Abstract
Aims
The aim of this study was to develop a pharmacokinetic model in order to characterize the free and total ropivacaine concentrations after transversus abdominis plane block in a population of patients undergoing liver resection surgery. In particular, we evaluated the impact of the size of liver resection on ropivacaine pharmacokinetics.
Methods
This work is based on a single-centre, double-blinded, randomized, placebo-controlled study. Among the 39 patients included, 19 patients were randomized to the ropivacaine group. The free and total ropivacaine concentrations were measured in nine or 10 blood samples per patient. A pharmacokinetic model was built using a nonlinear mixed-effect modelling approach.
Results
The free ropivacaine concentrations remained under the previously published toxic threshold. A one-compartment model, including protein binding site with a first-order absorption, best described the data. The protein binding site concentration was considered as a latent variable. Bodyweight, the number of resected liver segments and postoperative fibrinogen evolution were, respectively, included in the calculation of the volume of distribution, clearance and binding site production rate. The resection of three or more liver segments was associated with a 53% decrease in the free ropivacaine clearance.
Conclusions
Although large liver resections were associated with lower free ropivacaine clearance, the ropivacaine pharmacokinetic profile remained within the safe range after this type of surgery.
Keywords: liver resection, model, population pharmacokinetics, protein binding, ropivacaine, transversus abdominis plane block
What is Already Known about this Subject
Ropivacaine is highly bound to plasma proteins (α1-acid glycoprotein).
Ropivacaine is mainly metabolized by the liver.
Liver resection affects the protein binding and metabolism of ropivacaine.
What this Study Adds
The free ropivacaine fraction is low after liver resection surgery (<2%).
The size of the liver resection affects the free ropivacaine clearance.
The pharmacokinetics of free and total ropivacaine could be analysed effectively even without α1-acid glycoprotein measurements.
Introduction
Transversus abdominis plane (TAP) nerve block is a regional anaesthetic technique that inhibits the generation and conduction of nerve impulses of the anterolateral abdominal wall by introducing a local anaesthetic between the internal oblique and the transversus abdominis muscles. Transversus abdominis plane blocks are currently used frequently in abdominal surgery and allow for reductions in postoperative opioid consumption and pain. Ropivacaine is a local anaesthetic drug with a long duration of action that is frequently used in this technique. Among the pharmacological properties of ropivacaine, the most important are as follows: (i) lipid solubility that results in high protein binding, particularly with α1-acid glycoprotein (AAG); (ii) extensive metabolism in the liver by different cytochromes P450 (CYP1A2 and CYP3A4); and (iii) high systemic exposure of ropivacaine mainly results in central nervous system (i.e. convulsions, respiration disruption) and cardiovascular disorders (hypotension, bradycardia, arrhythmia and cardiac arrest).
The safety of ropivacaine use for TAP block in liver resection surgery raises some questions because the metabolism and disposition of local anaesthetics may be altered in patients as a result of postoperative liver dysfunction. For example, fluctuations in plasma concentrations have been observed and are related to a postoperative increase in AAG. These modifications were associated with a decrease in the free (unbound) fraction of ropivacaine and an increase in the total plasma ropivacaine concentration 1. The elimination of ropivacaine may also be altered by a reduction of liver blood flow and metabolic function resulting from hepatic resection 2. As a result of the relatively low hepatic extraction ratio, ropivacaine clearance mainly depends on hepatic enzyme activity and plasma protein binding 3.
Transversus abdominis plane blocks are now used more commonly in surgeries involving the abdominal wall, and few pharmacokinetic data are available but none in liver surgery. No clear guidelines have been established concerning dosing and regimen. Different doses (weight adjusted vs. fixed dose) and regimens (continuous vs. discontinuous perfusion) have been used in various studies 4,5]. The lack of understanding that may result from limited data could result in ineffective nerve block; therefore, the aim of this study was to investigate the pharmacokinetics of ropivacaine administered by a TAP catheter in this specific population.
Patients
This single-centre, double-blinded, randomized, placebo-controlled study was conducted to evaluate the effect of ropivacaine TAP block on postoperative opioid consumption and pain in liver resection surgery for treatment of hepatic neoplasm (benign or malignant). It was performed in accordance with the Declaration of Helsinki. A local independent ethics committee approved the protocol (CPP Sud Est I, #0908127). Written informed consent was obtained from all patients or their relatives before randomization. Of the 39 patients included in the study, 19 were randomized to ropivacaine treatment and 20 to placebo. The exclusion criteria included allergy or contraindication to ropivacaine, creatinine clearance <30 ml min−1, severe sepsis, anticoagulant overdosage and a platelet count <50 × 109 l−1.
