Growth and development can be investigated using readily observable demographic factors such as weight and age. Size is the primary covariate and can be referenced to a 70-kg person with allometry using a coefficient of 0.75 for clearance and 1 for volume. The use of these coefficients is supported by fractal geometric concepts and observations from diverse areas in biology. Fat free mass (FFM) might be expected to do better than total body weight when there are wide variations in fat affecting body composition. Clearance pathways develop in the fetus before birth. The use of postnatal age as a descriptor of maturation is unsatisfactory because birth may occur prematurely; therefore postmenstrual age is a superior predictor of elimination function. A sigmoid E(max) model (Hill equation) describes gradual maturation of clearance in early life leading to a mature adult clearance achieved at a later age.

Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics

L. David Hillis, MD, FACC, Chair†; Peter K. Smith, MD, FACC, Vice Chair*†; Jeffrey L. Anderson, MD, FACC, FAHA*‡; John A. Bittl, MD, FACC§; Charles R. Bridges, MD, SCD, FACC, FAHA*†; John G. Byrne, MD, FACC†; Joaquin E. Cigarroa, MD, FACC†; Verdi J. DiSesa, MD, FACC†; Loren F. Hiratzka, MD, FACC, FAHA†; Adolph M. Hutter, Jr, MD, MACC, FAHA†; Michael E. Jessen, MD, FACC*†; Ellen C. Keeley, MD, MS†; Stephen J. Lahey, MD†; Richard A. Lange, MD, FACC, FAHA†§; Martin J. London, MD ; Michael J. Mack, MD, FACC*¶; Manesh R. Patel, MD, FACC†; John D. Puskas, MD, FACC*†; Joseph F. Sabik, MD, FACC*#; Ola Selnes, PhD†; David M. Shahian, MD, FACC, FAHA**; Jeffrey C. Trost, MD, FACC*†; Michael D. Winniford, MD, FACC†

2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

https://www.medpagetoday.com/upload/2011/11/8/j.jacc.2011.08.009v1.pdf

2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery

2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: Executive Summary A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

/pdf/partial-reversal-of-rett-syndrome-like-symptoms-in-mecp2-2j2cwbn2x1.pdf

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Background:Persistent chest pain may originate from cardiac surgery. Conflicting results have been reported on the incidence of persistent poststernotomy pain with considerable discrepancies between the retrospective reports and the one prospective study conducted to assess this pain. Therefore, the

Pain after cardiac surgery: a prospective cohort study of 1-year incidence and intensity.

There has been little exploration of major biologic regulators of cerebral development in autism We measured insulin-like growth factors (IGF) -1 and -2 from cerebrospinal fluid (CSF) by radio immunoassay in 25 children with autism (median age 5y 5mo; range 1y 11mo-15y 10mo; 20 males, 5 females), and in 16 age-matched comparison children without disability (median age 7y 4mo; range 1y 1mo-15y 2mo; eight males, eight females) IGF-1 and -2 concentrations were further correlated with age of patients and head size CSF IGF-1 concentration was significantly lower in patients with autism than in the comparison group The CSF concentrations of children with autism under 5 years of age were significantly lower than their age-matched comparisons The head circumferences correlated with CSF IGF-1 in children with autism but no such correlation was found in the comparison group There was no difference between the two groups in CSF IGF-2 concentrations No patients with autism had macrocephaly We conclude that low concentrations of CSF IGF-1 at an early age might be linked with the pathogenesis in autism because IGF-1 is important for the survival of Purkinje cells of the cerebellum The head growth might be explained by the actions of IGF-1 and -2 reflected in CSF concentrations

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.2006.tb01361.x

Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism.

Objectives/Hypothesis: Endoscopic sinus surgery (ESS) is increasingly performed by otorhinolaryngologists. However, the early recovery and pain management after ESS is still largely unexplored. In the present study, we have evaluated the incidence and severity of pain and the efficacy and safety of acetaminophen (paracetamol) for pain management in patients undergoing ESS.

Study Design: The authors conducted a prospective, double-blind, placebo-controlled clinical trial.

Methods: Seventy-four patients with ESS were randomized to receive either 1 g intravenous acetaminophen (Perfalgan) (n = 36) or 0.9% normal saline as a placebo (n = 38) after ESS was performed under local anesthesia. No other analgesic medication was permitted during the study. Need for rescue analgesic during the first 4 hours after surgery as well as all adverse events were recorded.

Results: Most patients, 27 of 38 (71%), in the placebo group needed rescue analgesics but significantly fewer patients in the acetaminophen group required rescue analgesia, i.e., only nine of 36 (25%) patients needed oxycodone. The worst pain after surgery was also more severe in the placebo group than that in the acetaminophen group. There was no significant difference between groups in the incidence of adverse events. The most common adverse events were vomiting, nausea, and headache.

Conclusions: ESS is associated with significant postoperative pain. Acetaminophen provides adequate pain relief in most patients who have undergone ESS. However, the analgesic efficacy of acetaminophen alone is insufficient in some patients, and hence all patients with ESS must be followed closely to identify those patients in need of more efficient analgesia during the early phase of recovery.

Acetaminophen is highly effective in pain treatment after endoscopic sinus surgery.

Video-assisted thoracoscopic versus open surgery for persistent ductus arteriosus.

Young children are often undertreated for pain. One barrier to effective pain treatment is understanding the pharmacokinetic behavior of analgesics in this age group. Oxycodone is a commonly prescribed opioid for severe pain, yet little is known about its pharmacokinetics in young children. This article used population pharmacokinetic modeling to synthesize pharmacokinetic data from several studies into a model. A single population model that described the observed pharmacokinetics was developed. The combined data were best described with a 2-compartment linear model with different first-order absorption rates depending on route of administration. Weight was found to significantly influence both clearance (CL) and volume of distribution (Vd). The following model adequately describes the population pharmacokinetic profile of oxycodone where absolute bioavailability (F) is estimated for each administration route: CL/F=55x(body weight/70)0.87; V/F=86x(body weight/70)1.16. The interindividual coefficients of variation in CL and Vd were 20.2 and 19.7%, respectively. This finding confirms that the allometric scaling using the above model explained most of the variability in exposure observed among children. This model confirms using a weight-based dose for oxycodone without adjustment for age between 6 months and 7 years and is valuable for evaluating dosing schedules and dosing routes.

Hannu Kokki

Papers

Pain after cardiac surgery: a prospective cohort study of 1-year incidence and intensity.

Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism.

Acetaminophen is highly effective in pain treatment after endoscopic sinus surgery.

Video-assisted thoracoscopic versus open surgery for persistent ductus arteriosus.

Population Pharmacokinetics of Oxycodone in Children 6 Months to 7 Years Old