Twenty year surveillance of invasive pneumococcal disease in Nottingham: serogroups responsible and implications for immunisation.

AIMS: To evaluate the incidence, spectrum of clinical manifestations, and outcome of invasive pneumococcal disease (IPD) in children. To determine the major serogroups of Streptococcus pneumoniae responsible for invasive disease and the potential coverage by the new pneumococcal conjugate vaccines. METHODS: Analysis of prospectively recorded information of all children admitted to two teaching hospitals in Nottingham with IPD between January 1980 and December 1999. RESULTS: A total of 266 episodes of IPD in children were identified; 103 (39%) were aged <1 year and 160 (60%) <2 years. Major clinical presentations were meningitis in 86 (32%), pneumonia in 82 (31%), and bacteraemia without an obvious focus in 80 (30%). The age specific mean annual incidence rates of IPD overall among children aged <1, <2, and <5 years were 47.1, 37.8, and 20 per 100 000 population, respectively. Mortality rates for children with meningitis and non-meningitic infection were 20% and 7%, respectively. Neurological sequelae following meningitis were documented in 16 (26%) of the 61 survivors assessed. The potential coverage rates in children between the ages of 6 months and 5 years are 84% by the 7-valent, 91% by the 9-valent, and 95% by the 11-valent conjugate vaccines. CONCLUSION: This study indicates that inclusion of a pneumococcal conjugate vaccine in the primary immunisation programme in the UK would have a considerable effect on the mortality and morbidity associated with IPD.

The child with a non-blanching rash: how likely is meningococcal disease?

AIMS: To examine a number of simple clinical features and investigations in children with a non-blanching rash to see which predict meningococcal infection. METHODS: A total of 233 infants and children up to 15 years of age presenting with a non-blanching rash were studied over a period of 12 months. Clinical features and laboratory investigations were recorded at presentation. The ability of each to predict meningococcal infection was examined. RESULTS: Eleven per cent had proven meningococcal infection. Children with meningococcal infection were more likely to be ill, pyrexial (>38.5 degrees C), have purpura, and a capillary refill time of more than two seconds than non-meningococcal children. Five children with meningococcal disease had an axillary temperature below 37.5 degrees C. No child with a rash confined to the distribution of the superior vena cava had meningococcal infection. Investigations were less helpful, although children with meningococcal infection were more likely to have an abnormal neutrophil count and a prolonged international normalised ratio. No child with a C reactive protein of less than 6 mg/l had meningococcal infection. CONCLUSIONS: Most children with meningococcal infection are ill, have a purpuric rash, a fever, and delayed capillary refill. They should be admitted to hospital and treated without delay. Children with a non-blanching rash confined to the distribution of the superior vena cava are very unlikely to have meningococcal infection. Measurement of C reactive protein may be helpful-no child with a normal value had meningococcal infection. Lack of fever at the time of assessment does not exclude meningococcal disease.

Kingella kingae endocarditis in a sixteen-month-old-child.

We report the case of a child with acute neurologic symptoms who was found to have bacterial endocarditis caused by Kingella kingae. The case alerts microbiologists and pediatricians to an organism that has rarely been reported to cause endocarditis in children.

Topical amethocaine gel for pain relief of heel prick blood sampling: a randomised double blind controlled trial.

