The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients.

BACKGROUND: Norepinephrine (NE) is a cornerstone drug in the management of septic shock, with its dose being used clinically as a marker of disease severity and as mortality predictor. However, variations in NE dose reporting either as salt formulations or base molecule may lead to misinterpretation of mortality risks and hinder the process of care. METHODS: We conducted a retrospective analysis of the MIMIC-IV database to assess the impact of NE dose reporting heterogeneity on mortality prediction in a cohort of septic shock patients. NE doses were converted from the base molecule to equivalent salt doses, and their ability to predict 28-day mortality at common severity dose cut-offs was compared. RESULTS: 4086 eligible patients with septic shock were identified, with a median age of 68 [57-78] years, an admission SOFA score of 7 [6-10], and lactate at diagnosis of 3.2 [2.4-5.1] mmol/L. Median peak NE dose at day 1 was 0.24 [0.12-0.42] µg/kg/min, with a 28-day mortality of 39.3%. The NE dose showed significant heterogeneity in mortality prediction depending on which formulation was reported, with doses reported as bitartrate and tartrate presenting 65 (95% CI 79-43)% and 67 (95% CI 80-47)% lower ORs than base molecule, respectively. This divergence in prediction widened at increasing NE doses. When using a 1 µg/kg/min threshold, predicted mortality was 54 (95% CI 52-56)% and 83 (95% CI 80-87)% for tartrate formulation and base molecule, respectively. CONCLUSIONS: Heterogeneous reporting of NE doses significantly affects mortality prediction in septic shock. Standardizing NE dose reporting as base molecule could enhance risk stratification and improve processes of care. These findings underscore the importance of consistent NE dose reporting practices in critical care settings.

Pediatric anesthesiology in Brazil, Chile, and Mexico.

BACKGROUND: Latin America comprises an extensive and diverse territory composed of 33 countries in the Caribbean, Central, and South America where Romance languages-languages derived from Latin are predominantly spoken. Economic disparities exist, with inequitable access to pediatric surgical care. The Latin American Surgical Outcomes Study in Pediatrics (LASOS-Peds), a multi-national collaboration, will determine safety of pediatric anesthesia and perioperative care. OBJECTIVE: Below, we provide a descriptive initiative to share how pediatric anesthesia in Brazil, Chile, and Mexico operate. Theses descriptions do not represent all of Latin America. DESCRIPTIONS AND CONCLUSIONS: Brazil an upper middle-income country, population 203 million, has a public system insufficiently resourced and a private system, resulting in inequitable safety and accessibility. Surgical complications constitute the third leading cause of mortality. Anesthesiology residency is 3 years, with required rotations in pediatric anesthesia; five hospitals offer pediatric anesthesia fellowships. Anesthesiology is a physician-only practice. A Pediatric Anesthesia Committee within the Brazilian Society of Anesthesiology offers education through seasonal courses and workshops including pediatric advanced life support. Chile is a high-income country, population 19.5 million, the majority cared for in the public system, the remainder in university, private, or military systems. Government efforts have gradually corrected the long-standing anesthesiology shortage: twenty 3-year residency programs prepare graduates for routine pediatric cases. The Chilean Society of Anesthesiology runs a 1-month program for general anesthesiologists to enhance pediatric anesthesia skills. Pediatric anesthesia fellowship training occurs in Europe, USA, and Australia, or in two 2-year Chilean university programs. Public health policies have increased the medical and surgical pediatric specialists and general anesthesiologists, but not pediatric anesthesiologists, which creates safety concerns for neonates, infants, and medically complex. Chile needs more pediatric anesthesia fellowship programs. Mexico, an upper middle-income country, with a population of about 126 million, has a five-sector healthcare system: public, social security for union workers, state for public employees, armed forces for the military, and a private "self-pay." There are inequities in safety and accessibility for children. Pediatric Anesthesiology fellowship is 2 years, after 3 years residency. A shortage of pediatric anesthesiologists limits accessibility and safety for surgical care, driven by added training at low salary and hospital under appreciation. The Mexican Society of Pediatric Anesthesiology conducts refresher courses, workshops, and case conferences. Insufficient resources and culture limits research.

Population pharmacokinetics of amikacin in suspected cases of neonatal sepsis.