All patients received a standardized general anaesthetic. One hour before the operation, the subjects were given a weight-determined dose of between 1 and 2 mg kg−1 oral hydroxyzine. Anaesthesia was induced with propofol and remifentanil through a computer-assisted continuous infusion method. The neuromuscular blocking agent atracurium was administered at a dose of 0.5 mg kg−1. Anaesthesia was maintained with nitrous oxide in an oxygen–air mix to obtain a bispectral index between 50 and 55.
Ropivacaine administration
Transversus abdominis plane blocks were performed after the induction of general anaesthesia. The blocks were inserted with ultrasound guidance under sterile conditions using an 18-gauge Tuohy needle (Perifix®; B. Braun Medical, Boulogne, France) using an in-plane approach according to the technique described by Hebbard et al. 6. After the successful visualization of the needle tip between the internal oblique and transversus abdominis muscles, the infusion catheters were inserted, and the potential TAP space was expanded with NaCl 0.9%. The patients received a dose of 3 mg kg−1 (10.9 μ m kg−1) of ropivacaine (Naropin®; AstraZeneca, Rueil-Malmaison, France) diluted with 0.9% saline to a total volume of 30 ml. Bolus doses of ropivacaine were administered at 0, 12, 24, 36 and 48 h after surgical incision.
Sample collection and ropivacaine quantification
Nine or 10 peripheral venous blood samples were collected in heparinized tubes (5 ml) after the second ropivacaine bolus (at 12 h, H12). The blood was centrifuged for 15 min at 1100 g within 2 h of sampling, and the plasma was frozen at −80°C until assayed. The total and free ropivacaine concentrations were determined using a high-performance liquid chromatography–tandem mass spectrometry method (UPLC-Quattro Micro; Waters, Saint-Quentin Fallavier, France) using a Luna MercuryMS C18 column (20 mm x 4 mm x 3 µm; Phenomenex, Saint-Quentin en Yvelines, France) for chromatographic separation. The mobile phase was a mix of distilled water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. The total ropivacaine concentrations were measured after protein precipitation using methanol containing 0.1 mg l−1 of internal standard (ropivacaine-2H7). Ropivacaine and the internal standard were detected through electrospray positive ionization in a multiple reaction monitoring mode. The unbound ropivacaine concentrations were determined using the same technique after ultrafiltration with Vivaspin 2 and 10 kDa molecular weight cut-off concentrators (Sartorius, Aubagne, France). The method was linear over the concentration range of 0.001–5.00 mg l−1 (lower limit of quantification was 0.001 mg l−1). Two ranges of calibrations were used (0.01–5 and 0.001–0.5 mg l−1) for quantification of total ropivacaine and free ropivacaine, respectively. Following ultrafiltration, the free concentration is measured along with the total concentration, and the free fraction can be calculated. The precision and accuracy were measured at three quality control levels. Relative standard deviations were 8.9 and 9.2% for within- and between-day precision, respectively. Accuracy shows a deviation <10% from the target concentration at each tested level.
Model development and evaluation
The total and free ropivacaine concentrations were analysed jointly using a nonlinear mixed-effect model. The data analysis was performed using MONOLIX® nonlinear mixed effects modelling software (version 4.3.2) 7 with the SAEM algorithm 8. All graphics were generated using the package ggplot2 9 with R software 10.
Base model
The free ropivacaine concentrations (Rfree) were modelled using a compartmental approach. Different absorptions (zero and first order) and structures (one and two compartments) were tested. The pharmacokinetic parameters were estimated in terms of the distribution volume (V) and clearance of free ropivacaine (Cl). As the bioavailability (F) could not be quantified, the parameter values correspond to the ratios
and
, respectively.
Next, a model was proposed to describe both the free (Rfree) and bound (Rbound) ropivacaine concentrations. The concentration of total ropivacaine was modelled as the sum of Rfree and Rbound. This model allowed us to reproduce the impact of changes in the AAG concentration on the bound ropivacaine concentration observed in our data (Figure1). The postoperative inflammatory process induced a delayed (∼12 h) increase in binding site concentrations 11. We made the approximation that binding site concentrations do not change between the first two doses. The increase in the binding site concentration from the administration of the second dose was modelled as a rate of production constant (kin). The model (Figure2) corresponds to the following equations:
 |
Figure 1.
