Nancy Sikich

The Pharmacology of Sevoflurane in Infants and Children

Background:Sevoflurane is a new volatile anesthetic with physical properties that should make it suitable for anesthesia in children. In this study, the minimum alveolar concentration (MAC) of sevoflurane in oxygen alone and in 60% nitrous oxide, the hemodynamic, induction and emergence responses to sevoflurane and the metabolism to inorganic fluoride were studied in 90 ASA physical status 1 or 2 neonates, infants, and children. Methods:MAC of sevoflurane in oxygen was determined in six groups of subjects stratified according to age: full-term neonates, infants 1-6 and > 6-12 months and children > 1- 3, > 3-5 and > 5-12 yr. MAC in 60% nitrous oxide was determined in a separate group of children 1-3 yr of age. After an inhalational induction, the trachea was intubated (except for neonates in whom an awake intubation was performed). MAC for each age group was determined using the Up-and-Down technique of Dixon. Results:MAC of sevoflurane in neonates, 3.3 ± 0.2% and in infants 1-6 months of age, 3.2 ± 0.1%, were similar; MAC in older infants 6-12 months and children 1-12 yr was constant at ≈ 2.5%; MAC of sevoflurane in 60% nitrous oxide in children 1-3 yr of age was 2.0 ± 0.2%. Systolic arterial pressure decreased significantly at 1 MAC before skin incision compared with awake values in all subjects except children 1-3 yr with 60% nitrous oxide and children 5-12 yr in oxygen, and then returned toward awake values after skin incision. Heart rate was unchanged at ≈ 1 MAC sevoflurane before incision compared with awake values in all subjects except children > 3-5 and > 5-12 yr in whom heart rate increased before incision. Induction of anesthesia, particularly with respect to airway irritability, and emergence from sevoflurane anesthesia were not remarkable. The plasma concentration of inorganic fluoride reached maximum values (8.8-16.7 µM) 30 min after discontinuation of anesthesia. Conclusions:We conclude that sevoflurane appears to be a suitable anesthetic agent for use in neonates, infants and children undergoing ≤ 1 h of anesthesia.

Development and psychometric evaluation of the Pediatric anesthesia Emergence Delirium scale

Background: Emergence delirium has been investigated in several clinical trials. However, no reliable and valid rating scale exists to measure this phenomenon in children. Therefore, the authors developed and evaluated the Pediatric Anesthesia Emergence Delirium (PAED) scale to measure emergence delirium in children. Methods: A list of scale items that were statements describing the emergence behavior of children was compiled, and the items were evaluated for content validity and statistical significance. Items that satisfied these evaluations comprised the PAED scale. Each item was scored from 1 to 4 (with reverse scoring where applicable), and the scores were summed to obtain a total scale score. The degree of emergence delirium varied directly with the total score. Fifty children were enrolled to determine the reliability and validity of the PAED scale. Scale validity was evaluated using five hypotheses: The PAED scale scores correlated negatively with age and time to awakening and positively with clinical judgment scores and Post Hospital Behavior Questionnaire scores, and were greater after sevoflurane than after halo-thane. The sensitivity of the scale was also determined. Results: Five of 27 items that satisfied the content validity and statistical analysis became the PAED scale: (1) The child makes eye contact with the caregiver, (2) the child’s actions are purposeful, (3) the child is aware of his/her surroundings, (4) the child is restless, and (5) the child is inconsolable. The internal consistency of the PAED scale was 0.89, and the reliability was 0.84 (95% confidence interval, 0.76–0.90). Three hypotheses supported the validity of the scale: The scores correlated negatively with age (r = −0.31, P <0.04) and time to awakening (r = −0.5, P <0.001) and were greater after sevoflurane anesthesia than halothane (P <0.008). The sensitivity was 0.64. Conclusions: These results support the reliability and validity of the PAED scale.

Premedication of children with oral midazolam.

