Urinary creatinine adjusted reference ranges for homovanillic and vanillylmandelic acid in children and adults.

The relationship between urinary homovanillic acid (HVA), vanillylmandelic acid (VMA) and creatinine is investigated and reference ranges are constructed for HVA and VMA. A total of 769 urine samples were obtained from children and adults. The ratios HVA/creatinine and VMA/creatinine were highly correlated with creatinine concentration; hence, reference to creatinine was found to be an inappropriate adjustment for urinary dilution. An alternative method based upon linear regression is proposed. After allowing for differing levels of creatinine, HVA and VMA were found to be significantly correlated with age, height and weight for individuals aged less than 20 years. In those aged over 20 years, HVA was significantly correlated with weight and VMA with age. Differences between sexes were found in the levels of HVA and VMA, the exception being VMA in the over 20 age group. Reference ranges were constructed for HVA and VMA which are variously dependent upon creatinine, age, sex and weight.

Urinary excretion of HMMA and HVA in infants.

Gas chromatography with flame ionisation detection has been used to establish the normal urinary excretion values of homovanillic acid and 4-hydroxy-3-methoxymandelic acid in 808 infants aged 6 months. This study, the essential pre-requisite for population screening for neuroblastoma in babies, reveals a mean homovanillic acid of 10.9 mumol/mmol creatinine and mean 4-hydroxy-3-methoxymandelic of 6.8 mumol/mmol creatinine. The upper 95% confidence interval were 25.5 mumol/mmol creatinine for homovanillic acid and 15.0 mumol/mmol creatinine for 4-hydroxy-3-methoxymandelic. Gas chromatography/mass spectrometry analysis of the 39 samples, (4.8%) with apparent increased excretion of one or both metabolites, revealed that this was, in each case, due to interfering peaks on chromatography.

Screening for neuroblastoma in the north of England.

OBJECTIVE: To determine the feasibility of establishing a system of screening for neuroblastoma. DESIGN: Prospective study of mass screening in four clearly defined geographical areas. SETTING: Four health districts of the Northern region of England. SUBJECTS: 20,829 babies aged 6 months, 92% of target population. INTERVENTIONS: Collection of urine on filter paper for analysis of content of homovanillic and vanillylmandelic acid in relation to urinary creatinine concentrations. MAIN OUTCOME MEASURES: Derivation of reference range. Identification of babies with homovanillic or vanillylmandelic acid > 3 SD above the mean (positive cases). Investigation of positive cases for evidence of neuroblastoma. RESULTS: The upper limit of normal (3 SD above the mean) for vanillylmandelic acid was 15 mumol/mmol creatinine and for homovanillic acid 24 mumol/mmol creatinine. Of the 20,829 babies screened, 2537 (12.2%) required a second sample to be taken because the first sample was inadequate. Of these, 527 (2.5%) provided a liquid urine specimen and 10 (0.04%) had positive results for neuroblastoma. Two of them had neuroblastoma (true positives) and eight did not (false positives). A further three children from the cohort were subsequently found to have neuroblastoma; they had raised homovanillic acid or vanillylmandelic acid values, or both, but screened negative at 6 months. CONCLUSIONS: Screening for neuroblastoma is possible in the health care system of the United Kingdom. Evaluation of the efficacy of screening in reducing the mortality from neuroblastoma requires a controlled trial.

The stability of preservative-free morphine in plastic syringes.

The stability of preservative-free morphine in plastic syringes over 36 hours in the range of concentrations commonly used in our hospital to provide continuous morphine infusions was investigated. The morphine concentration remained at 100% (SD 1.5 percent) of the control values over 36 hours and demonstrates that the concentration of morphine is not reduced with time in these circumstances.

Plasma morphine levels produced by continuous infusion in children.

Blood samples were taken from six children aged between 10 months and 15 years, at intervals over a period of 40 hours while they were receiving continuous morphine infusions. The plasma morphine values obtained showed similar and consistent levels 15-30 minutes after starting the infusions.

Creatinine related reference ranges for urinary homovanillic acid and vanillylmandelic acid at 6 months of age.

The relationship between homovanillic acid (HVA), vanillylmandelic acid (VMA), and creatinine in the urine of 6 month old babies has been studied and reference ranges in the form of centiles constructed for HVA and VMA against creatinine. Over 10,000 urine samples were collected from babies in four health districts in the north of England. HVA and VMA concentration, either independently or when divided by creatinine concentration, were dependent upon the absolute concentration of creatinine in the sample. After adjustment for creatinine significant differences in the mean concentration of HVA were found between sexes. No such differences were found for VMA. HVA and VMA were also found to be age dependent. Centiles were constructed using a procedure which makes no distributional assumptions about the data. The net effect of utilising these centiles was to increase the predictive value of a positive screening test from 20% to 40% without any increase in the false negative rate.

Screening for neuroblastoma in the northern region of England. Laboratory aspects.

Our pilot study for neuroblastoma screening started in 1986. The study has progressed through several phases, with use of several analytical methods to a procedure based primarily on the use of automated gas chromatography mass spectrometry. The northern region of England has a relatively static population of approximately 3.5 million, with an annual birth rate of 41,000. The region consists of 16 administrative health districts. In 4 years, we have screened 20,829 infants from four health districts. In this program, we screen all children at 6 months of age. A urine sample is collected on filter paper by a health visitor, either at the time of the infant's routine clinic visit or during the health visitor's follow-up visit at home. In the laboratory, the sample is dried and processed for analysis of homovanillic acid (HVA) and vanillylmandelic acid (VMA), using a benchtop Hewlett Packard gas chromatograph mass spectrometer. The results are related to the creatinine content of the urine. Using cut-off limits of 39 micrograms/mg of creatinine for HVA and 25 micrograms/mg of creatinine for VMA, 2,537 infants (12.2%) required a second paper sample and 527 infants (2.5%) were observed with a liquid urine collection. Of these, the conditions of nine infants with elevated levels of HVA or VMA were investigated clinically for the possible presence of neuroblastoma. Two infants were found to have neuroblastoma; the other seven showed no evidence of tumor. In addition, there were three children who, when screened at 6 months of age, had normal levels of HVA and VMA but in whom neuroblastoma subsequently developed.

A pilot study of screening for neuroblastoma in the north of England.

A pilot study has been carried out to assess the feasibility of screening for neuroblastoma in 6-month-old infants in the north of England. A total of 20,829 infants were screened. Two true-positive cases were found, along with eight false-positive and three false-negative cases. It was shown that the concentrations of catecholamine metabolites in the urine are dependent on the creatinine content; centiles have been established to allow this relationship to be taken into account. Five of the eight false-positive cases would have been correctly assessed as normal if the new centiles had been used. Preliminary results lend support to the need for a well-designed study of neuroblastoma screening to be carried out, with death from this disease as the only end point.