Differences in the free ropivacaine fraction over time. The orange line represents the median change in the free fraction predicted by the model. The green envelope represents the interval between the 5 and the 95% quantiles predicted by the model. The grey circles represent the data for patients with two liver segments resected. The grey triangles represent the data for patients with three, four or five liver segments resected
Figure 2.
Schematic representation of the protein-binding model. Abbreviations are as follows: Cl, free ropivacaine clearance; kb, binding rate; Kd, dissociation constant; kin, binding site production rate; kub, unbinding rate;N, volume of distribution
The parameters kb and kub are the rate constants for transport between the free and the bound compartments, respectively. Inputd corresponds to absorption rate of dose d. Parameter td is the administration time of the dose d, and I(t ≥ td) corresponds to the indicator function equal to one when t ≥ td and zero otherwise. Parameter BS0 corresponds to the binding site concentration at t = 0. We tested whether kin was significantly different from zero. This model could be subject to an identifiability issue, particularly on BS0, kb and kub. Concerning BS0, a prior has been added to the model, based on the physiological value. The prior distribution followed a lognormal distribution with mean equal to 20 μ m and SD = 0.5. This distribution takes into account the uncertainty of initial binding site concentration due to the postoperative inflammatory process and neoplastic disease 12. Concerning kb and kub, the model has been parameterized as kub = kb × Kd, where Kd corresponds to the dissociation constant of ropivacaine. A prior distribution based on the work of Aarons et al. was introduced for Kd 13. This prior followed a normal distribution with mean equal to 0.58 μ m and an SD of 0.05. The value of kb was arbitrary fixed to 1012 μ m−1 h−1, which corresponds to a realistic order of magnitude. However, different values for kb from 100 to 1015 μ m−1 h−1 have been tested, and no impact on ropivacaine pharmacokinetics has been observed.
The individual parameters θi were modelled assuming a lognormal distribution of the general form:
 |
where
is the population mean of the jth parameter and ηij are independent, normally distributed random effects with a mean of zero and variance–covariance matrix Ω. Different residual variability models (constant, proportional and combined) between the observed and predicted concentrations were tested.
The model evaluation and selection were based on a visual inspection of the goodness-of-fit plots, the precision of parameter estimates and a decrease in objective function. The goodness of fit was established by plotting the population predictions of the model vs. observations and the individual predictions vs. observations. A visual predictive check 14 was used to establish the ability of the model to describe the observations.
Covariate model
Age, weight and biomarker values on the first postoperative day (aspartate transaminase, creatinine clearance, prothrombin time and fibrinogen) were tested as continuous covariates using an exponential model, as follows:
 |
where
is the population value for bodyweight W = 70 kg and βW is the covariate effect for the weight.
The variation of these biomarkers during the postoperative period could also have influenced the pharmacokinetics of ropivacaine. Temporal variations of aspartate transaminase, creatinine clearance and prothrombin time were included in the model as the difference between their level on the first and second postoperative day. For fibrinogen, we performed a linear regression of its concentration values vs. time (day of quantification) for each subject. The estimated individual linear regression coefficient (δ) was tested as continuous covariate using the following model:
 |
where δi corresponds to the linear regression coefficient of subject i and
to the mean value of δ in the population.
The number of resected liver segments [NSH = 0 (2 segments), NSH = 1 (3, 4 or 5 segments)], sex and the surgical indication were tested as categorical covariates using the following model:
 |
where is the population value for NSH = 0 and βNSH the covariate effect for NSH = 1.
The covariates were included in the model using a stepwise method with forward inclusion and backward elimination 15.
Results
Population description
Among the 19 subjects who received ropivacaine, three subjects were excluded from the analysis due to pharmacokinetic profiles incompatible (very slow absorption rate) with a correctly placed TAP catheter. The characteristics of the patients are described in Table1.
Table 1.
