Marja Heikkinen

Paracetamol (acetaminophen) penetrates readily into the cerebrospinal fluid of children after intravenous administration

INTRODUCTION. The main action of paracetamol (acetaminophen) is presumed to be in the central nervous system. The central nervous system penetration of paracetamol has been described in children with intracranial pathologies but not in children with an intact blood-brain barrier. OBJECTIVE. We investigated the cerebrospinal fluid penetration of paracetamol in 32 healthy children, aged 3 months to 12 years, who were undergoing surgery in the lower body using spinal anesthesia. MATERIALS AND METHODS. In this open-label prospective study, children were given a single intravenous injection of paracetamol (15 mg/kg). Cerebrospinal fluid and venous blood samples were obtained between 5 minutes and 5 hours after injection. Paracetamol concentrations were determined from the cerebrospinal fluid and plasma by using a fluorescence polarization immunoassay. RESULTS. Paracetamol was detected in cerebrospinal fluid from the earliest sample at 5 minutes, although in this sample paracetamol concentration was below the limit of quantification of 1.0 mg/L. Subsequent paracetamol concentrations in cerebrospinal fluid ranged between 1.3 and 18 mg/L (median: 7.2 mg/L), plasma concentrations ranged between 2.4 and 33 mg/L, and cerebrospinal fluid/plasma ratios ranged between 0.06 and 2.0. The highest CSF paracetamol concentration was detected at 57 minutes. CONCLUSIONS. Paracetamol permeates readily into the cerebrospinal fluid of children. This fast and extensive transfer enables the rapid central analgesic and antipyretic action of intravenous paracetamol.

Cerebrospinal Fluid Distribution of Ibuprofen After Intravenous Administration in Children

BACKGROUND. Ibuprofen is the most commonly used nonsteroidal, antipyretic, antiinflammatory analgesic in children. Nonsteroidal, antipyretic, antiinflammatory analgesics act in both the peripheral tissues and the central nervous system. The central nervous system penetration of ibuprofen has been described in adults but not in children. OBJECTIVES. Our goals were to investigate the cerebrospinal fluid penetration of ibuprofen in children and evaluate the analgesic plasma concentration of ibuprofen after inguinal surgery in children. MATERIALS AND METHODS. A total 36 healthy children (25 boys) aged 3 months to 12 years received a single intravenous injection of ibuprofen (10 mg/kg). A paired cerebrospinal fluid and blood sample was obtained 10 minutes to 8 hours after the injection. In children having inguinal surgery, a second blood sample was obtained at the time that the child first had wound pain. RESULTS. The ibuprofen level was determined in all cerebrospinal fluid and plasma samples. Cerebrospinal fluid concentrations ranged between 15 and 541 μg/L, and the highest concentrations were measured 30 to 38 minutes after dosing. In all cerebrospinal fluid samples collected after 30 minutes, ibuprofen concentration exceeded that of unbound plasma. The plasma analgesic concentrations after inguinal surgery ranged between 10 and 25 mg/L. CONCLUSIONS. Ibuprofen penetrates the cerebrospinal fluid readily, with peak concentrations attained 30 to 40 minutes after intravenous injection of a 10 mg/kg dose. The plasma analgesic concentration after inguinal surgery with spinal anesthesia is 10 to 25 mg/L.

Isobaric Ropivacaine 5 mg/ml for Spinal Anesthesia in Children

In this clinical trial, we evaluated the clinical effects of ropivacaine for spinal anesthesia in children. An open, prospective study was performed on 93 children, aged 1–17 yr, undergoing elective lower abdominal or lower limb surgery. A plain solution of ropivacaine 5 mg/mL at a dose of 0.5 mg/kg body weight (up to 20 mg) was administered via the L3-4 or L4-5 interspace with the patient in the lateral decubitus position. After injection, the patients were placed supine. The spread and duration of sensory analgesia and the degree of motor block were recorded. Satisfactory surgical anesthesia was achieved in 92 of the 93 children. Three children received general anesthesia; in one child spinal anesthesia failed, and in two cases surgery outlasted the duration of the sensory block. Four children received supplemental analgesia for skin incision. The mean highest level of sensory block was T6 (range, T2 to T12), and the mean time to the regression of sensory block to T10 was 96 min (range, 34–210 min). One child developed transient bradycardia and one hypotension. After discharge four children developed mild transient radiating neurologic symptoms and one epidural blood patch was performed for persistent position-dependent headache. We conclude that the block performance of intrathecal isobaric ropivacaine in children (>1 yr) is similar to that obtained in adults but the safety of the larger dose used in children warrants further studies.

Recovery after paediatric daycase herniotomy performed under spinal anaesthesia

In this prospective survey, recovery in hospital and at home was evaluated in 195 children aged 6 months to 10 years who had undergone herniotomy under spinal anaesthesia as a daycase procedure. Spinal anaesthesia was successful in most of the children, with only two patients being given general anaesthesia. Eighty‐three percent of the children had pain at home and 19% had moderate or severe pain. Eighty‐five percent of the children needed pain medication at home; the median dose of analgesics was 4 (1–9, 10th and 90th percentiles). Vomiting was noted in two of 195 children in hospital and in 10 of 192 children at home. Eleven children developed a mild position‐dependent headache. Most of the children (183/191) recovered their normal daily activities during the first three postoperative days. We conclude that spinal anaesthesia is a safe and effective technique for paediatric herniotomy. Moreover, pain is common following herniotomy and children should be given analgesics for the first two or three postoperative days.

Cerebrospinal fluid distribution of ketoprofen after intravenous administration in young children.

