Suspected opioid-induced hyperalgesia in an infant.

One explanation for diminished opioid analgesic efficacy is opioid-induced hyperalgesia (OIH). We report a case of OIH in an infant with gastroschisis, requiring multiple surgical interventions and prolonged sedation for ventilation. This is the first report of OIH in an infant. On day 41 of life after nine separate surgical interventions, the patient's pain scores increased and remained elevated, despite increasing opioid administration. The patient also developed hyperalgesia, allodynia, and photophobia and became extremely irritable upon handling. Other possible causes were excluded, including interruption to opioid delivery, sepsis, acid-base and electrolyte disturbance, and ongoing surgical pathology. An opioid rotation to hydromorphone was initiated and ketamine was commenced. Sedation for ventilation was achieved with dexmedetomidine and midazolam infusions. Over a period of 24 h after opioid de-escalation, pain scores reduced rapidly and the patient became significantly less irritable with handling. All infusions were gradually weaned and eventually ceased.

I.V. acetaminophen pharmacokinetics in neonates after multiple doses.

BACKGROUND: Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation. METHODS: Neonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM). RESULTS: Fifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled. CONCLUSIONS: The parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

Postoperative sleep disturbance in pediatric patients using patient-controlled devices (PCA).

BACKGROUND: Sleep disturbance has not been well quantified in pediatric postoperative management, yet has broad implications in pain management as well as upon the physical and psychological well-being of the young patient admitted for surgery. We aimed to describe sleep disturbance in this population using patient-controlled analgesia (PCA) and then identify the predictors of disturbed sleep. METHODS: A retrospective audit and analysis of sleep disturbance in postoperative pediatric patients using PCA devices were performed in a postoperative surgical ward population of a major tertiary referral center. PCA presses were used as a proxy measure of sleep. The description of the sleep disturbance included an unadjusted and adjusted analysis of the proposed predictors of sleep disturbance: age, sex, nature of presentation, operation type, PCA opioid type, presence of background infusion, postoperative night number, and adjuvant medication. All data were entered into an access database developed for the audit and analyzed using stata 8.0. RESULTS: The first 126 children prescribed PCA devices in the year 2004 were audited. One-third of patients in the population prescribed PCA experienced sleep disturbance. Observed predictors of sleep disturbance include older children (OR: 0.86, P=0.001) and those receiving a background infusion (OR: 0.19, P=0.002). Other predictors were not significant. CONCLUSIONS: Sleep disruption is common in children-prescribed PCA opioid analgesia. Older children and those receiving a background infusion were observed to experience less sleep. Other proposed predictors were not found to be reliable. Further investigation into the predictors of disturbed sleep in the postoperative patient is warranted.

Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age.

BACKGROUND: There are few data describing levobupivacaine pharmacokinetics in infants (<3 months) after caudal administration. METHODS: An open-label study was undertaken to examine the pharmacokinetics of levobupivacaine 2.5 mg ml(-1), 2 mg kg(-1) in children aged less than 3 months after single-shot caudal epidural administration. Plasma concentrations were determined at intervals from 0.5 to 4 h after injection. A population pharmacokinetic analysis of levobupivacaine time-concentration profiles (84 observations) from 22 infants with mean postnatal age (PNA) 2.0 (range 0.6-2.9) months was undertaken using non-linear mixed effects models (NONMEM). Time-concentration profiles were analysed using a one-compartment model with first-order input and first-order elimination. Estimates were standardized to a 70 kg adult using allometric size models. RESULTS: Population parameter estimates (between-subject variability) for total levobupivacaine were clearance (CLt) 12.8 [coefficient of variation (CV) 50.6%] litre h(-1) 70 kg(-1), volume of distribution (Vt) 202 (CV 31.6%) litre 70 kg(-1), absorption half-life (Tabs) 0.323 (CV 18.6%) h 70 kg(-1). Estimates for the unbound drug were clearance (CLfree) 104 (CV 43.5%) litre h(-1) 70 kg(-1), volume of distribution (Vfree) 1700 (CV 44.9%) litre 70 kg(-1), absorption half-life (Tabsfree) 0.175 (CV 83.7%) h 70 kg(-1). There was no effect attributable to PNA on CL or V. Time to peak plasma concentration (Tmax) was 0.82 (CV 18%) h. Peak plasma concentration (Cmax) was 0.69 (CV 25%) microg ml(-1) for total levobupivacaine and 0.09 (CV 37%) microg ml(-1) for unbound levobupivacaine. CONCLUSIONS: Clearance in infants is approximately half that described in adults, suggesting immaturity of P450 CYP3A4 and CYP1A2 enzyme isoforms that metabolize levobupivacaine in infants. This lower clearance delays Tmax, which was noted to occur approximately 50 min after administration of caudal epidural levobupivacaine.

