elimination processes, including phase I metabolism, phase II metabolism, liver blood flow, glomerular filtration and tubular processes. This literature study shows that the influence of obesity on drug metabolism and elimination greatly differs per specific metabolic or elimination pathway. Clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese as compared with non-obese patients. In contrast, clearance of drugs primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT), glomerular filtration and/or tubular-mediated mechanisms, xanthine oxidase, N-acetyltransferase or CYP2E1 appears higher in obese versus non-obese patients. Additionally, in obese patients, trends indicating higher clearance values were seen for drugs metabolized via CYP1A2, CYP2C9, CYP2C19 and CYP2D6, while studies on high-extraction-ratio drugs showed somewhat inconclusive results. Very limited information is available in obese children, which prevents a direct comparison between data obtained in obese children and obese adults. Future clinical studies, especially in children, adolescents and morbidly obese individuals, are needed to extend our knowledge in this clinically important area of adult and paediatric clinical pharmacology.

Anti-Xa Levels 4 h After Subcutaneous Administration of 5,700 IU Nadroparin Strongly Correlate with Lean Body Weight in Morbidly Obese Patients.

BACKGROUND: Morbidly obese patients (BMI > 40 kg/m(2)) are at increased risk for venous thromboembolism, especially after surgery. Despite limited evidence, morbidly obese patients are often administered a double dose of nadroparin for thromboprophylaxis compared to non-obese patients. The aim of this study was to evaluate the influence of different body size descriptors on anti-Xa levels after a double dose of nadroparin (5,700 IU) in morbidly obese patients. METHODS: In 27 morbidly obese patients with a mean total body weight of 148 kg (range 107-260 kg), anti-Xa levels were determined peri-operatively until 24 h after administration of a subcutaneous dose of 5,700 IU of nadroparin. RESULTS: Anti-Xa level 4 h after administration (A(4h), mean 0.22 ± 0.07 IU/ml) negatively correlated strongly with lean body weight (r = -0.66 (p < 0.001)) and moderately with total body weight (r = -0.56 (p = 0.003)) and did not correlate with body mass index (r = -0.26 (p = 0.187)). The area under the anti-Xa level-time curve from 0 to 24 h (AUA(0-24h), mean 2.80 ± 0.97 h IU/ml) correlated with lean body weight (r = -0.63 (p = 0.007)), but did not correlate with total body weight (r = -0.44 (p = 0.075)) or body mass index (r = -0.10 (p = 0.709)). CONCLUCIONS: Following a subcutaneous dose of nadroparin 5,700 IU, A(4h) and AUA(0-24h) were found to negatively correlate strongly with lean body weight. From these results, individualized dosing of nadroparin based on lean body weight should be considered in morbidly obese patients.

Propofol Clearance in Morbidly Obese Children and Adolescents : Influence of Age and Body Size.

BACKGROUND AND OBJECTIVE: Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. METHODS: A prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM® was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors. RESULTS: Twenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9-18 years), a mean total body weight (TBW) of 125 kg (range 70-184 kg) and a mean body mass index of 46kg/m2 (range 31-63 kg/m2) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min)= 1.70 × (TBW/70)0.8]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable. CONCLUSION: In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT00948597.

Population pharmacokinetics and pharmacodynamics of propofol in morbidly obese patients.

BACKGROUND AND OBJECTIVES: In view of the increasing prevalence of morbidly obese patients, the influence of excessive total bodyweight (TBW) on the pharmacokinetics and pharmacodynamics of propofol was characterized in this study using bispectral index (BIS) values as a pharmacodynamic endpoint. METHODS: A population pharmacokinetic and pharmacodynamic model was developed with the nonlinear mixed-effects modelling software NONMEM VI, on the basis of 491 blood samples from 20 morbidly obese patients (TBW range 98-167 kg) and 725 blood samples from 44 lean patients (TBW range 55-98 kg) from previously published studies. In addition, 2246 BIS values from the 20 morbidly obese patients were available for pharmacodynamic analysis. RESULTS: In a three-compartment pharmacokinetic model, TBW proved to be the most predictive covariate for clearance from the central compartment (CL) in the 20 morbidly obese patients (CL 2.33 L/min × [TBW/70]^[0.72]). Similar results were obtained when the morbidly obese patients and the 44 lean patients were analysed together (CL 2.22 L/min × [TBW/70]^[0.67]). No covariates were identified for other pharmacokinetic parameters. The depth of anaesthesia in the morbidly obese patients was adequately described by a two-compartment biophase-distribution model with a sigmoid maximum possible effect (E(max)) pharmacodynamic model (concentration at half-maximum effect [EC(50)] 2.12 mg/L) without covariates. CONCLUSION: We developed a pharmacokinetic and pharmacodynamic model of propofol in morbidly obese patients, in which TBW proved to be the major determinant of clearance, using an allometric function with an exponent of 0.72. For the other pharmacokinetic and pharmacodynamic parameters, no covariates could be identified. Trial registration number (clinicaltrials.gov): NCT00395681.