AIMS: This study aimed to characterize the population pharmacokinetic parameters of intravenously administered amikacin in newborns and assess the effect of sepsis in amikacin exposure. METHODS: Newborns aged ≥3 days who received at least 1 dose of amikacin during their hospitalization period were eligible for the study. Amikacin was administered intravenously during a 60-min infusion period. Three venous blood samples were taken from each patient during the first 48 h. Population pharmacokinetic parameter estimates were obtained using a population approach with the programme NONMEM. RESULTS: Data from 329 drug assay samples were obtained from 116 newborn patients (postmenstrual age [PMA] 38.3, range 32-42.4 weeks; weight 2.8, range 1.6-3.8 kg). Measured amikacin concentrations ranged from 0.8 to 56.4 mg/L. A 2-compartment model with linear elimination produced a good fit of the data. Estimated parameters for a typical subject (2.8 kg, 38.3 weeks) were clearance (Cl = 0.16 L/h), intercompartmental clearance (Q = 0.15 L/h), volume of distribution of the central compartment (Vc = 0.98 L) and peripheral volume of distribution (Vp = 1.23 L). Total bodyweight, PMA and the presence of sepsis positively influenced Cl. Plasma creatinine concentration and circulatory instability (shock) negatively influenced Cl. CONCLUSION: Our main results confirm previous findings showing that weight, PMA and renal function are relevant factors influencing newborn amikacin pharmacokinetics. In addition, current results showed that pathophysiological states of critically ill neonates, such as sepsis and shock, were associated with opposite effects in amikacin clearance and should be considered in dose adjustments.

Propofol context-sensitive decrement times in children.

Plasma drug concentration is the variable linking dose to effect. The decrement time required for plasma concentration of anesthetic agents to decrease by 50% (context-sensitive half-time) correlates with the time taken to regain consciousness. However, the decrement time to consciousness may not be 50%. An effect compartment concentration is associated more closely with return of consciousness than plasma concentration. An alternative decrement time, the time required for propofol to decrease to a predetermined effect compartment concentration associated with movement (eg, 2 µg.ml-1 ), was used to simulate time for the concentration to decrease from steady state at a typical targeted effect compartment concentration 3.5 µg.ml-1 in children. These times were short and reflected a decrement time to consciousness (CSTAWAKE ) increase that was small with longer infusion time. CSTAWAKE ranged from 7.5 min in 1-year-old infant given propofol for 15 min to 13.5 min in a 15-year-old adolescent given a 2-hour infusion. Changes in decrement time with age reflect maturation of drug clearance. Neonates had prolonged increment times, 10 min after 15 min infusion and 18 min after 120 min infusion using a target concentration of 3.5 µg.ml-1 . Decrement times to a targeted arousal concentration are context-sensitive. Use of a higher target concentration of 6 µg.ml-1 doubled decrement times. Decrement times are associated with variability: delayed recovery beyond these simulated times is likely more attributable to the use of adjuvant drugs or the child's clinical status. An understanding of propofol decrement times can be used to guide recovery after anesthesia.

Levobupivacaine plasma concentrations following repeat caudal anesthetics.

AIM: A single caudal anesthetic at the start of lower abdominal surgery is unlikely to provide prolonged analgesia. A second caudal at the end of the procedure extends the analgesia duration but total plasma concentrations may be associated with toxicity. Our aim was to measure total plasma levobupivacaine concentrations after repeat caudal anesthesia in infants and to generate a pharmacokinetic model for prediction of plasma concentrations after repeat caudal anesthesia in neonates, infants and children. METHODS: Infants undergoing definitive repair of anorectal malformations or Hirschsprung's disease received a second caudal anesthesia at the end of the procedure. Total levobupivacaine concentrations were assayed 3-4 times in the first 6 h after the initial caudal. These data were pooled with data from four studies describing plasma concentrations after levobupivacaine caudal or spinal anesthesia. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects models. Covariates included postmenstrual age and body weight. Parameter estimates were used to simulate concentrations after a repeat levobupivacaine 2.5 mg kg-1 caudal at 3 or 4 h following an initial levobupivacaine 2.5 mg kg-1 caudal. RESULTS: Twenty-one infants (postnatal age 11-32 weeks, gestation 37-39 weeks, weight 5.2-8.6 kg) were included. The measured peak plasma concentration after repeat caudal levobupivacaine 2.5 mg kg-1 4 h after initial caudal was 1.38 mg L-1 (95% prediction interval 0.60-2.6 mg L-1 ) and 3 h after initial caudal was 1.46 mg L-1 (0.60-2.80) mg L-1 . Simulation of total plasma concentrations in neonates (7 kg, 57 weeks postmenstrual age) given caudal levobupivacaine 4 h after the initial caudal were 1.76 mg L-1 (0.68-3.50) mg L-1 if 2.5 mg kg-1 levobupivacaine was used and 0.88 mg L-1 (0.34-1.73) mg L-1 if 1.25 mg kg-1 of 0.125% levobupivacaine was used. In simulated older children (20 kg, 6 years), the mean maximum concentration was 1.43 mg L-1 (0.60-2.70) mg L-1 if 2.5 mg kg-1 levobupivacaine was repeated at 3 h. CONCLUSION: Repeat caudal levobupivacaine 2.5 mg kg-1 at 3 h after an initial 2.5 mg kg-1 dose does not exceed the concentration associated with systemic local anesthetic toxicity. In 2.5% of simulated neonates (weight 3.8 kg, PMA 40 weeks), repeat caudal anesthesia demonstrates broaching of the lower concentration limit associated with toxicity at both 3 and 4 h after initial caudal.