ObjectiveThe purpose of this study was to evaluate the cerebrospinal fluid (CSF) distribution of an NSAID, ketoprofen, in children. Ketoprofen concentrations were determined from the CSF, plasma and protein-free plasma samples.MethodsChildren (n = 21), aged 13–94 months, were given intravenous ketoprofen (1 mg/kg) prior to surgery under spinal anaesthesia. Single venous blood and CSF samples from each patient were collected simultaneously 7–67 minutes after the drug administration. Ketoprofen concentrations in the samples were determined using gas chromatography-mass spectrometry.ResultsKetoprofen entered the CSF and was detectable in all samples. However, CSF delivery was limited; the ratio of ketoprofen concentration in CSF to plasma remained below 0.006 at all times. Ketoprofen was highly bound (>98%) to plasma proteins. The free ketoprofen fraction was not in equilibrium with the CSF, and no clear peak drug concentration in the CSF was observed.ConclusionThis study shows that ketoprofen is able to enter the CSF of children, which enables central analgesic effects of ketoprofen. However, the slow distribution of ketoprofen into the CSF and the apparently low absolute concentrations has to be taken into account when central analgesic effects are desired.

Plasma and Cerebrospinal Fluid Concentrations of Indomethacin in Children After Intravenous Administration

The objective of this study was to evaluate the cerebrospinal fluid (CSF) permeation of indomethacin in healthy children. The participants (n = 31, aged 4–144 months) received indomethacin (0.35 mg/kg) as a 10‐minute intravenous infusion prior to surgery under spinal anaesthesia. A single CSF and plasma sample from each individual was collected 14 to 225 minutes after the infusion. Indomethacin concentrations were determined from the CSF, plasma, and protein‐free plasma. Total plasma, protein‐free plasma, and CSF concentrations of indomethacin ranged between 90 and 2200 ng/mL (median, 780 ng/mL), 0.3 and 0.8 ng/mL (median, 0.5 ng/mL), and 0.2 and 5.0 ng/mL (median, 1.4 ng/mL), respectively. The CSF to plasma concentration ratio remained less than 0.01. There was no correlation between the administration time and CSF concentrations. Eleven children developed 12 nonserious adverse effects, from which 5 were central nervous system (CNS) effects (agitation). In conclusion, indomethacin permeated into the CSF of children, which enables both desired and adverse CNS effects of indomethacin.

Pharmacokinetics of Ketoprofen Syrup in Small Children

Ketoprofen is a nonsteroidal anti‐inflammatory drug with analgesic, anti‐inflammatory, and antipyretic properties. Its pharmacokinetics has not been determined in small children. The objective here was to determine the pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children. Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and Group 2 was from ages 2 to 7years. Venous blood samples were collected before drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC method was used to determine plasma levels of ketoprofen. The lower limit of quantification was 0.02 μg/ml of plasma. Ketoprofen syrup was absorbed rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3 μg/ml. The pharmacokinetics was similar between the two groups of children. The elimination half‐life, 2.0 hours in Group 1 or 1.9 hours in Group 2, was similar to that reported in adults.

How readily does ketorolac penetrate cerebrospinal fluid in children

Ketorolac is a potent nonsteroidal anti‐inflammatory analgesic used in postoperative pain management. Ketorolac elicits its analgesic action by inhibiting the cyclo‐oxygenase enzyme in peripheral tissues and in the spinal cord. Central nervous system penetration of parenteral ketorolac has been evaluated in adults but not in children. In the present study we investigated ketorolac cerebrospinal fluid penetration via spinal anesthesia in 30 healthy children undergoing surgery in the lower part of the body. A single cerebrospinal fluid and blood sample was obtained between 11 minutes and 6 hours after receiving ketorolac 0.5 mgṁkg−1 IV. Ketorolac concentrations were determined by gas chromatography with mass spectrometric detection. Ketorolac was detected from 22 of the 30 cerebrospinal fluid samples, and the concentrations ranged between 0.2 and 7.6 μgṁL−1 (median, 0.6 μgṁL−1). The cerebrospinal fluid to unbound plasma concentration‐ratio ranged between 0.01 and 0.69 (median, 0.08). These low concentrations indicate that ketorolac does not readily penetrate cerebrospinal fluid in children.

Maturation of oxycodone pharmacokinetics in neonates and infants: Oxycodone and its metabolites in plasma and urine

AIMS This study aimed to characterize the pharmacokinetics of oxycodone and its major metabolites in infants and covered the age range between extremely preterm neonates and 2‐year‐old infants. METHODS Seventy‐nine infants (gestational age 23–42 weeks; postnatal age 0–650 days) received intravenous oxycodone hydrochloride trihydrate at a dose of 0.1 mg kg−1 during or after surgery. Three to seven blood samples were taken from each infant, and plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were quantified. The unconjugated forms of these compounds were determined in urine collected after up to 24 or 48 h from 25 infants. Pharmacokinetics was determined using noncompartmental analysis and reported for six clinically relevant age groups based on postmenstrual age. RESULTS Oxycodone pharmacokinetics changed markedly with patient age. Preterm neonates were found to have the highest pharmacokinetic variability out of the study population. In extremely preterm neonates (n = 6) median of elimination half‐life was 8.8 h (range 6.8–12.5), in preterm (n = 11) 7.4 h (4.2–11.6), and in older neonates (n = 22) 4.1 h (2.4–5.8), all of which were significantly longer than that in infants aged 6–24 months (n = 12) 2.0 h (1.7–2.6). Median renal clearance was fairly constant in all age groups, whereas non‐renal clearance markedly increased with age. Noroxycodone was the major metabolite in plasma and urine. CONCLUSIONS Oxycodone elimination is slower and pharmacokinetic variability more pronounced in neonates when compared to older infants. These findings highlight the importance of careful dose titration for neonates.