Pharmacokinetics and protein binding of cefazolin in morbidly obese patients.

PURPOSE: The aim of this study was to assess the pharmacokinetics and protein binding of cefazolin in morbidly obese patients undergoing bariatric surgery, to study the influence of bodyweight measures and age on pharmacokinetic parameters and to evaluate unbound cefazolin concentrations over time in this population. METHODS: Twenty morbidly obese patients (bodyweight 112-260 kg, body mass index 38-79 kg m(-2)) were studied following the administration of cefazolin 2 g at induction of anaesthesia. Blood samples were collected up to 4 h post-dosing to determine total and unbound plasma cefazolin concentrations. Non-compartmental pharmacokinetic data analysis was performed. RESULTS: Cefazolin clearance was 4.2 ± 1.0 L h(-1) (mean ± standard deviation) and showed a negative correlation with age (p = 0.003) but not with bodyweight measures (p > 0.05). Volume of distribution was 13.0 ± 3.1 L and correlated positively with bodyweight measures (p ≤ 0.001). Saturable protein binding was observed with a median protein binding of 79% (interquartile range 74-82), which proved similar to reported protein binding in non-obese patients. In all patients, unbound cefazolin concentrations remained above 1 mg L(-1) (minimal inhibitory concentration for 90% (MIC(90)) of methicillin-sensitive isolates of Staphylococcus aureus in Europe) until 4 h post-dosing. CONCLUSIONS: Younger age--and not bodyweight--was significantly associated with higher cefazolin clearance. However, as in all patients with bodyweights up to 260 kg, unbound plasma cefazolin concentrations remained above 1 mg L(-1) until 4 h after the intravenous administration of a 2-g dose. As such, re-dosing within 4 h or dosing with another antibiotic class should only be considered in the case of a higher MIC(90) of the local isolates.

Comparative evaluation of atracurium dosed on ideal body weight vs. total body weight in morbidly obese patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Different conflicting reports have been published for the use of atracurium in morbidly obese patients. Dosing of atracurium based on lean body mass, total body weight, and total body weight with a dose reduction for every 10 kg more than 70 kg have been proposed. WHAT THIS STUDY ADDS: The current prospective randomized double-blind study compares atracurium 0.5 mg kg(-1) ideal body weight vs. 0.5 mg kg(-1) total body weight when used as a muscle relaxant in morbidly obese patients undergoing bariatric surgery. Based on our results in patients with body weights varying from 112 to 260 kg, we have concluded that atracurium 0.5 mg kg(-1) ideal body weight results in a predictable profile of muscle relaxation allowing for adequate intubation conditions and recovery of muscle strength within 60 min with lack of need for antagonism. A dose-dependent prolongation of action is shown when dosing is based on total body weight. AIMS: This double-blind randomized study evaluated atracurium dosing based on ideal body weight vs. total body weight for muscle relaxation in morbidly obese patients undergoing bariatric surgery. METHODS: Twenty patients (body weight 112-260 kg, BMI 38-79 kg m(-2) ) were randomized to receive atracurium 0.5 mg kg(-1) ideal body weight vs. 0.5 mg kg(-1) total body weight. Primary endpoint was neuromuscular blockade using train-of-four ratios (TOF ratios) and secondary endpoints were intubation conditions and need for antagonism with neostigmine. RESULTS: In the ideal body weight group, times to recovery of TOF ratio from 0 to 5%, 50% and 75% were significantly shorter [TOF ratio from 0 to 5%: mean difference 30 min (95% CI 23, 39 min)] and with lower variability compared with the total body weight group. In the total body weight group there was a significant correlation between atracurium dose and time to a TOF ratio of 5% (r= 0.82, P < 0.001), which was absent in the ideal body weight group (r= 0.24). In both groups, intubation conditions were good while 70% of the patients in the total body weight group needed neostigmine at the end of surgery compared with 0% in the ideal body weight group. CONCLUSION: In morbid obesity (112-260 kg), atracurium 0.5 mg kg(-1) ideal body weight results in a predictable profile of muscle relaxation allowing for adequate intubation conditions and recovery of muscle strength to a TOF ratio >90% within 60 min with lack of need for antagonism. A dose-dependent prolongation of action is shown when dosing is based on total body weight.