Brain activity complexity has a nonlinear relation to the level of propofol sedation.

BACKGROUND: Brain activity complexity is a promising correlate of states of consciousness. Previous studies have shown higher complexity for awake compared with deep anaesthesia states. However, little attention has been paid to complexity in intermediate states of sedation. METHODS: We analysed the Lempel-Ziv complexity of EEG signals from subjects undergoing moderate propofol sedation, from an open access database, and related it to behavioural performance as a continuous marker of the level of sedation and to plasma propofol concentrations. We explored its relation to spectral properties, to propofol susceptibility, and its topographical distribution. RESULTS: Subjects who retained behavioural performance despite propofol sedation showed increased brain activity complexity compared with baseline (M=13.9%, 95% confidence interval=7.5-20.3). This was not the case for subjects who lost behavioural performance. The increase was most prominent in frontal electrodes, and correlated with behavioural performance and propofol susceptibility. This effect was positively correlated with high-frequency activity. However, abolishing specific frequency ranges (e.g. alpha or gamma) did not reduce the propofol-induced increase in Lempel-Ziv complexity. CONCLUSIONS: Brain activity complexity can increase in response to propofol, particularly during low-dose sedation. Propofol-mediated Lempel-Ziv complexity increase was independent of frequency-specific spectral power manipulations, and most prominent in frontal areas. Taken together, these results advance our understanding of brain activity complexity and anaesthetics. They do not support models of consciousness that propose a direct relation between brain activity complexity and states of consciousness.

Prediction of levobupivacaine concentrations in neonates and infants following neuraxial rescue blocks.

AIM: Pharmacokinetic simulation was used to characterize levobupivacaine disposition after regional anesthetic rescue for failed spinal anesthesia in neonates and infants. METHODS: Population pharmacokinetics of levobupivacaine were estimated after spinal blockade in a cohort of neonates and infants (n = 25, postnatal age 5-18 weeks, gestation 21-41 weeks, weight 2.4-6 kg). Total levobupivacaine concentrations were assayed 3-4 times in the first hour after spinal levobupivacaine 1 mg kg-1 administration. Parameters were estimated using nonlinear mixed-effects models and supported by priors. Covariates included postnatal age and total body weight. Parameter estimates were used to simulate total levobupivacaine concentrations after a primary spinal levobupivacaine 1 mg kg-1 with rescue caudal levobupivacaine 1.5-2.5 mg kg-1 . RESULTS: A one-compartment model with a mature clearance 21.5 L h-1  70 kg-1 (CV 47.3%) and central volume 189 L 70 kg-1 (CV 37%) adequately described time-concentration profiles. Clearance maturation was described using a maturation half-time of 11.5 weeks postnatal age. The absorption half-time for spinal levobupivacaine was 2.6 min (CV 56.8%). The upper (97.5% prediction) for peak concentrations after rescue caudal levobupivacaine were 1.5 mg kg-1 , 2 mg kg-1 , and 2.5 mg kg-1 was 2.05 mg L-1 , 2.5 mg L-1 , and 2.9 mg L-1 respectively. CONCLUSION: Total bupivacaine concentrations greater than 2.5 mg L-1 are associated with neurotoxicity in adults. Predicted concentrations after either a repeat spinal or a caudal rescue dose of levobupivacaine 1.5 mg kg-1 1 h after spinal levobupivacaine administration are below the neurotoxic concentration threshold.