Patient characteristics
| Characteristics | Median (minimum–maximum) |
|---|---|
| Clinical data | |
| Age (years) | 65 (29–77) |
| Bodyweight (kg) | 75.5 (44–130) |
| Number of resected liver segments (n) | |
| 2 | 7 |
| 3 | 2 |
| 4 | 6 |
| 5 | 1 |
| Surgical indications (n) | |
| Hepatocellular carcinoma | 4 |
| Metastasis | 10 |
| Hepatocellular adenoma | 2 |
| Preoperative biological data | |
| Plasma creatinine concentration (μ m) | 71 (45–135) |
| Prothrombin time (%) | 100 (87–100) |
| Aspartate aminotransferase (UI l−1) | 35 (25–61) |
| Fibrinogen (g l−1) | 3.0 (1.1–5.6) |
| Postoperative biological data | |
| Plasma creatinine concentration (μ m) | |
| Day 0 | 55 (44–193) |
| Day 1 | 59 (44–209) |
| Prothrombin time (%) | |
| Day 0 | 65 (41–97) |
| Day 1 | 60 (46–89) |
| AST (UI l−1) | |
| Day 0 | 491(159–1398) |
| Day 1 | 262 (93–1145) |
| Fibrinogen (g l−1) | |
| Day 0 | 3.6 (1.5–5.8) |
| Day 1 | 4.5 (3.4–7.1) |
| Day 2 | 5.8 (2.4–8.9) |
Abbreviations are as follows: AST, aspartate transaminase; n, number of patients.
Population pharmacokinetic model
A one-compartment model with first-order absorption best described the free and total ropivacaine concentrations. Intersubject variability was detected for V, ka, Cl, kin and BSH0. The estimates of the population parameters are listed in Table2. The estimated change in the free ropivacaine fraction is represented in Figure1.
Table 2.
Values of the pharmacokinetic parameters
| Parameter | Population Mean (%RSE) | Intersubject SD (%RSE) |
|---|---|---|
| ka (h−1) | 3.58 (33) | 0.854 (22) |
| V (l) | 103 (12) | 0.452 (19) |
| Cl (NSH = 2; l h−1) | 1310(16) | 0.41 (22) |
| Cl (NSH = 3,4,5; l h−1) | 620 (17) | |
| Kd (μ m) | 0.557 (–) | |
| BS12 (μ m) | 71.2(12) | 0.443 (19) |
| kin (h−1) | 1.57 (12) | 0.15 (94) |
| Continuous covariates | ||
| Weight on V | 1.28 (37) | – |
| Freg on kin | 0.422 (45) | – |
| Model error | ||
| σFree,additive | 0.00169 (45) | – |
| σFree,proportional | 0.159 (16) | – |
| σTotal,additive | 0.318 (36) | – |
| σTotal,proportional | 0.0966 (22) | – |
BSH12, binding site concentration at t = 12 h
Cl, free ropivacaine clearance
Freg, linear regression coefficient of postoperative individual fibrinogen concentrations
Kd, ropivacaine dissociation constant
kin, binding site production rate
NSH, number of liver segments resected
σFree,additive, constant residual variability in free ropivacaine
σFree,proportional, proportional residual variability in free ropivacaine
σTotal,additive, constant residual variability in total ropivacaine
σTotal,proportional, total residual variability in total ropivacaine
V, volume of distribution.
Covariate analysis
Among the available covariates, bodyweight demonstrated a statistically significant influence on V (P = 0.0089) and resulted in a 9.5% decrease in intersubject variability. The stepwise method also detected an influence of the number of resected liver segments on Cl (P = 0.0083), generating a 13.7% decrease in intersubject variability. The mean population model (stratified based on the number of resected liver segments) for a dose of 210 mg is represented in Figure3 Finally, a significant correlation was observed between the linear regression coefficient for postoperative fibrinogen concentrations and the parameter kin (P = 0.0018). The introduction of this covariate decreased intersubject variability for kin by 40.5%.
Figure 3.
Mean population model for the free and total ropivacaine concentrations. The green and orange curves represent the population model for two liver segments resected and three, four or five liver segments resected, respectively
Final model evaluation
The goodness-of-fit plots of the final model were evaluated for free and total ropivacaine (Figure S1). The data exhibited no apparent bias in model prediction. According to the visual predictive check (Figure4), the average observed values were well predicted. For free ropivacaine, only extreme profiles were not within 90% of the simulated values, demonstrating the good predictive properties of the model.
Figure 4.
