Incidence of severe critical events in paediatric anaesthesia in the United Kingdom: secondary analysis of the anaesthesia practice in children observational trial (APRICOT study).

The anaesthesia practice in children observational trial of 31,127 patients in 261 European hospitals revealed a high (5.2%) incidence of severe critical events in the peri-operative period and wide variability in practice. A sub-analysis of the UK data was undertaken to investigate differences compared with the non-UK cohort in the incidence and nature of peri-operative severe critical events and to attempt to identify areas for quality improvement. In the UK cohort of 7040 paediatric patients from 43 hospitals, the overall incidence of peri-operative severe critical events was lower than in the non-UK cohort (3.3%, 95%CI: 2.9-3.8 vs. 5.8%, 95%CI: 5.5-6.1, RR 0.57, p < 0.001). There was a lower rate of bronchospasm (RR 0.22, 95%CI: 0.14-0.33; p < 0.001), stridor (RR 0.42, 95%CI: 0.28-0.65; p < 0.001) and cardiovascular instability (RR 0.69, 95%CI: 0.55-0.86; p = 0.001) than in the non-UK cohort. The proportion of sicker patients where less experienced teams were managing care was lower in the UK than in the non-UK cohort (10.4% vs. 20.4% of the ASA physical status 3 and 9% vs. 12.9% of the ASA physical status 4 patients). Differences in work-load between centres did not affect the incidence and outcomes of severe critical events when stratified for age and ASA physical status. The lower incidence of cardiovascular and respiratory complications could be partly attributed to more experienced dedicated paediatric anaesthesia providers managing the higher risk patients in the UK. Areas for quality improvement include: standardisation of serious critical event definitions; increased reporting; development of evidence-based protocols for management of serious critical events; development and rational use of paediatric peri-operative risk assessment scores; implementation of current best practice in provision of competent paediatric anaesthesia services in Europe; development of specific training in the management of severe peri-operative critical events; and implementation of systems for ensuring maintenance of skills.

Differences in Blood Pressure in Infants After General Anesthesia Compared to Awake Regional Anesthesia (GAS Study-A Prospective Randomized Trial).

BACKGROUND: The General Anesthesia compared to Spinal anesthesia (GAS) study is a prospective randomized, controlled, multisite, trial designed to assess the influence of general anesthesia (GA) on neurodevelopment at 5 years of age. A secondary aim obtained from the blood pressure data of the GAS trial is to compare rates of intraoperative hypotension after anesthesia and to identify risk factors for intraoperative hypotension. METHODS: A total of 722 infants ≤60 weeks postmenstrual age undergoing inguinal herniorrhaphy were randomized to either bupivacaine regional anesthesia (RA) or sevoflurane GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born at <26 weeks of gestation. Moderate hypotension was defined as mean arterial pressure measurement of <35 mm Hg. Any hypotension was defined as mean arterial pressure of <45 mm Hg. Epochs were defined as 5-minute measurement periods. The primary outcome was any measured hypotension <35 mm Hg from start of anesthesia to leaving the operating room. This analysis is reported primarily as intention to treat (ITT) and secondarily as per protocol. RESULTS: The relative risk of GA compared with RA predicting any measured hypotension of <35 mm Hg from the start of anesthesia to leaving the operating room was 2.8 (confidence interval [CI], 2.0-4.1; P < .001) by ITT analysis and 4.5 (CI, 2.7-7.4, P < .001) as per protocol analysis. In the GA group, 87% and 49%, and in the RA group, 41% and 16%, exhibited any or moderate hypotension by ITT, respectively. In multivariable modeling, group assignment (GA versus RA), weight at the time of surgery, and minimal intraoperative temperature were risk factors for hypotension. Interventions for hypotension occurred more commonly in the GA group compared with the RA group (relative risk, 2.8, 95% CI, 1.7-4.4 by ITT). CONCLUSIONS: RA reduces the incidence of hypotension and the chance of intervention to treat it compared with sevoflurane anesthesia in young infants undergoing inguinal hernia repair.

High-performance liquid chromatography determination of alpha1-acid glycoprotein in small volumes of plasma from neonates.

In order to investigate how the alpha1-acid glycoprotein (AGP) concentrations of neonates change in response to surgical stress, a simple high-performance liquid chromatography (HPLC)-assay for the measurement of alpha1-acid glycoprotein levels was developed. A fraction containing alpha1-acid glycoprotein was isolated from the bulk of plasma protein by addition of 0.6M perchloric acid and was then analysed directly on a short PLRP-S 4000A reversed phase column column. The method was validated by analysis of pooled plasma from healthy adults both in comparison with a calibration curve and by standard additions. The procedure was able to isolate alpha1-acid glycoprotein rapidly (<30 min) and required only 50 microl of plasma. The mean extraction recovery was 79.1% (CV 6.4%). The within-run precision for the analysis of three replicates of quality control sample ranged from +/-1.2 to +/-3.8% and the between-run precision was +/-6.1%. The method was linear (r(2)=0.988) over a concentration range from 6 to 100.0 mg/100 ml. The AGP levels in neonatal samples ranged from 25 to 93 mg/100 ml.