Pharmacokinetic concepts for dexmedetomidine target-controlled infusion pumps in children.

Pharmacokinetic parameter estimates are used in mathematical equations (pharmacokinetic models) to describe concentration changes with time in a population and are specific to that population. Simulation using these models and their parameter estimates can enrich understanding of drug behavior and serve as a basis for study design. Pharmacokinetic concepts are presented pertaining to future designs of dexmedetomidine target-controlled infusion pumps in children. This manuscript provides the pediatric anesthesiologist with an understanding of the nuances that should be considered when using target-controlled infusion pumps; how the central volume may differ between populations, how clearance changes with age, and the impact of adverse effects on dose. In addition, the ideal loading dose and rate of delivery to achieve target concentration without adverse cardiovascular effects are reviewed, and finally, dose considerations for obese children, based on contact-sensitive half-time, are introduced. An understanding of context-sensitive half-time changes with age enables anesthetic practitioners to better estimate duration of effect after cessation of dexmedetomidine infusion. Use of these known pharmacokinetic parameters and covariate information for the pediatric patient could readily be incorporated into commercial target-controlled infusion pumps to allow effective and safe open-loop administration of dexmedetomidine in children.

A Pharmacokinetic and Pharmacodynamic Study of Oral Dexmedetomidine.

BACKGROUND: Dexmedetomidine is only approved for use in humans as an intravenous medication. An oral formulation may broaden the use and benefits of dexmedetomidine to numerous care settings. The authors hypothesized that oral dexmedetomidine (300 mcg to 700 mcg) would result in plasma concentrations consistent with sedation while maintaining hemodynamic stability. METHODS: The authors performed a single-site, open-label, phase I dose-escalation study of a solid oral dosage formulation of dexmedetomidine in healthy volunteers (n = 5, 300 mcg; followed by n = 5, 500 mcg; followed by n = 5, 700 mcg). The primary study outcome was hemodynamic stability defined as lack of hypertension, hypotension, or bradycardia. The authors assessed this outcome by analyzing raw hemodynamic data. Plasma dexmedetomidine concentrations were determined by liquid chromatograph-tandem mass spectrometry. Nonlinear mixed effect models were used for pharmacokinetic and pharmacodynamic analyses. RESULTS: Oral dexmedetomidine was associated with plasma concentration-dependent decreases in heart rate and mean arterial pressure. All but one subject in the 500-mcg group met our criteria for hemodynamic stability. The plasma concentration profile was adequately described by a 2-compartment, weight allometric, first-order absorption, first-order elimination pharmacokinetic model. The standardized estimated parameters for an individual of 70 kg was V1 = 35.6 [95% CI, 23.8 to 52.8] l; V2 = 54.7 [34.2 to 81.7] l; CL = 0.56 [0.49 to 0.64] l/min; and F = 7.2 [4.7 to 14.4]%. Linear models with effect sites adequately described the decreases in mean arterial pressure and heart rate associated with oral dexmedetomidine administration. However, only the 700-mcg group reached plasma concentrations that have previously been associated with sedation (>0.2 ng/ml). CONCLUSIONS: Oral administration of dexmedetomidine in doses between 300 and 700 mcg was associated with decreases in heart rate and mean arterial pressure. Despite low oral absorption, the 700-mcg dose scheme reached clinically relevant concentrations for possible use as a sleep-enhancing medication.

Nebulization of Vancomycin Provides Higher Lung Tissue Concentrations than Intravenous Administration in Ventilated Female Piglets with Healthy Lungs.