Visual predictive check. The envelope represents the 90% confidence interval for the simulations. The grey circles represent the data for patients with two liver segments resected. The grey triangles represent the data for patients with three, four or five liver segments resected
Discussion
This study is the first population-based approach to evaluate ropivacaine levels after TAP block and allowed us to characterize the pharmacokinetic profile of free and total ropivacaine after TAP block in patients undergoing liver resection surgery.
No signs of ropivacaine toxicity were observed during the study. The observed free ropivacaine concentrations (maximal plasma concentration 0.34 µmol l−1) were below the toxic threshold previously described (0.55 µmol l−1 16).
The observed free ropivacaine fractions (Figure3) were lower than most of the values from previously published reports. Indeed, in the literature, the free ropivacaine fraction is highly variable (ranging from 1.6 17 to 25% 11). The two main reasons for this variability are as follows: (i) the differing analytical methods used to determine the total and free ropivacaine concentrations; and (ii) different levels of AAG concentrations across studies. Analytical method variability depends on the analytical system (liquid chromatography-mass spectrometry, liquid chromatography-UV detection, gas chromatography-mass spectrometry) to measure ropivacaine concentrations and especially methods to obtain the free fraction (microdialysis vs. ultrafiltration, dilution steps). The quantification method (one-step extraction with ultrafiltration coupled with mass spectrometry and isotopically labelled internal standard) used in the present study minimized these sources of variability and bias. A recent paper 18 with a similar approach found comparable free ropivacaine plasma concentrations. Regarding the AAG concentrations, the type of surgery, the importance of the inflammatory process 19 and certain comorbidities 20 could explain part of the interstudy variation. Liver resection surgery may be associated with higher AAG concentrations and thus with a lower free drug fraction, as observed in the present study.
In the population analysis, the free and the total ropivacaine pharmacokinetics were jointly modelled using a protein binding compartment. Using a mass balance principle, this model reproduced the protein binding process of ropivacaine. In previously used approaches13,21, the binding site concentrations (AAG concentrations) did not affect free ropivacaine pharmacokinetics and were therefore unable to reproduce the decrease in free ropivacaine over time (Figure1). Our model accurately described the temporal changes in the unbound ropivacaine fraction (Figures1, 3 and 4). Other semi-mechanistic approaches have already been proposed 22, but they do not allow for the possibility of treating the concentration of binding sites as an observation. Moreover, the estimation of the dissociation constant Kd and binding site number were not close to physiological values, maybe due to an identifiability issue. The measurement of the AAG concentrations was not initially planned and was not possible a posteriori. The latent variable BS corresponds to the unbound binding site concentration. This variable is an approximation of the AAG concentration, because ropivacaine binds specifically to AAG. Between the first two doses, the binding site concentration was estimated as 71.2 μ m, which corresponds to a higher value than the physiological AAG concentration in adults (between 10 and 30 μ m), as was expected. During the model development, the parameter kin was estimated to be significantly different from zero, which corresponds to a temporal increase in the binding site concentration. These results are consistent with the literature, because the AAG concentration is known to increase during the postoperative period 23. The inflammatory process principally drives this phenomenon, and simple inflammatory biomarkers could serve as useful surrogates for the AAG concentration. This relationship was confirmed by the covariate analysis, which indicated a significant correlation between the individual linear regression coefficient of the postoperative fibrinogen values and kin. The ropivacaine dissociation constant (Kd) with AAG can be approximated by the ratio
. This ratio is estimated to be 0.557 based on the data. This estimation is consistent with previously published work that reported values of 0.58 13 and 0.56 21.
Among the tested covariates, the patient bodyweight and the number of resected liver segments significantly influenced the volume of distribution and the free ropivacaine clearance, respectively. The inclusion of bodyweight as a factor decreased the interindividual variability in distribution volume by 9.5%. Given the remaining interpatient variability (0.455), this dose adjustment may be not necessary. Some protocols have already proposed a fixed dose for administration 5. Concerning the clearance parameter, due to their lack of specificity, the biological values traditionally used to monitor liver function (prothrombin time, Aspartate transaminase) were not correlated to the observed decrease in clearance. The categorical classification based on the number of resected liver segments allows a decrease of 13.7% in interindividual variability. In our model, free ropivacaine clearance was decreased by 53% in patients with three or more resected liver segments. This reduction could be explained by a loss of enzymatic activity but is not irreversible. Indeed, the complete recovery of liver function can be observed within 2–3 weeks in patients with normal livers 24.
