Pulse-contour derived cardiac output measurements in morbid obesity: influence of actual, ideal and adjusted bodyweight.

The non-invasive Nexfin cardiac output (CO) monitor shows a low level of agreement with the gold standard thermodilution method in morbidly obese patients. Here we investigate whether this disagreement is related to excessive bodyweight, and can be improved when bodyweight derivatives are used instead. We performed offline analyses of cardiac output recordings of patient data previously used and partly published in an earlier study by our group. In 30 morbidly obese patients (BMI > 35 kg/m2) undergoing laparoscopic gastric bypass, cardiac output was simultaneously determined with PiCCO thermodilution and Nexfin pulse-contour method. We investigated if agreement of Nexfin-derived CO with thermodilution CO improved when ideal and adjusted-instead of actual- bodyweight were used as input to the Nexfin. Bodyweight correlated with the difference between Nexfin-derived and thermodilution-derived CO (r = -0.56; p = 0.001). Bland Altman analysis of agreement between Nexfin and thermodilution-derived CO revealed a bias of 0.4 ± 1.6 with limits of agreement (LOA) from -2.6 to 3.5 L min when actual bodyweight was used. Bias was -0.6 ± 1.4 and LOA ranged from -3.4 to 2.3 L min when ideal bodyweight was used. With adjusted bodyweight, bias improved to 0.04 ± 1.4 with LOA from -2.8 to 2.9 L min. Our study shows that agreement of the Nexfin-derived with invasive CO measurements in morbidly obese patients is influenced by body weight, suggesting that Nexfin CO measurements in patients with a BMI above 35 kg/m2 should be interpreted with caution. Using adjusted body weight in the Nexfin CO-trek algorithm reduced the bias.

Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide.

INTRODUCTION: Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers. METHODS: In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m2 (range 37.6-78.6 kg/m2) and weight 151.3 kg (range 112-251.9 kg)] and 20 healthy volunteers [mean weight 70.6 kg (range 58-85 kg)] were included. Morbidly obese patients received 10 mg of intravenous (I.V.) morphine after gastric bypass surgery, with additional morphine I.V. doses as needed. Healthy volunteers received an I.V. bolus of morphine of 0.1 mg/kg followed by an infusion of 0.030 mg kg-1 h-1 for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2. RESULTS: In morbidly obese patients, elimination clearance of M3G and M6G was decreased substantially compared with healthy volunteers (p < 0.001). Regarding glucuronidation, only a slight decrease in the formation of M6G and a delay in the formation of M3G was found (both p < 0.001). Obesity was also identified as a covariate for the peripheral volume of distribution of morphine (p < 0.001). CONCLUSION: Metabolism of morphine is not altered in morbidly obese patients. However, decreased elimination of both M3G and M6G is evident, resulting in a substantial increase in exposure to these two metabolites. A rational explanation of this finding is that it results from alterations in membrane transporter function and/or expression in the liver. ClinicalTrials.gov identifier: NCT01097148.

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.

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.

Comparative evaluation of propofol 350 and 200 mg for induction of anaesthesia in morbidly obese patients: a randomized double-blind pilot study.

BACKGROUND AND OBJECTIVE: The aim of this pilot study was to evaluate efficacy and safety of propofol 350 versus 200 mg for induction of anaesthesia in morbidly obese patients undergoing bariatric surgery. PATIENTS AND METHODS: Twenty morbidly obese patients (BMI range 38-60 kg m) were randomized to receive propofol 350 or 200 mg over 60 s for induction of anaesthesia. Bispectral index (BIS) values, induction characteristics and haemodynamic parameters were compared. RESULTS: At the time of intubation, in the 200 mg group, mean BIS values were more variable and significantly higher [53 (range 27-86) versus 31 (range 18-52), 200 versus 350 mg group (P = 0.01)]. In 20% of the 200 mg group, an additional propofol dose was needed, whereas no additional doses were judged necessary in the 350 mg group. At the time of intubation, six patients in the 200 mg group had systolic arterial pressures above 160 mmHg [mean 162 (range 100-210)], whereas mean pressures in the first 10 min were more in the target range in the 350 mg group [mean 122 (range 90-170)] (P = 0.01). One patient in the 350 mg group experienced a serious decrease in systolic arterial pressure (below 60 mmHg), immediately upon starting the maintenance dose. There were no significant differences in heart rate. CONCLUSION: Although propofol 200 mg proved to be an inadequate induction dose for morbidly obese patients, the 350 mg induction dose deserves further study, provided the maintenance dose is not started within 5 min, thereby preventing temporary cardiovascular instability.

Treatment of pulmonary embolism in an extremely obese patient.

Low-molecular-weight heparins are effective as initial therapy for pulmonary embolism (PE) in a weight-based dosing regimen up to known body weights of 160 kg. The present case reports an extremely obese man of 252 kg (body mass index (BMI) 74 kg/m2) with PE who was treated with tinzaparin, dosed on a body weight of 160 kg. Morbid obesity defined as a BMI higher than 40 kg/m2 is becoming more common in general practice, but there are no evidence-based drug dosing strategies for these patients. This case demonstrates the successful use of a maximum dose of 28,000 anti-Xa international units of tinzaparin for an extremely obese patient with proven PE, instead of the accepted doses of 175 IU/kg, as bridge therapy to a coumarin.