Peter Larsson

The place of premedication in pediatric practice.

Behind the multiple arguments for and against the use of premedication, sedative drugs in children is a noble principle that of minimizing psychological trauma related to anesthesia and surgery. However, several confounding factors make it very difficult to reach didactic evidence‐based conclusions. One of the key confounding issues is that the nature of expectations and responses for both parent and child vary greatly in different environments around the world. Studies applicable to one culture and to one hospital system (albeit multicultural) may not apply elsewhere. Moreover, the study of hospital‐related distress begins at the start of the patient’s journey and ends long after hospital discharge; it cannot be focused completely on just the moment of anesthetic induction. Taking an example from actual practice experience, the trauma caused by the actual giving of a premedication to a child who absolutely does not want it and may struggle may not be recorded in a study but could form a significant component of overall effect and later psychological pathology. Clearly, attitudes by health professionals and parents to the practice of routine pediatric premedication, vary considerably, often provoking strong opinions. In this pro–con article we highlight two very different approaches to premedication. It is hoped that this helps the reader to critically re‐evaluate a practice, which was universal historically and now in many centers is more selective.

Clonidine disposition in children; a population analysis.

Background:  There are few data describing clonidine population pharmacokinetics in children (0–15 years) despite common use. Current pediatric data, described in terms of elimination half‐life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically.

A maturation model for midazolam clearance

Background:  Physiological‐based pharmacokinetic models have been used to describe midazolam clearance (CL) maturation. There are no maturation descriptors of CL from neonate to adulthood based on reported estimates at different ages.

Oral bioavailability of clonidine in children.

Background:  Oral clonidine is used as premedication in children. The bioavailability of clonidine given orally in adults is 75–100% but is unknown in children.

Absorption pharmacokinetics of clonidine nasal drops in children.

Background:  The α2 agonist clonidine has become a popular drug for premedication in children. Effects and pharmacokinetics after oral, rectal, and intravenous administration are well known. The aim of this study was to investigate the absorption pharmacokinetics of clonidine nasal drops in children.

Onset time for pharmacologic premedication with clonidine as a nasal aerosol: a double-blind, placebo-controlled, randomized trial.

Objectives/Aim:  To investigate whether nasal aerosol clonidine can reduce the onset time of preoperative sedation.

Incidence of bradycardia at arrival to the operating room after oral or intravenous premedication with clonidine in children

Clonidine has been advocated as a valid alternative for premedication in children but one of the few limitations is its association with reduced heart rate (HR), which thus raises the question of the safety of clonidine as premedication in children. The aim of this study was to investigate the incidence of bradycardia in children premedicated with oral or intravenous clonidine as compared to children not receiving pharmacologic premedication.

Intranasal clonidine pharmacokinetics

portion of the PLM was once again tightly approximated to the shaft and gently introduced into the oral cavity from the right side by railroading over the suction catheter (Fig. 1). With minimal manipulation, the laryngeal mask airway could be introduced. Suction catheter was removed and breathing circuit was attached (Figure S2). With just 3-ml air to inflate the laryngeal mask airway cuff, adequate spontaneous respiration was noted by the movement of the reservoir bag and capnographic curves. Subsequently, the patient was maintained on 1–3% sevoflurane in a mixture of 50% nitrous oxide in oxygen on spontaneous breathing. The attending anesthesiologist attempted fiberscopy through the laryngeal mask airway but failed as the laryngeal mask airway was noted to be poorly positioned, a finding noted by others also (4). Throughout this period, patient had been breathing spontaneously receiving sevoflurane in oxygen via face mask between attempts. Oxygen saturation remained between 98 and 100% and heart rate ranged between 113 and 146/min. As the patient has to come for multiple surgeries over the next few weeks, it was decided to perform surgical tracheostomy prior to the release of various contractures in stages (Figure S3). Since then, the patient has been anesthetized uneventfully several times using tracheostomy as an airway. This case report highlights the fact that a distorted airway anatomy secondary to scarring may impair both mask ventilation and much advocated fiberoptic tracheal intubation. In addition, traditional rescue methods such as the laryngeal mask airway may fail using the conventional approach. The key to success is adequate planning, preparation, and the ability to improvise to suit the occasion as demonstrated by successful catheterguided placement of the laryngeal mask airway in this patient.

The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: Study protocol for a multicentre randomised controlled trial

Introduction Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. Methods and analysis The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2–18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. Ethics Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trial Registration EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results.

Anesthesia and Ancillary Drugs and the Neonate

Neonates are a heterogeneous population characterised by a limited weight or size range. They are the group of children from birth up to the age of 28 days of life and include both preterm (i.e. born before 37 weeks of gestational age) and term neonates. In practice, the word “neonate” extends to former preterm neonates. Consequently, postmenstrual age (PMA) may range from extreme preterm birth at 22 weeks to 50 weeks PMA, while weight commonly ranges from 0.5 to 5 kg, an entire order of magnitude. Age, size, co-morbidity, coadministration of drugs and genetic polymorphisms contribute to the extensive interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability in this population. These phenomena distinguish neonates as a specific population with major pharmacological differences from their older counterparts. Although the general principles of clinical pharmacology also apply to neonates, their characteristics warrant a tailored approach. History provides us with evidence of the deleterious effects of drugs in this age group including chloramphenicol (grey baby syndrome) and benzyl alcohol (gasping syndrome) in neonates. Neonatal bupivacaine toxicity in those receiving long-term infusion and acute fentanyl tolerance are two recent anaesthesia examples.