Scaling for size: some implications for paediatric anaesthesia dosing

Anderson, Brian J.; Meakin, G.

doi:10.1046/j.1460-9592.2002.00616.x

Cited by 177 publications

(142 citation statements)

References 126 publications

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“…To explore the dose-exposure relationships with the currently available preparation of BPG, we scaled the penicillin G PK parameters to weight, BSA, and allometric size and found them to be roughly equivalent. In our model, however, allometric scaling was slightly better, and it allowed for better extrapolation from adult to pediatric populations (14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

Neely

Kaplan

Blumer

et al. 2014

Antimicrob Agents Chemother

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Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks. Studies performed during the 60 years since the original investigations (1) of the persistence of serum penicillin G after parenteral administration of benzathine penicillin G (BPG) generally found that serum concentrations remain above a putative minimum protective level for the prevention and treatment of group A Streptococcus pyogenes (GAS) infections. This minimum threshold differs among authorities but is usually set as Ͼ0.01 to 0.03 g/ml (2) for between 3 and 4 weeks after a dose.Recently, we reported that the serum penicillin G levels in 329 military trainees fell more rapidly than expected during the 29 days following a 1.2-million-unit intramuscular injection of the only formulation of BPG currently available in the United States (2). That study was prompted by observations of unexpectedly high GAS treatment failures with BPG, defined as a failure to eradicate GAS from the throat (3-6), and previous reports of undetectable serum penicillin G 3 weeks after the same dose (5, 7).In this report, we develop a population pharmacokinetic (PK) model of penicillin G concentrations following intramuscular administration of 1.2 million units of BPG in healthy young adult males, using data from our prior study. We set three objectives: (i) to find the optimal body size metric, i.e., weight, body surface area (BSA), or allometry, for scaling PK parameter values; (ii) to use the final model f...

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Section: Discussionmentioning

confidence: 99%

A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

Neely

Kaplan

Blumer

et al. 2014

Antimicrob Agents Chemother

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“…Because sildenafil pharmacokinetics were not previously characterized in pediatric patients, parameters were predicted by scaling adult parameters with general scaling factors based on other drugs. [15][16][17] To provide a practical dosing scheme based on body weight, 3 body weight categories were specified. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8-to 20-kg patients (ie, patients would receive the same dose because of the available tablet strengths); consequently, these patients were not randomized to low-dose sildenafil (Revatio, Pfizer Inc, New York, NY).…”

Section: Methodsmentioning

confidence: 99%

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children With Pulmonary Arterial Hypertension

et al. 2012

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Background-Safe, effective therapy is needed for pediatric pulmonary arterial hypertension. Methods and Results-Children (nϭ235; weight Ն8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV O 2 ) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated meanϮSE percent change in PV O 2 for the 3 doses combined versus placebo was 7.7Ϯ4.0% (95% confidence interval, Ϫ0.2% to 15.6%; Pϭ0.056). PV O 2 , functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses. Conclusions-Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV O 2 for the 3 sildenafil doses combined was only marginally significant; however, PV O 2 , functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight. Clinical Trial Registration-http://www.clinicaltrials.gov. Unique identifier: NCT00159913. (Circulation. 2012;125:324-334.)

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“…Before drug administration, special attention must be paid to the calculation of dosage (ie, mg/kg); for obese patients, most drug doses should likely be adjusted lower to ideal body weight rather than actual weight. 345 When a programmable pump is used for the infusion of sedating medications, the dose/kilogram per minute or hour and the child's weight in kilograms should be doublechecked and confirmed by a separate individual. The patient's chart shall contain documentation at the time of treatment that the patient's level of consciousness and responsiveness, heart rate, blood pressure, respiratory rate, expired carbon dioxide values, and oxygen saturation were monitored.…”

Section: Documentation During Treatmentmentioning

confidence: 99%

Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures: Update 2016

Coté¹,

Wilson²

2016

Pediatrics

251

199

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The safe sedation of children for procedures requires a systematic approach that includes the following: no administration of sedating medication without the safety net of medical/dental supervision, careful presedation evaluation for underlying medical or surgical conditions that would place the child at increased risk from sedating medications, appropriate fasting for elective procedures and a balance between the depth of sedation and risk for those who are unable to fast because of the urgent nature of the procedure, a focused airway examination for large (kissing) tonsils or anatomic airway abnormalities that might increase the potential for airway obstruction, a clear understanding of the medication's pharmacokinetic and pharmacodynamic effects and drug interactions, appropriate training and skills in airway management to allow rescue of the patient, age-and size-appropriate equipment for airway management and venous access, appropriate medications and reversal agents, suffi cient numbers of staff to both carry out the procedure and monitor the patient, appropriate physiologic monitoring during and after the procedure, a properly equipped and staffed recovery area, recovery to the presedation level of consciousness before discharge from medical/dental supervision, and appropriate discharge instructions. This report was developed through a collaborative effort of the

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Scaling for size: some implications for paediatric anaesthesia dosing

Cited by 177 publications

References 126 publications

A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children With Pulmonary Arterial Hypertension

Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures: Update 2016

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