Pharmacokinetics of levobupivacaine 0.25% following caudal administration in children under 2 years of age.

BACKGROUND: Levobupivacaine, the S(-)enantiomer of racemic bupivacaine is less cardiotoxic than racemic bupivacaine and the R(+)enantiomer dexbupivacaine, while retaining similar local anaesthetic properties and potency to racemic bupivacaine. The pharmacokinetic profiles of the two bupivacaine enantiomers differs and that of racemic bupivacaine may be age dependent. We examined the pharmacokinetics of levobupivacaine after its single shot caudal epidural administration in children. METHODS: An open-label phase 2 study was undertaken to examine the pharmacokinetics of levobupivacaine 0.25% 2 mg kg(-1) in 49 children aged less than 2 yr, after single shot caudal epidural administration. Plasma concentrations were determined at intervals up to 60 min after caudal injection. RESULTS: Time to peak plasma concentration (T(max)) ranged between 5 and 60 min (median 30 min) and was reached later in children aged less than 3 months (P<0.005). Peak plasma concentration (C(max)) ranged between 0.41 and 2.12 micro g ml(-1) (median 0.80, mean (SD) 0.91 (0.40) micro g ml(-1)). CONCLUSION: After the caudal epidural administration of levobupivacaine 2 mg kg(-1) in children less than 2 yr of age, C(max) was within the accepted safe range for racemic bupivacaine. T(max) varied and occurred later in some children, particularly those aged less than 3 months. Sampling in future pharmacokinetic studies in this age group should extend beyond 60 min.

Efficacy and safety of caudal injection of levobupivacaine, 0.25%, in children under 2 years of age undergoing inguinal hernia repair, circumcision or orchidopexy.

BACKGROUND: Levobupivacaine is the S(-)-enantiomer of racemic bupivacaine. Evidence suggests that it is less cardiotoxic than racemic bupivacaine and the R(+)-enantiomer, dexbupivacaine, while retaining similar local anaesthetic properties and potency to racemic bupivacaine. METHODS: This was an open study designed to assess the efficacy and safety of 0.25% levobupivacaine administered as a caudal injection at a dose of 2 mg.kg(-1) to 49 paediatric patients aged less than 2 years old undergoing circumcision (group 1), or hernia repair or orchidopexy (group 2). RESULTS: Adequate analgesia (an increase of <20% in pulse or respiratory rate compared with baseline and an absence of gross movement on application of surgical stimulus) was achieved in 43/48 patients evaluable for efficacy (89.6%). All 22 patients in the circumcision group had adequate analgesia, and two of these patients did not require additional analgesia. The mean time to the use of additional analgesia was 7.3 h. Only one event (a mild rash) was considered possibly related to study medication. CONCLUSIONS: Levobupivacaine is a promising new local anaesthetic agent for pain management in paediatric patients and appears to offer similar anaesthetic efficacy to racemic bupivacaine with a potentially improved tolerability profile.

Management of chronic pain in children.