BACKGROUND: Intravenous vancomycin is used to treat ventilator-associated pneumonia caused by methicillin-resistant Staphylococcus aureus, but achieves high rates of failure. Vancomycin nebulization may be efficient to provide high vancomycin lung tissue concentrations. The aim of this study was to compare lung tissue and serum concentrations of vancomycin administered intravenously and by aerosol in mechanically ventilated and anesthetized healthy piglets. METHODS: Twelve female piglets received a single intravenous dose of vancomycin (15 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of administration. Twelve piglets received a single nebulized dose of vancomycin (37.5 mg/kg) and were killed 1 (n = 6) or 12 h (n = 6) after the end of the aerosol administration. In each group, vancomycin lung tissue concentrations were assessed on postmortem lung specimens using high-performance liquid chromatography. Blood samples were collected for serum vancomycin concentration measurement 30 min and 1, 2, 4, 6, 8, and 12 h after the end of vancomycin administration. Pharmacokinetics was analyzed by nonlinear mixed effect modeling. RESULTS: One hour after vancomycin administration, lung tissue concentrations in the aerosol group were 13 times the concentrations in the intravenous group (median and interquartile range: 161 [71, 301] µg/g versus 12 [4, 42] µg/g; P < 0.0001). Twelve hours after vancomycin administration, lung tissue concentrations in the aerosol group were 63 (23, 119) µg/g and 0 (0, 19) µg/g in the intravenous group (P < 0.0001). A two-compartment weight-scaled allometric model with first-order absorption and elimination best fit serum pharmacokinetics after both routes of administration. Area under the time-concentration curve from 0 to 12 h was lower in the aerosol group in comparison to the intravenous group (56 [8, 70] mg · h · l vs. 121 [103, 149] mg · h · l, P = 0.002). Using a population model, vancomycin bioavailability was 13% (95% CI, 6 to 69; coefficient of variation = 85%) and absorption rate was slow (absorption half life = 0.3 h). CONCLUSIONS: Administration of vancomycin by nebulization resulted in higher lung tissue concentrations than the intravenous route.

Impact of the COVID-19 pandemic on anaesthesia trainees and their training.

Coronavirus disease 2019 (COVID-19; severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] has dislocated clinical services and postgraduate training. To better understand and to document these impacts, we contacted anaesthesia trainees and trainers across six continents and collated their experiences during the pandemic. All aspects of training programmes have been affected. Trainees report that reduced caseload, sub-specialty experience, and supervised procedures are impairing learning. Cancelled educational activities, postponed examinations, and altered rotations threaten progression through training. Job prospects and international opportunities are downgraded. Work-related anxieties about provision of personal protective equipment, and risks to self and to colleagues are superimposed on concerns for family and friends and domestic disruption. These seismic changes have had consequences for well-being and mental health. In response, anaesthetists have developed innovations in teaching and trainee support. New technologies support trainer-trainee interactions, with a focus on e-learning. National training bodies and medical regulators that specify training and oversee assessment of trainees and their progression have provided flexibility in their requirements. Within anaesthesia departments, support transcends grades and job titles with lessons for the future. Attention to wellness, awareness of mental health issues and multimodal support can attenuate but not eliminate trainee distress.

A manual propofol infusion regimen for neonates and infants.

AIMS: Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3 years undergoing anesthesia. We assessed the performance of these regimens using reported age-specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens. METHODS: Simulations using a reported general purpose pharmacokinetic propofol model were used to predict propofol blood plasma concentrations during manual infusion regimens recommended for children 0-3 years. Simulated steady state concentrations were 6-8 µg.mL-1 in the first 30 minutes that were not sustained during 100 minutes infusions. Pooled clinical data (n = 161, 1902 plasma concentrations) were used to determine an alternative pharmacokinetic parameter set for propofol using nonlinear mixed effects models. A new manual infusion regimen for propofol that achieves a steady-state concentration of 3 µg.mL-1 was determined using a heuristic approach. RESULTS: A manual dosing regimen predicted to achieve steady-state plasma concentration of 3 µg.mL-1 comprised a loading dose of 2 mg.kg-1 followed by an infusion rate of 9 mg.kg-1 .h-1 for the first 15 minutes, 7 mg.kg-1 .h-1 from 15 to 30 minutes, 6 mg.kg-1 .h-1 from 30 to 60 minutes, 5 mg.kg-1 .h-1 from 1 to 2 hours in neonates (38-44 weeks postmenstrual age). Dose increased with age in those aged 1-2 years with a loading dose of 2.5 mg.kg-1 followed by an infusion rate of 13 mg.kg-1 .h-1 for the first 15 minutes, 12 mg.kg-1 .h-1 from 15 to 30 minutes, 11 mg.kg-1 .h-1 from 30 to 60 minutes, and 10 mg.kg-1 .h-1 from 1 to 2 hours. CONCLUSION: Propofol clearance increases throughout infancy to reach 92% that reported in adults (1.93 L.min.70 kg-1 ) by 6 months postnatal age and infusion regimens should reflect clearance maturation and be cognizant of adverse effects from concentrations greater than the target plasma concentration. Predicted concentrations using a published general purpose pharmacokinetic propofol model were similar to those determined using a new parameter set using richer neonatal and infant data.

