Effects of sevoflurane and clonidine on acid base status and long-term emotional and cognitive outcomes in spontaneously breathing rat pups.

BACKGROUND: Numerous experiments in rodents suggest a causative link between exposure to general anaesthetics during brain growth spurt and poor long-lasting neurological outcomes. Many of these studies have been questioned with regard of their translational value, mainly because of extremely long anaesthesia exposure. Therefore, the aim of the present study was to assess the impact of a short sevoflurane anaesthesia, alone or combined with clonidine treatment, on respiratory function in spontaneously breathing rat pups and overall effects on long-lasting emotional and cognitive functions. METHODS: At postnatal day (PND) 7, male Sprague Dawley rat pups were randomized into four groups and exposed to sevoflurane for one hour, to a single dose of intraperitoneal clonidine or to a combination of both and compared to a control group. Blood gas analysis was performed at the end of sevoflurane anaesthesia and after 60 minutes from clonidine or saline injection. Emotional and cognitive outcomes were evaluated in different group of animals at infancy (PND12), adolescence (PND 30-40) and adulthood (PND 70-90). RESULTS: Rat pups exposed to either sevoflurane or to a combination of sevoflurane and clonidine developed severe hypercapnic acidosis, but maintained normal arterial oxygenation. Emotional and cognitive outcomes were not found altered in any of the behavioural task used either at infancy, adolescence or adulthood. CONCLUSIONS: Sixty minutes of sevoflurane anaesthesia in newborn rats, either alone or combined with clonidine, caused severe hypercapnic acidosis in spontaneously breathing rat pups, but was devoid of long-term behavioural dysfunctions in the present setting.

Steal induction in preschool children: is melatonin as good as clonidine? A prospective, randomized study.

OBJECTIVES/AIMS: To investigate whether melatonin would be an alternative drug to clonidine for performance of steal induction. BACKGROUND: Distress during induction might have a negative impact on postoperative behavior. A steal induction is a technique for smooth anesthesia induction, and clonidine has been the primary agent for this purpose. There are conflicting results regarding the efficacy of melatonin for premedication, but its sleep inducing properties have been shown in children. METHODS: Pediatric patients ASA I and II were randomly assigned to receive either melatonin 0.3 mg·kg(-1) or clonidine 4 µg·kg(-1) orally. Primary outcome was the percentage of successful steal induction, while secondary outcomes were onset of sleep, overall quality of mask induction, and adverse events at emergence from anesthesia. RESULTS: A total of 87 patients were included for analysis with a median age of 33 months (range, 12-71) and median weight of 14 kg (range, 8-26). A successful steal induction was performed in 88.4% of group C and 75% of group M (P > 0.05). Onset of sleep in these patients occurred after a median time of 45 min (range 10-60) in group C and 35 min (range 15-60) in group M (P > 0.05). Children not falling asleep after melatonin received the premedication at a significantly earlier time point compared to those falling asleep (P = 0.001). CONCLUSIONS: Melatonin was effective for steal induction in 75% of children compared to 88% of children who had clonidine. Melatonin resulted less effective when administered early in the morning.

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. METHODS: Children (3-10 years) undergoing adenotonsillectomy were administered oral clonidine 4 mcg·kg(-1) mixed with apple fruit drink as premedication. Intravenous plasma was assayed for clonidine concentration at 5, 15, 30, 45 min and 1, 2, 4, 6, 12, 18 h after administration. Clonidine plasma concentrations were determined by liquid chromatography-mass spectroscopy, and pharmacokinetic parameters were calculated using nonlinear effects mixed-effects models. Current data were pooled with published time-concentration profiles from children (n = 49) administered intravenous clonidine to determine oral bioavailability. RESULTS: There were eight children studied (age 3-10 years, weight 10.5-36 kg). A two-compartment model with first-order absorption and elimination was used to describe time-concentration profiles. Population parameter estimates (CV%; 95% CI), standardized to a 70-kg person, were absorption half-life (Tabs), 0.45 (85.1; 0.221-0.884) h, absorption lag time (Tlag), 0.148 (91.2; 0.002-0.316) h, Clearance (CL) 17.9 (30.3; 16-20.3) l·h(-1) per 70 kg, between compartment clearance (Q) 121 (44.3; 80.1-165) l·h(-1) per 70 kg, central volume (V1) 81.2 (71.5; 60.7-105) l·70 kg(-1), peripheral volume of distribution (V2) 113 (33.9; 91-131) l·70 kg(-1). The oral bioavailability was 55.4% (CV 6.4%; 95% CI 0.469, 0.654). CONCLUSIONS: Clonidine administered with an apple fruit drink displays a variable and relatively slow absorption after oral administration (T(max) 1.04 h, C(max) 0.77 mcg·l(-1)). The oral bioavailability was 55.4%, which is less than reported in adults. Consequently, higher oral doses of clonidine (per kg) are required when this formulation is used to achieve concentrations similar to those reported in adults.

Absorption pharmacokinetics of clonidine nasal drops in children.