The accuracy of the generated model could have been improved with the use of the following: (i) longitudinal AAG concentration measurements as observations; and (ii) a specific liver function biomarker (indocyanine green clearance, for example 25). However, the model remains relevant because it is based on routine clinical data that are easily accessible.
In conclusion, the pharmacokinetic model developed in this work accurately reproduced the protein binding of ropivacaine, even in the absence of AAG measurements. Using this model, we demonstrated a 53% decrease in free ropivacaine clearance for patients with three or more resected liver segments. The dosing regimen used in this study was safe, because the free ropivacaine concentrations remained under the previously published toxic threshold.
This research has received funding support from the University Hospital of Saint-Etienne, and was sponsored by the University Hospital of Saint-Etienne.
Competing Interests
All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: a grant from the University Hospital of Saint-Etienne, which promoted the study; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
This research has received funding support from the University Hospital of Saint-Etienne, and was sponsored by the University Hospital of Saint-Etienne.
Supporting Information
Additional Supporting Information may be found in the online version of this article at the publisher's web-site:
Figure S1
Observed vs. predicted ropivacaine concentrations. The grey circles represent the data for patients with two liver segments resected. The grey triangles represent the data for patients with three, four or five liver segments resected. Green line corresponds to the identity line and orange line to the regression line.
Supporting info item
References
- 1.Erichsen CJ, Sjövall J, Kehlet H, Hedlund C. Pharmacokinetics and analgesic effect of ropivacaine during continuous epidural infusion for postoperative pain relief. Anesthesiology. 1996;84:834–42. doi: 10.1097/00000542-199604000-00010. [DOI] [PubMed] [Google Scholar]
- 2.Hayes PC. Liver disease and drug disposition. Br J Anaesth. 1992;68:459–61. doi: 10.1093/bja/68.5.459. [DOI] [PubMed] [Google Scholar]
- 3.Tucker GT. Safety in numbers. The role of pharmacokinetics in local anesthetic toxicity: the 1993 ASRA Lecture. Reg Anesth. 1994;19:155–63. [PubMed] [Google Scholar]
- 4.McDonnell JG, Curley G, Carney J, Benton A. The analgesic efficacy of transversus abdominis plane block after cesarean delivery: a randomized controlled trial. Anesth Analg. 2008;106:186–91. doi: 10.1213/01.ane.0000290294.64090.f3. [DOI] [PubMed] [Google Scholar]
- 5.Belavy D, Cowlishaw PJ, Howes M. Ultrasound-guided transversus abdominis plane block for analgesia after Caesarean delivery. Br J Anaesth. 2009;103:726–30. doi: 10.1093/bja/aep235. [DOI] [PubMed] [Google Scholar]
- 6.Hebbard PD, Barrington MJ, Vasey C. Ultrasound-guided continuous oblique subcostal transversus abdominis plane blockade: description of anatomy and clinical technique. Reg Anesth Pain Med. 2010;35:436–41. doi: 10.1097/aap.0b013e3181e66702. [DOI] [PubMed] [Google Scholar]
- 7.2012. Lixsoft-Incuballiance: Monolix User Guide Version 4.3.2. Available at http://www.lixoft.eu/wp-content/resources/docs/UsersGuide.pdf (last accessed 24 January 2015)
- 8.Kuhn E, Lavielle M. Coupling a stochastic approximation version of EM with an MCMC procedure. Probab Stat. 2004;8:115–31. [Google Scholar]
- 9.Wickham H. Ggplot2: Elegant Graphics for Data Analysis. New York: Springer; 2009. [Google Scholar]
- 10.R Development Core Team. 2013. Vienna R Foundation for Statistical Computing R: A Language and Environment for Statistical Computing, ISBN info:x-wiley/isbn/3900051070; Available at http://www.R-project.org (last accessed 24 January 2015)