[Liver transplantation: development, learning curve and results after the first 300 cases]. / Trasplante hepático: evolución, curva de aprendizaje y resultados después de los primeros 300 casos.

BACKGROUND: Liver transplantation (LT) is an option for people with liver failure who cannot be cured with other therapies and for some people with liver cancer. AIM: To describe, and analyze the first 300 LT clinical results, and to establish our learning curve. MATERIAL AND METHODS: Retrospective cohort study with data obtained from a prospectively collected LT Program database. We included all LT performed at a single center from March 1994 to September 2017. The database gathered demographics, diagnosis, indications for LT, surgical aspects and postoperative courses. We constructed a cumulative summation test for learning curve (LC-CUSUM) using 30-day post-LT mortality. Mortality at 30 days, and actuarial 1-, and 5-year survival rate were analyzed. RESULTS: A total of 281 patients aged 54 (0-71) years (129 women) underwent 300 LT. Ten percent of patients were younger than 18 years old. The first, second and third indications for LT were non-alcoholic steatohepatitis, chronic autoimmune hepatitis and alcoholic liver cirrhosis, respectively. Acute liver failure was the LT indication in 51 cases (17%). The overall complication rate was 71%. Infectious and biliary complications were the most common of them (47 and 31% respectively). The LC-CUSUM curve shows that the first 30 patients corresponded to the learning curve. The peri-operative mortality was 8%. Actuarial 1 and 5-year survival rates were 82 and 71.4%, respectively. CONCLUSIONS: Outcome improvement of a LT program depends on the accumulation of experience after the first 30 transplants and the peri-operative mortality directly impacted long-term survival.

Effect-Site Target-Controlled Infusion in the Obese: Model Derivation and Performance Assessment.

BACKGROUND: The aim of this study is to derive a propofol pharmacokinetic (PK) pharmacodynamic (PD) model to perform effect-site target-controlled infusion (TCI) in obese patients, and to analyze its performance along with that of other available PK models. METHODS: In the first step of the study, a 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (keo) was used to fit propofol concentration-bispectral index (BIS) data. Population modeling analysis was performed by nonlinear mixed effects regression in NONMEM (ICON, Dublin, Ireland). PK data from 3 previous studies in obese adult patients (n = 47), including PD (BIS) data from 1 of these studies (n = 20), were pooled and simultaneously analyzed. A decrease in NONMEM objective function (ΔOBJ) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. In the second step of the study, we analyzed the predictive performance (median predictive errors [MDPE] and median absolute predictive errors [MDAPE]) of the current model and of other available models using an independent data set (n = 14). RESULTS: Step 1: The selected PKPD model produced an adequate fit of the data. Total body weight resulted in the best size scalar for volumes and clearances (ΔOBJ, -18.173). Empirical allometric total body weight relationships did not improve model fit (ΔOBJ, 0.309). A lag time parameter for BIS response improved the fit (ΔOBJ, 89.593). No effect of age or gender was observed. Step 2: Current model MDPE and MDAPE were 11.5% (3.7-25.0) and 26.8% (20.7-32.6) in the PK part and 0.4% (-10.39 to 3.85) and 11.9% (20.7-32.6) in the PD part. The PK model developed by Eleveld et al resulted in the lowest PK predictive errors (MDPE = <10% and MDAPE = <25%). CONCLUSIONS: We derived and validated a propofol PKPD model to perform effect-site TCI in obese patients. This model, derived exclusively from obese patient's data, is not recommended for TCI in lean patients because it carries the risk of underdosing.

Modeling the pharmacokinetics and pharmacodynamics of sevoflurane using compartment models in children and adults.