OBJECTIVES: To describe the demography, clinical characteristics, treatment, functional limitations and outcomes of patients referred to a paediatric multidisciplinary pain clinic. DESIGN: Prospective data collection, descriptive study. PATIENTS AND SETTING: Tertiary referral centre pain clinic (Royal Children's Hospital, Melbourne) over two years (March 1998 - March 2000). MAIN OUTCOME MEASURES: Pain profile; functional disability (school absenteeism, sleep disturbance and inability to perform sport); treatments received; outcome. RESULTS: 207 patients (mean age, 13.1 years; 73% females; 29% rural residents) were referred in the two years. Concomitant medical conditions were present in 106/207 (51%) patients, the commonest being cerebral palsy or spasticity (22 patients) and malignancy (18). Complex regional pain syndrome was diagnosed in 44 patients. Functional disability due to pain included school absenteeism (95% of school attenders), sleep disruption (71% of all patients) and inability to perform sport (90% of those able to participate in sport previously). Of the 105 patients who missed five or more days of school because of pain, 93 attended school regularly after treatment. Sleep disturbance improved in 129/146 (88%) patients, and 129/147 (88%) resumed sporting activity after multidisciplinary intervention. Outcome was classified as good in 134 patients (65%), moderate in 32 (15%) and poor in 16 (8%). CONCLUSIONS: Chronic pain in children and adolescents often results in considerable functional disability. Functional improvement can be achieved using a multidisciplinary approach to pain management in children.

Anaesthesia and pain management in cerebral palsy.

Cerebral palsy is the result of an injury to the developing brain during the antenatal, perinatal or postnatal period. Clinical manifestations relate to the area affected. Some of the conditions associated with cerebral palsy require surgical intervention. Problems during the peri-operative period may include hypothermia, nausea and vomiting and muscle spasm. Peri-operative seizure control, respiratory function and gastro-oesophageal reflux also require consideration. Intellectual disability is common and, in those affected, may range from mild to severe. These children should be handled with sensitivity as communication disorders and sensory deficits may mask mild or normal intellect. They should be accompanied by their carers at induction and in the recovery room as they usually know how best to communicate with them. Postoperative pain management and the prevention of muscle spasm is important and some of the drugs used in the management of spasm such as baclofen and botulinum toxin are discussed. Epidural analgesia is particularly valuable when major orthopaedic procedures are performed.

Unintentional paediatric subdural catheter with oculomotor and abducens nerve palsies.

A 13-year-old female with a past history of lumbar laminectomy developed a subdural block 18 h after the commencement of an epidural infusion of bupivacaine 0.125% and fentanyl 2 micrograms.ml-1. Signs at presentation included bilateral abducens nerve palsies in the absence of headache and a previously unreported unilateral third cranial nerve palsy. An epidurogram displayed subdural placement.

Depth of central venous catheter insertion in adults: an audit and assessment of a technique to improve tip position.

A technique of subclavian vein catheterization is described, tailored to the individual patient, to reduce the risk of right atrial placement with central venous catheter (CVC) insertion. Using data gathered retrospectively for Quality Improvement purposes, CVC tip location was assessed. The standard technique used in our cardiac anaesthesia unit at that time was to insert all CVCs to a depth of 15 cm from the skin. We then compared CVC tip location using a new "tailored" technique. The tailored method involved measuring the distance from the skin at which venepuncture occurred and using this distance to determine depth of CVC insertion. Using the tailored technique significantly decreases the frequency with which CVC tips enter the right atrium (P < 0.001). An advantage of the tailored technique is that the distance between the most proximal and the distal ports of multi-lumen CVCs is taken into consideration, reducing the risk of extravasation via the proximal port.

The effect of aprotinin on thrombelastography in vitro.

The effect of low dose (50 KIU/ml) and high dose (200 KIU/ml) aprotinin on standard thrombelastographic variables (r, K, alpha, MA) was examined in vitro using blood from forty ASA Class 1 patients. Both concentrations of aprotinin resulted in minor increases in r time above the normal range (P < 0.05). Aprotinin did not alter other thrombelastographic variables. The results indicate that aprotinin is a mild direct anticoagulant in vitro as assessed by thrombelastography.

Cardiac arrest after isoflurane anaesthesia in a patient with Duchenne's muscular dystrophy.

An 8-year-old boy known to have Duchenne's muscular dystrophy suffered a cardiac arrest 10 minutes after he regained consciousness after isoflurane anaesthesia for an orchidopexy procedure. Resuscitation was successful 2 hours after the start of external cardiac compression and after correction of hyperkalaemia and the administration of dantrolene. He later developed myoglobinuria elevated creatine kinase and a metabolic and respiratory acidosis. He demonstrated a delayed increase in rectal temperature.