In a randomized, double-blind, placebo-controlled study, the safety, efficacy and feasibility of oral midazolam premedication in children were evaluated in an ambulatory surgery unit. Eighty unmedicated children (ASA PS I or II, ages 1–6 yr) were randomly assigned to one of four groups receiving midazolam 0.5, 0.75, or 10 mg · kg−1 or a placebo 30 min before separation from parents. Heart rate, systolic blood pressure, arterial oxygen saturation, respiratory rate, sedation and anxiolysis scores were recorded before premedication, every five minutes for 30 min and then during induction of anaesthesia and recovery. We found that heart rate, systolic blood pressure, arterial oxygen saturation and respiratory rate were unchanged during the study. Sedation and anxiolysis scores in the midazolam-treated groups were greater than those in the placebo group and that anxiolysis at the time of separation from the parents was judged excellent in 80–90% of the children who received midazolam. However, sedation and anxiolysis did not differ among the three midazolam groups. Mean times to discharge from hospital were similar for all four groups. The side effects, loss of balance and head control, blurred vision and dysphoric reactions were observed only in the 0.75 and 1.0 mg · kg−1 midazolam groups. We conclude that oral midazolam 0.5 mg · kg−1 is a safe and effective premedication and that 0.75 and 1 mg · kg−1 while offering no additional benefit, may cause more side effects.RésuméLa sécurité, l’efficacité et la possibilité d’utiliser le midazolam oral en prémédication chez les enfants ont été évaluées dans une unite de chirurgie d’un jour, a l’aide d’une étude randomisee, a double insue et comprenant des contrôles placebos. Quatre-vingt enfants non premediques (ASA PS I ou II, âgés entre 1 et 6 ans) ont ete divises, au hasard, en quatre groupes, recevant du midazolam a des doses de 0,5, 0,75, ou 1 mg · kg−1 ou un placebo 30 minutes avant de quitter leurs parents. La fréquence cardiaque, la tension artérielle systolique, la saturation artérielle, la fréquence respiratoire, ainsi que les pointages de sédation et d’anxiolyse étaient notés avant la prémédication, toutes les 5 minutes pendant 30 minutes et par la suite pendant l’induction et l’émergence de l’anesthésie. Nous avons noté que les fréquences cardiaques, la tension artérielle systolique, la saturation artérielle et la fréquence respiratoire étaient inchangées pendant l’étude. Les pointages de sédation et d’anxiolyse dans les groupes traités avec du midazolam étaient plus élevés que dans le groupe placebo, et l’anxiolyse au moment de quitter les parents etait jugee excellente chez 80 à 90% des enfants qui avaient recu du midazolam. Cependant, la sédation et l’anxiolyse étaient semblables pour les trois groupes traités avec du midazolam. En moyenne, le congé de l’hôpital survenait au même moment pour les quatre groupes. Les effets secondaires tels la perte d’equilibre, la perte du contrôle de la tête, la vision embrouillée et les réactions dysphoriques n’étaient observés que dans les groupes ayant recu du midazolam à des doses de 0,75 et 1,0 mg — kg−1. En conclusion, une dose orale de midazolam de 0,5 mg · kg−1 est efficace et sécuritaire en prémédication, mais des doses de 0.75 et 1 mg · kg−1 peuvent causer plus d’effets secondaires tout en n’offrant aucun avantage additionnel.

A Phase I, Two-center Study of the Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children

Background:To investigate dexmedetomidine in children, the authors performed an open-label study of the pharmacokinetics and pharmacodynamics of dexmedetomidine. Methods:Thirty-six children were assigned to three groups; 24 received dexmedetomidine and 12 received no drug. Three doses of dexmedetomidine, 2, 4, and 6 &mgr;g · kg−1 · h−1, were infused for 10 min. Cardiorespiratory responses and sedation were recorded for 24 h. Plasma concentrations of dexmedetomidine were collected for 24 h and analyzed. Pharmacokinetic variables were determined using nonlinear mixed effects modeling (NONMEM program). Cardiorespiratory responses were analyzed. Results:Thirty-six children completed the study. There was an apparent difference in the pharmacokinetics between Canadian and South African children. The derived volumes and clearances in the Canadian children were V1 = 0.81 l/kg, V2 = 1.0 l/kg, Cl1 (systemic clearance) = 0.013 l · kg−1 · min−1, Cl2 = 0.030 l · kg−1 · min−1. The intersubject variabilities for V1, V2, and Cl1 were 45%, 38%, and 22%, respectively. Plasma concentrations in South African children were 29% less than in Canadian children. The volumes and clearances in the South African children were 29% larger. The terminal half-life was 110 min (1.8 h). Median absolute prediction error for the two-compartment mammillary model was 18%. Heart rate and systolic blood pressure decreased with time and with increasing doses of dexmedetomidine. Respiratory rate and oxygen saturation (in air) were maintained. Sedation was transient. Conclusion:The pharmacokinetics of dexmedetomidine in children are predictable with a terminal half-life of 1.8 h. Hemodynamic responses decreased with increasing doses of dexmedetomidine. Respiratory responses were maintained, whereas sedation was transient.

