Perioperative Acetaminophen Dosing in Obese Children.

Acetaminophen is a commonly used perioperative analgesic drug in children. The use of a preoperative loading dose achieves a target concentration of 10 mg/L associated with a target analgesic effect that is 2.6 pain units (visual analogue scale 1-10). Postoperative maintenance dosing is used to keep this effect at a steady-state concentration. The loading dose in children is commonly prescribed per kilogram. That dose is consistent with the linear relationship between the volume of distribution and total body weight. Total body weight is made up of both fat and fat-free mass. The fat mass has little influence on the volume of distribution of acetaminophen but fat mass should be considered for maintenance dosing that is determined by clearance. The relationship between the pharmacokinetic parameter, clearance, and size is not linear. A number of size metrics (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale clearance and all consequent dosing schedules recognize curvilinear relationships between clearance and size. This relationship can be described using allometric theory. Fat mass also has an indirect influence on clearance that is independent of its effects due to increased body mass. Normal fat mass, used in conjunction with allometry, has proven a useful size metric for acetaminophen; it is calculated using fat-free mass and a fraction (Ffat) of the additional mass contributing to total body weight. However, the Ffat for acetaminophen is large (Ffat = 0.82), pharmacokinetic and pharmacodynamic parameter variability high, and the concentration-response slope gentle at the target concentration. Consequently, total body weight with allometry is acceptable for the calculation of maintenance dose. The dose of acetaminophen is tempered by concerns about adverse effects, notably hepatotoxicity associated with use after 2-3 days at doses greater than 90 mg/kg/day.

Considerations for Intravenous Anesthesia Dose in Obese Children: Understanding PKPD.

The intravenous induction or loading dose in children is commonly prescribed per kilogram. That dose recognizes the linear relationship between volume of distribution and total body weight. Total body weight comprises both fat and fat-free mass. Fat mass influences the volume of distribution and the use of total body weight fails to recognize the impact of fat mass on pharmacokinetics in children. Size metrics alternative to total body mass (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale pharmacokinetic parameters (clearance, volume of distribution) for size. Clearance is the key parameter used to calculate infusion rates or maintenance dosing at steady state. Dosing schedules recognize the curvilinear relationship, described using allometric theory, between clearance and size. Fat mass also has an indirect influence on clearance through both metabolic and renal function that is independent of its effects due to increased body mass. Fat-free mass, lean body mass and ideal body mass are not drug specific and fail to recognize the variable impact of fat mass contributing to body composition in children, both lean and obese. Normal fat mass, used in conjunction with allometry, may prove a useful size metric but computation by clinicians for the individual child is not facile. Dosing is further complicated by the need for multicompartment models to describe intravenous drug pharmacokinetics and the concentration effect relationship, both beneficial and adverse, is often poorly understood. Obesity is also associated with other morbidity that may also influence pharmacokinetics. Dose is best determined using pharmacokinetic-pharmacodynamic (PKPD) models that account for these varied factors. These models, along with covariates (age, weight, body composition), can be incorporated into programmable target-controlled infusion pumps. The use of target-controlled infusion pumps, assuming practitioners have a sound understanding of the PKPD within programs, provide the best available guide to intravenous dose in obese children.

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.

Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice.

The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have tempered dose regimens. Quantification of drug interactions has improved the understanding of the effects of drug combinations. Repurposed drugs (e.g., antiviral drugs used for COVID-19) within the community can have important effects on drugs used in paediatric anaesthesia, and the use of simulation educates about these drug vagaries.

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.

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.

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.

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.

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.

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.

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.