A simple microanalytical technique for the determination of paracetamol and its main metabolites in blood spots.

The use of blood spot collection cards is a simple way to obtain specimens for analysis of drugs with a narrow therapeutic window. We describe the development and validation of a microanalytical technique for the determination of paracetamol and its glucuronide and sulphate metabolites from blood spots. The method is based on reversed phase high-performance liquid chromatography with ultraviolet detection. The limit of detection of the method is 600 pg on column for paracetamol. Intra- and inter-day precision of the determination of paracetamol was 7.1 and 3.2% respectively. The small volume of blood required (20 microl), combined with the simplicity of the analytical technique makes this a useful procedure for monitoring paracetamol concentrations. The method was applied to the analysis of blood spots taken from neonates being treated with paracetamol.

Review of ethics in paediatric anaesthesia: intensive care issues.

This is the third of a series of three articles examining the recent changes in the law in relation to ethics and the practice of paediatric anaesthesia. The review covers, in a practical question and answer format, the topics of consent, research, intensive care issues and organ donation in children.

Review of ethics in paediatric anaesthesia: research issues.

This is the second of a series of three articles reviewing the recent changes in the law in relation to ethics and the practice of paediatric anaesthesia. The review covers, in a practical question and answer format, the topics of consent, research, intensive care issues and organ donation in children.

Review of ethics in paediatric anaesthesia: consent issues.

The concepts of law and ethics as related to medical practice have always been of paramount importance to the medical profession. This series of three reviews, examines the changes in the law in the last 10 years in relation to ethics and the practice of paediatric anaesthesia. The reviews cover, in a practical question and answer format, the topics of consent, research, intensive care and organ donation issues in children.

Treatment with paracetamol in infants.

BACKGROUND: Paracetamol (N-acetyl-p-amino-phenol) or acetaminophen has become the most widely used analgesic and antipyretic in children. However, there is a wide discrepancy between the extent to which paracetamol is used and the limited available pharmacological data in small infants. The purpose of this article is to present a review of the current literature regarding the use of paracetamol in neonates and infants with a particular emphasis on pharmacological issues. METHODS: A MEDLINE search (up to March 2000) was conducted to identify relevant English-language publications using paracetamol, children, infants and neonates as search terms. Additional studies were identified from bibliographies of the reviewed literature. RESULTS: Pharmacological studies on paracetamol in infants are few. Most studies have focused on the administration of one single paracetamol dose, and the problem of cumulative toxicity with repeated dosing has not been addressed. Plasma paracetamol concentration should be 10-20 mg ml(-1) to achieve antipyretic and analgesic effects. The bioavailability of the different formulations and routes of administration vary with age. Rectal absorption is slower and more erratic than the oral; however, in the very young, rectal bioavailability is higher than in older patients. Volume of distribution seems to be age-independent, whereas clearance is reduced in neonates and particularly in preterm babies. Neonates and infants are capable of forming the reactive intermediate metabolite that causes hepatocellular damage, particularly after multiple doses. They have an immature glucuronide conjugation system, but the rate constant for the sulphation metabolic pathway is larger than in older children, and this is the most important route of metabolism. CONCLUSIONS: The pharmacokinetics and pharmacodynamics of paracetamol differ substantially in neonates and infants from those in older children and adults; hence, dosing should be adjusted accordingly.

Plasma concentrations and pharmacokinetics of bupivacaine with and without adrenaline following caudal anaesthesia in infants.

BACKGROUND: The aim of this study was to determine whether the use of adrenaline 1/400000 added to 0.25% bupivacaine significantly delays the systemic absorption of the drug from the caudal epidural space in young infants. METHODS: Fifteen infants less than 5 months of age undergoing minor lower abdominal procedures under a standardised general anaesthetic were randomised to receive a caudal block with either 0.25% plain bupivacaine 2.5 mg/kg (n=7) or bupivacaine 0.25% with 1/400000 adrenaline (n=8). Blood samples were drawn at 30, 60, 90, 180, 240 and 360 min according to the infant's weight and analysed for total and free bupivacaine concentrations using a gas chromatography-mass spectrometry (GC-MS) technique. RESULTS: The total C(MAX) and T(MAX) were comparable in both groups. The total bupivacaine concentration at t=360 min was significantly higher in the "adrenaline" group compared to the "plain" group, i.e. a median (range) 742 ng/ml (372-1423 ng/ml) vs. 400.5 ng/ml (114-446 ng/ml), P=0.0080. The median "apparent" terminal half-life (t1/2) was significantly longer in the "adrenaline" group (363 min; range 238-537 min) compared to the "plain" group (n=6) (165 min; range 104-264 min), P=0.0087. The free bupivacaine concentrations (n=3 in both groups) ranged between 13 ng/ml and 52 ng/ml, corresponding to a percentage of free bupivacaine between 1.3% and 6.7%. CONCLUSION: The addition of 1/400.000 adrenaline prolongs the systemic absorption of caudally administered bupivacaine in infants less than 5 months of age.