Dimenhydrinate Decreases Vomiting After Strabismus Surgery in Children

Dimenhydrinate, a H1-receptor antagonist, has been used to both prevent and treat postoperative vomiting (POV) in children for several decades. However, its effectiveness for POV after strabismus surgery remains anecdotal. This study was designed to determine the effectiveness and side effects of dimenhydrinate for the prevention of POV in children after strabismus surgery. Eighty ASA physical status I or II children, ages 1-12 yr inclusive, who were undergoing strabismus surgery, were prospectively and randomly allocated to receive either dimenhydrinate 0.5 mg/kg intravenously (n = 40) or placebo (n = 40) at induction of anesthesia. The incidence of POV and the times to arousal and discharge from the recovery room and hospital were recorded postoperatively in a double-blinded manner. For 24 h after discharge from the hospital, all emetic episodes and medications given were recorded by the parents. Demographic data did not differ between the groups. Children who received dimenhydrinate had significantly less POV both inhospital (10%) and overall (30%) than those who received placebo (in-hospital 38%, P < 0.008; overall 65%, P < 0.003). The times to arousal and discharge from the hospital did not differ between the two groups. Dimenhydrinate (0.5 mg/kg) is an effective, safe, and inexpensive antiemetic in children undergoing strabismus surgery. It significantly reduces the incidence of vomiting for 24 h postoperatively and is not associated with prolonged sedation or other adverse effects. (Anesth Analg 1996;82:728-31)

Single-breath vital capacity rapid inhalation induction in children. 8% sevoflurane versus 5% halothane

Background The authors compared the speed of induction of anesthesia with sevoflurane with and without nitrous oxide with the speed of halothane and nitrous oxide using a single‐breath vital capacity induction. Methods With informed parental consent, 51 healthy unpremedicated children aged 5–12 yr were randomized to inhale a single breath of one of three gas mixtures: 8% sevoflurane in 66% nitrous oxide, 8% sevoflurane in oxygen, or 5% halothane in 66% nitrous oxide. A blinded observer recorded the times to loss of the eyelash reflex, return of conjugate gaze, the presence of airway reflex responses, involuntary movement, and hemodynamic responses. Results Forty‐two children completed the study. The times (mean +/‐ SD) to loss of the eyelash reflex with sevoflurane/nitrous oxide, 38 +/‐ 8 s, and for sevoflurane‐oxygen, 34 +/‐ 12 s, were less than that with halothane‐nitrous oxide, 58 +/‐ 17 s (P < 0.01). Movement occurred less frequently during sevoflurane than during halothane anesthesia (P < 0.05). The times to return of conjugate gaze and the incidence of airway reflex responses were similar among the groups. The incidence of dysrhythmias in the sevoflurane groups was less than that in the halothane group (P < 0.01). Conclusions Induction of anesthesia with a single breath of 8% sevoflurane with or without 66% nitrous oxide is more rapid than with 5% inspired halothane with 66% nitrous oxide in children. The incidence of movement and dysrhythmias during a single‐breath induction with sevoflurane are less than they are with halothane.

Plasma Inorganic Fluoride Concentrations after Sevoflurane Anesthesia in Children