BACKGROUND: Sevoflurane pharmacokinetics have been traditionally described using physiological models, while pharmacodynamics employed the use of minimal alveolar concentration. AIMS: The integrated pharmacokinetic-pharmacodynamic relationship of sevoflurane in both adults and children was reviewed using compartment models. We wished to delineate age-related changes in both pharmacokinetics and pharmacodynamics. METHODS: The bispectral index and sevoflurane endtidal concentration were continuously measured in 50 patients, aged 3-71 years, scheduled for minor surgery. During maintenance of anesthesia and after stable bispectral index values of 60-65 were obtained, the inspired concentration of sevoflurane was increased to 5 vol % for 5 minutes or until BIS 40 and then decreased. Data were analyzed using mammillary compartments with nonlinear mixed effects population modeling. The covariate effects of age and size were investigated. RESULTS: A three-compartment PK model adequately described sevoflurane pharmacokinetics. Size standardization using allometry explained clearance and volume changes with age. The equilibration half-time (1.48 minutes) increased with age, but could be predicted using allometry in those under 40 years. The effect site concentration eliciting half the maximum response at age 40 years was 1.3% (95%CI 1.22, 1.42) decreased with age from 1.6% at 3 years to 1.1% at 70 years. CONCLUSION: Pharmacokinetic compartment models offer an alternative method to describe inhalation anesthetic drug disposition and effects.

Propofol pharmacokinetic and pharmacodynamic profile and its electroencephalographic interaction with remifentanil in children.

BACKGROUND: Propofol and remifentanil are commonly combined during total intravenous anesthesia. The impact of remifentanil in this relationship is poorly quantified in children. Derivation of an integrated pharmacokinetic and pharmacodynamic propofol model, containing remifentanil pharmacodynamic interaction information, enables propofol effect-site target-controlled infusion in children with a better prediction of its hypnotic effect when both drugs are combined. AIMS: We designed this study to derive an integrated propofol pharmacokinetic-pharmacodynamic model in children and to describe the pharmacodynamic interaction between propofol and remifentanil on the electroencephalographic bispectral index effect. METHODS: Thirty children (mean age: 5.45 years, range 1.3-11.9; mean weight: 23.5 kg, range 8.5-61) scheduled for elective surgery with general anesthesia were studied. After sevoflurane induction, maintenance of anesthesia was based on propofol and remifentanil. Blood samples to measure propofol concentration were collected during anesthesia maintenance and up to 6 hours in the postoperative period. Bispectral index data were continuously recorded throughout the study. A pharmacokinetic-pharmacodynamic model was developed using population modeling. The Greco model was used to examine the pharmacokinetic-pharmacodynamic interaction between propofol and remifentanil for BIS response RESULTS: Propofol pharmacokinetic data from a previous study in 53 children were pooled with current data and simultaneously analyzed. Propofol pharmacokinetics were adequately described by a three-compartment distribution model with first-order elimination. Theory-based allometric relationships based on TBW improved the model fit. The Greco model supported an additive interaction between propofol and remifentanil. Remifentanil showed only a minor effect in BIS response. CONCLUSION: We have developed an integrated propofol pharmacokinetic-pharmacodynamic model that can describe the pharmacodynamic interaction between propofol and remifentanil for BIS response. An additive interaction was supported by our modeling analysis.

Advances in pharmacokinetic modeling: target controlled infusions in the obese.

PURPOSE OF REVIEW: The use of conventional pharmacokinetic parameters sets 'models' derived from nonobese patients has proven inadequate to administer intravenous anesthetics in the obese population and is commonly associated with higher than anticipated plasma propofol concentrations when used with target (plasma or effect site) controlled infusion pumps. In this review we will describe recent modeling strategies to characterize the disposition of intravenous anesthetics in the obese patient and will show clinically relevant aspects of new model's performance in the obese population. RECENT FINDINGS: Because clearance of a drug increases in a nonlinear manner with weight, nonlinear relationships better scale infusion rates between lean and obese individuals. Allometric concepts have been successfully used to describe size-related nonlinear changes in clearances. Other nonlinear scaling options include the use of descriptors such as body surface area, lean body weight, fat-free mass, and normal fat mass. Newer pharmacokinetic models, determined from obese patient data, have been developed for propofol and remifentanil using allometric concepts and comprehensive size descriptors. SUMMARY: Pharmacokinetic models to perform target-controlled infusion in the obese population should incorporate descriptors that reflect with greater precision the influence of body composition in volumes and clearances of each drug. It is our hope that commercially available pumps will soon incorporate these new models to improve the performance of this technique in the obese population.