Determination of free concentrations of ropivacaine and bupivacaine in plasma from neonates using small-scale equilibrium-dialysis followed by liquid chromatography-mass spectrometry.

Attempts to determine a safe plasma concentration of ropivacaine and bupivacaine in neonates have not been consistent. This might be due to an underestimation of free drug in small plasma samples by currently used techniques, e.g., ultrafiltration. We describe a simple microscale equilibrium-dialysis technique for the separation of free and bound ropivacaine and bupivacaine. The free drug in the dialysate was determined using solid-phase extraction and liquid chromatography with mass spectrometry. Pentycaine was used as an internal standard and added to the dialysates prior to extraction. The method is very selective and sensitive, as no compounds other than the analyte and internal standard were observed in the resulting chromatograms at low ng/ml levels. The limit of quantitation was 2.5 ng/ml. The calibration curve was linear in the range of 2 to 1000 ng/ml. The precision of the whole procedure was 8.1% (n=10) and 6.5% (n=7) for ropivacaine and bupivacaine, respectively. The method was tested in the analysis of plasma samples taken from neonates who had received epidural injections.

Analgesic efficacy of paracetamol and diclofenac in children receiving PCA morphine.

We studied 80 children, aged 5-13 yr, who received PCA with morphine after appendicectomy using a standardized tracheal general anaesthetic. All patients received morphine 0.1 mg kg-1 before surgical incision and all had wound infiltration with bupivacaine 1 mg kg-1 at the end of surgery. Patients were allocated randomly to receive postoperative analgesia with PCA morphine alone, morphine plus diclofenac 1 mg kg-1, morphine plus paracetamol 15-20 mg kg-1 or morphine plus a combination of both diclofenac and paracetamol. Cumulative morphine consumption was significantly reduced by concurrent administration of diclofenac but no additive effect of paracetamol was demonstrable with the doses used in the study. Analgesia, as assessed by movement pain scoring, was significantly improved by the addition of diclofenac despite lower morphine consumption. Adverse effects and duration of PCA were comparable in the four groups.

Plasma paracetamol concentrations and pharmacokinetics following rectal administration in neonates and young infants.

BACKGROUND: Despite widespread use in children pharmacokinetic data about paracetamol are relatively scarce, not the least in the youngest age groups. This study aimed to describe plasma paracetamol concentrations and pharmacokinetics of a single rectal paracetamol dose in neonates and young infants. METHODS: Perioperatively, 17 neonates and infants < or =160 days of age received one rectal paracetamol dose (mean 23.9 mg/kg (+/-4.2 mg/kg)). Blood samples were drawn at 60, 120, 180, 240, 300 and 360 min, according to the infants' weights. Plasma paracetamol concentrations were measured by a Colorometric Assay, Ectachem Clinical Chemistry Slides (Johnson & Johnson Clinical Diagsnostics). RESULTS: The plasma paracetamol concentrations were mainly below the therapeutic (i.e. antipyretic) range of 66-132 micromol/l and did not exceed 160 micromol/l in any infant. The mean maximum plasma concentration (Cmax) was 72.4 micromol/l (+/-33.5 micromol/l) and the time to Cmax, i.e. the mean Tmax was 102.4 min (_+59.1 min). The mean "apparent" terminal half-life (n=10) was 243.6 min (+/-114.1 min). CONCLUSION: The absorption of rectal paracetamol (mean dose 23.9 mg/kg, +/-4.2mg/kg) in young infants <160 days is variable and often prolonged and achieves mainly subtherapeutic plasma concentrations.

Paracetamol-induced fulminant hepatic failure in a child after 5 days of therapeutic doses.

We report the case of a two and a half year-old girl who developed fulminant hepatic failure following 5 days of regular oral ingestion of paracetamol, approximately 90 mg x kg-1 x day-1. She presented with the typical findings of hepatomegaly, encephalopathy, high ammonia levels, high transaminases, hypoglycaemia and lactic acidosis. After stabilization, she was transferred to a specialist paediatric liver failure unit and fortunately she made a full recovery with intensive medical management.