BACKGROUND: The alpha2 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. METHODS: Thirteen ASA I pediatric patients received after induction of anesthesia 4 mcg x kg(-1) of clonidine by the nasal route. Blood samples were taken during a 12-h period and plasma levels of clonidine were analyzed by liquid chromatography-mass spectrometry. Data were calculated by a computer-aided curve-fitting program. RESULTS: Plasma pharmacokinetics following administration of clonidine nasal drops showed a considerable interindividual variability and absorption was delayed and limited. A total of 95% confidence intervals for maximum plasma concentration and time to achieve maximum plasma concentration were 0.4-0.6 ng x ml(-1) and 1.4-3.0 h, respectively. CONCLUSIONS: Clonidine nasal drops are erratically absorbed from the nasal mucosa and, thus, this mode of drug administration is not recommended for premedication purposes.

Premedication in children: a comparison of oral midazolam and oral clonidine.

BACKGROUND: Oral premedication is widely used in pediatric anesthesia to reduce preoperative anxiety and ensure smooth induction. Midazolam is currently the most commonly used premedicant, but good results have also been reported with clonidine. The aim of the present study was to compare clinical effects of oral midazolam and oral clonidine. METHODS: We performed a prospective open study in 64 children who were randomly assigned to receive either oral midazolam 0.5 mg.kg (-1) (group M) or oral clonidine 4 microg.kg (-1) (group C) prior to mask induction. Drug acceptance, preoperative sedation and anxiolysis, quality of mask acceptance, recovery profile and parental satisfaction were evaluated. RESULTS: The taste of oral clonidine was judged as significantly better; 14% of children rejected oral midazolam. Onset of sedation was significantly faster after premedication with midazolam (30+/-13.1 min) than with clonidine (38.5+/-14.6 min), but level of sedation was significantly better after premedication with clonidine. Quality of mask induction was equally successful in both groups. A steal-induction was performed in 66% of patients of group C, but none in group M. We observed a trend towards an increased incidence of emergence agitation after premedication with midazolam. Parental satisfaction was significantly higher in group C. CONCLUSIONS: In this study, premedication with oral clonidine appeared to be superior to oral midazolam. Quality of mask acceptance was comparable between groups, but oral clonidine was better accepted by the child, produced more effective preoperative sedation, showed a trend towards better recovery from anesthesia and had a higher degree of parental satisfaction.

Insertion characteristics, sealing pressure and fiberoptic positioning of CobraPLA in children.

BACKGROUND: The CobraPLA(TM) is a new supraglottic airway device designed for the use in spontaneously breathing and mechanically ventilated patients. In adults it has been found as effective as the LMA, but with better sealing qualities. The aim of the present study was to evaluate fit and sealing characteristics of CobraPLA size 1.5 and 2 in mechanically ventilated children. METHODS: Forty children, ASA I/II, aged 1-10 years, weighing 10-35 kg were scheduled for minor surgical procedures. The number of attempts for insertion and fiberoptic positioning of the CobraPLA was assessed. After muscle relaxation had been achieved, airway sealing pressure was measured by gradually increasing maximum inspiratory pressure to a maximum of 30 cm H(2)O. RESULTS: Insertion of CobraPLA was successful at the first attempt in 90% of patients. The vocal cords were visualized in 90% of patients (grade 0: 2.5%, grade 1: 7.5%, grade 2: 30%, grade 3: 15%, grade 4: 45%). Median sealing pressure was 20.0 +/- 6.0 cm H(2)O. In 21% of patients gastric insufflation was observed at a peak inspiratory pressure of 20 cm H(2)O or below. CONCLUSIONS: The CobraPLA was found to have easy insertion characteristics and good anatomical fitting in children between 10 and 35 kg. If positive pressure ventilation with CobraPLA size 1.5 and 2.0 is required, peak inspiratory pressure should be kept below the leak pressure and the abdomen closely monitored for signs of gastric insufflation.

Steal-induction after clonidine premedication: a comparison of the oral and nasal route.

BACKGROUND: Clonidine premedication in children reliably provides preoperative sedation and anxiolysis, but onset of oral clonidine is known to be slow. Nasal clonidine has been shown to reach peak plasma levels within 10 min in rodents. The aim of the present study was to compare clinical effects and percentage of steal-induction after clonidine premedication by the oral and nasal route. METHODS: Forty children, aged 1-6 years, scheduled for minor infraumbilical surgery, were randomly assigned to receive either pure clonidine 4 microgxkg(-1) intranasally (group CN, n = 20) or clonidine 4 microgxkg(-1) orally in syrup (group CO, n = 20) prior to mask induction. Drug acceptance, preoperative sedation and anxiolysis, quality of mask acceptance, recovery profile and parents' satisfaction were evaluated. RESULTS: Drug acceptance was similar between groups, but quality of taste was significantly better in the oral group. There was no significant difference of preoperative anxiolysis and sedation. The onset of sedative effect was after 38.3 min for oral clonidine and 47.5 min for nasal clonidine. A steal-induction could be performed in 60% of children in each group. Emergence from anesthesia and parents' satisfaction were comparable. CONCLUSIONS: Intranasal clonidine administration has no advantage over the oral route. Clinical effects were similar with both routes; there was a trend towards a faster onset of sedation with oral clonidine. Clonidine premedication causes light sleep, which allows a steal-induction in 60% of patients.