- 11.Yokogawa K, Shimomura S, Ishizaki J, Shimada T, Fukuwa C, Kawada M, Tsubokawa T, Yamamoto K, Miyamoto K. Involvement of α1-acid glycoprotein in inter-individual variation of disposition kinetics of ropivacaine following epidural infusion in off-pump coronary artery bypass grafting. J Pharm Pharmacol. 2007;59:67–73. doi: 10.1211/jpp.59.1.0009. [DOI] [PubMed] [Google Scholar]
- 12.Chio LF, Oon CJ. Changes in serum alpha1 antitrypsin, alpha1 acid glycoprotein and beta2 glycoprotein i in patients with malignant hepatocellular carcinoma. Cancer. 1979;43:596–604. doi: 10.1002/1097-0142(197902)43:2<596::aid-cncr2820430229>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
- 13.Aarons L, Sadler B, Pitsiu M, Sjövall J, Henriksson J, Molnár V. Population pharmacokinetic analysis of ropivacaine and its metabolite 2',6'-pipecoloxylidide from pooled data in neonates, infants, and children. Br J Anaesth. 2011;107:409–24. doi: 10.1093/bja/aer154. [DOI] [PubMed] [Google Scholar]
- 14.Holford NH. 2005. The visual predictive check—superiority to standard diagnostic (Rorschach) plots. Population Approach Group in Europe (PAGE), Pamplona, Spain,. Available at http://www.page-meeting.org/?abstract=738 (last accessed 24 January 2015)
- 15.Jonsson EN, Karlsson MO. Automated covariate model building within NONMEM. Pharm Res. 1998;15:1463–8. doi: 10.1023/a:1011970125687. [DOI] [PubMed] [Google Scholar]
- 16.Knudsen K, Suurküla MB, Blomberg S, Sjövall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth. 1997;78:507–14. doi: 10.1093/bja/78.5.507. [DOI] [PubMed] [Google Scholar]
- 17.Maurer K, Blumenthal S, Rentsch KM, Schmid ER. Continuous extrapleural infusion of ropivacaine 0.2% after cardiovascular surgery via the lateral thoracotomy approach. J Cardiothorac Vasc Anesth. 2008;22:249–54. doi: 10.1053/j.jvca.2007.06.005. [DOI] [PubMed] [Google Scholar]
- 18.Bleckner L, Solla C, Fileta BB, Howard R, Morales CE, Buckenmaier CC. Serum free ropivacaine concentrations among patients receiving continuous peripheral nerve block catheters. Anesth Analg. 2014;118:225–9. doi: 10.1213/ANE.0000000000000019. [DOI] [PubMed] [Google Scholar]
- 19.Fournier T, Medjoubi NN, Porquet D. Alpha-1-acid glycoprotein. Biochim Biophys Acta. 2000;1482:157–71. doi: 10.1016/s0167-4838(00)00153-9. [DOI] [PubMed] [Google Scholar]
- 20.Piafsky KM, Borgå O, Odar-Cederlöf I, Johansson C, Sjöqvist F. Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma α1 acid glycoprotein. N Engl J Med. 1978;299:1435–9. doi: 10.1056/NEJM197812282992604. [DOI] [PubMed] [Google Scholar]
- 21.Rapp HJ, Molnár V, Austin S, Krohn S, Gädeke V, Motsch J, Boos K, Williams DG, Gustafsson U, Huledal G, Larsson LE. Ropivacaine in neonates and infants: a population pharmacokinetic evaluation following single caudal block. Paediatr Anaesth. 2004;14:724–32. doi: 10.1111/j.1460-9592.2004.01373.x. [DOI] [PubMed] [Google Scholar]
- 22.de Winter BCM, van Gelder T, Sombogaard F, Shaw LM, van Hest RM, Mathot RAA. Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. J Pharmacokinet Pharmacodyn. 2009;36:541–64. doi: 10.1007/s10928-009-9136-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Booker PD, Taylor C, Saba G. Perioperative changes in α1-acid glycoprotein concentrations in infants undergoing major surgery. Br J Anaesth. 1996;76:365–8. doi: 10.1093/bja/76.3.365. [DOI] [PubMed] [Google Scholar]
- 24.Nagasue N, Yukaya H, Ogawa Y, Kohno H, Nakamura T. Human liver regeneration after major hepatic resection. A study of normal liver and livers with chronic hepatitis and cirrhosis. Ann Surg. 1987;206:30–9. doi: 10.1097/00000658-198707000-00005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Leevy CM, Smith F, Longueville J, Paumgartner G, Howard MM. Indocyanine green clearance as a test for hepatic function: evaluation by dichromatic ear densitometry. JAMA. 1967;200:236–40. [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting info item