BACKGROUND: Sevoflurane is degraded in vivo in adults yielding plasma concentrations of inorganic fluoride [F-] that, in some patients, approach or exceed the 50- micron theoretical threshold for nephrotoxicity. To determine whether the plasma concentration of inorganic fluoride [F-] after 1-5 MAC x h sevoflurane approaches a similar concentration in children, the following study in 120 children scheduled for elective surgery was undertaken. METHODS: Children were randomly assigned to one of three treatment groups before induction of anesthesia: group 1 received sevoflurane in air/oxygen 30% (n = 40), group 2 received sevoflurane in 70% N2O/30% O2 (n = 40), and group 3 received halothane in 70% N2O/30% O2 (n = 40). Mapleson D or F circuits with fresh gas flows between 3 and 61/min were used Whole blood was collected at induction and termination of anesthesia and at 1, 4, 6, 12, and 18 or 24 h postoperatively for determination of the [F-]. Plasma urea and creatinine concentrations were determined at induction of anesthesia and 18 or 24 h postoperatively. RESULTS: The mean (+/- SD) duration of sevoflurane anesthesia, 2.7 +/- 1.6 MAC x h (range 1.1-8.9 MAC x h), was similar to that of halothane, 2.5 +/- 1.1 MAC x h. The peak [F-] after sevoflurane was recorded at 1 h after termination of the anesthetic in all but three children (whose peak values were recorded between 4 and 6 h postanesthesia). The mean peak [F-] after sevoflurane was 15.8 +/- 4.6 microns. The [F-] decreased to <6.2 microns b 24 h postanesthesia. Both the peak [F-] (r2 = 0.50) and the area under the plasma concentration of inorganic fluoride-time curve (r2 = 0.57) increased in parallel with the MAC x h of sevoflurane. The peak [F-] after halothane, 2.0 +/- 1.2 microns, was significantly less than that after sevoflurane (P<0.00012) and did not correlate with the duration of halothane anesthesia (MAC x h; r2 = 0.007). Plasma urea concentrations decreased 24 h after surgery compared with preoperative values for both anesthetics (P<0.01), whereas plasma creatinine concentrations did not change significantly with either anesthetic. CONCLUSIONS: It was concluded that, during the 24 h after 2.7 +/- 1.6 MAC x h sevoflurane, the peak recorded [F-] is low (15.8 microns), F- is eliminated rapidly, and children are unlikely to be at risk of nephrotoxicity from high [F-].

Pharmacokinetics of intravenous ondansetron in healthy children undergoing ear, nose, and throat surgery

To determine the pharmacokinetics of the 5‐HT3 antagonist ondansetron in children, informed written consent was obtained from the parents of 21 healthy children aged from 3 to 12 years scheduled for ear, nose, and throat surgery.

Recovery characteristics of propofol anaesthesia, with and without nitrous oxide: a comparison with halothane/nitrous oxide anaesthesia in children

Few studies have examined whether nitrous oxide influences the recovery characteristics of propofol anaesthesia. The present study examined the effect of nitrous oxide on the recovery characteristics of propofol anaesthesia, and compared these data with those for halothane/nitrous oxide anaesthesia. Sixty children aged 3–12 years were assigned at random to receive one of three maintenance regimens: propofol with or without nitrous oxide (70%) or halothane/nitrous oxide (70%). During propofol/N2O anaesthesia, the infusion rate of propofol (180±39 μg·kg−1·min−1) required to maintain the mean arterial pressure and heart rate within 20% of the baseline values was significantly less than that during propofol/O2 (220±37 μg·kg−1·min−1; P<0.005). The time from discontinuation of anaesthesia to eye‐opening (11±6 min), to response to commands (12±6 min), and to return of full wakefulness (21±10 min) after propofol/N2O were similar to those after propofol/O2, but significantly less (by approximately 30%) than those after halothane (P<0.05). The overall incidence of emesis after propofol/N2O (53%) was greater than that after propofol/O2 (17%, P<0.05) and comparable to that after halothane/N2O (58%). These data suggest that N2O has little effect on the rate of recovery after propofol, but significantly increases the incidence of postoperative emesis, thereby attenuating one of the main attributes of propofol anaesthesia.

Parental perceptions, expectations and preferences for the postanaesthetic recovery of children

Improvements in anaesthesia have led to the introduction of rapid‐acting agents which quicken recovery and decrease sleepiness. Whether parents believe a rapid postanaesthetic recovery is an advantage is unknown. Therefore, we evaluated the parental perceptions, expectations and preferences for the postanaesthetic recovery of children. One hundred and three parents of children having ambulatory surgery completed a structured questionnaire and the results of 101 are presented. Results indicate that 93% of parents expect their child to be sleepy after surgery. Seventy‐four per cent of parents indicated they would prefer their child to be sleepy or tired in the first 24 h postoperatively. Eight‐five percent of parents would not be upset if their childs discharge was delayed up to three hours because their child was too sleepy. Finally 45.5% of parents are extremely concerned about their child experiencing postoperative pain and 68% believe that their child would be in more pain if they recovered rapidly from the anaesthetic. These results indicate that rapid recovery from anaesthesia and quick discharge from hospital are not key expectations of parents of children admitted for day surgery. Parents associate a rapid recovery with more pain. Parents need to be more fully informed of the advantages of a rapid recovery and reassured that children can recover quickly and completely but at the same time be comfortable postanaesthetic.