BACKGROUND: Heel prick blood sampling is a commonly performed and painful procedure in the newborn infant. Use of a topical local anaesthetic does not relieve this pain. A 4% w/w amethocaine gel (Ametop) reduces the pain of venepuncture in the newborn but has not been tried with heel pricks. AIM: To investigate the effect of topical amethocaine gel on the pain of heel prick in the newborn infant. DESIGN: Randomised, double blind, placebo controlled trial. SUBJECTS: Sixty newborn infants, gestation 28-42 weeks (median 36), postnatal age 1-16 days (median 5) undergoing routine heel prick blood sampling. METHODS: A 1.5 g portion of 4% w/w amethocaine gel or placebo was applied to the skin under occlusion for one hour, then wiped away. Heel prick blood sampling with a spring loaded lance was performed five minutes later. The procedure was videotaped and pain assessed at one second intervals using an adaptation of the neonatal facial coding system (NFCS). No or minimal pain was defined as a cumulative score of less than 5 (out of 15) in the three seconds after firing of the lance and as lack of a cry in the first five seconds. RESULTS: In terms of a low NFCS core and lack of cry (p = 0.12) 20 of 30 (67%) in the amethocaine group and 13 of 29 (45%) in the placebo group had no or minimal pain in response to the heel prick. The median cumulative NFCS score over the three seconds after firing the lance was 3 (interquartile range 0-6) in the amethocaine group compared with 5 (interquartile range 1-10) in the placebo group (p = 0.07). These differences are not significant. CONCLUSIONS: Topical amethocaine gel does not have a clinically important effect on the pain of heel prick blood sampling and its use for this purpose cannot therefore be recommended. Alternative approaches to the relief of pain from this procedure should be explored.

Clinical consequences of an immature barrier.

The epidermal barrier is well developed in the term infant. It is poorly developed in the most immature infants, leading to three major effects: high transepidermal water loss (TEWL), percutaneous absorption, and trauma. A high TEWL leads to poor temperature control and difficulty in fluid balance: it can and should be reduced by manipulating the ambient humidity or by covering the skin. Topical antiseptics should be used sparingly and with care to prevent toxic damage from absorption. The chances of trauma can be reduced by careful choice of monitoring probes and adhesives. Since the epidermal barrier develops rapidly in the postnatal period, these effects only cause problems in the first week or two of life.

The dermis.

All the dermal structures are less well developed in the newborn than in the older infant or child, but there are few important consequences of this. Sweating in response to a thermal stimulus occurs at birth in the term infant and can be detected in most preterm infants from 2 weeks of age. It is poorly developed though. Emotional (palmar/plantar) sweating is present from birth in term infants only. Skin blood flow can be regulated in term and preterm infants, and is often measured indirectly as a temperature gradient. Such a gradient is temperature as well as illness dependent which limits its use as a clinical tool. Sensory nerve endings are readily stimulated in the most immature infants. Finally, damage to the skin in the newborn period commonly leads to scarring, although this usually improves with time.

Topical amethocaine gel in the newborn infant: how soon does it work and how long does it last?

AIM: To explore the time of onset and duration of action of topical amethocaine gel in the newborn infant. DESIGN: A randomised double blind placebo controlled trial. SUBJECTS: Thirty six infants were studied after 30 minutes application and 36 after 60 minutes application. A total of 56 infants (gestation 27-42 weeks, weight 0. 79-4.1 kg) were studied in the first two weeks after delivery. METHOD: 1.5 g amethocaine or placebo was applied to the dorsum of either foot, occluded, and then left for 30 or 60 minutes. Local anaesthesia was assessed by observing the cutaneous withdrawal response to graded nylon filaments (von Frey hairs). If there was a difference between feet in filament thickness required to elicit a response, the infant was studied in an identical manner at hourly intervals until the difference had disappeared. RESULTS: Evidence of local anaesthetic action of amethocaine was seen in 23 of 36 (64%) infants after 30 minutes and 26 of 36 (72%) infants after 60 minutes application (no significant difference). Evidence of local anaesthetic action was independent of gestation and order of testing. Amethocaine responders showed a significantly deeper anaesthetic action than placebo responders. The median duration of action was 1.5 hours (range 0.5-3.5) after 30 minutes and three hours (range 1-5) after 60 minutes (p<0.001). CONCLUSION: Topical amethocaine gel has a local anaesthetic action after 30 minutes application, but application for 60 minutes results in longer duration of action.

Does topical amethocaine gel reduce the pain of venepuncture in newborn infants? A randomised double blind controlled trial.

BACKGROUND: Topical amethocaine provides effective pain relief during venepuncture in children, and has been shown to have a local anaesthetic action in the newborn. AIM: To investigate the effect of topical amethocaine on the pain of venepuncture in the newborn. DESIGN: Randomised double blind placebo controlled trial. SUBJECTS: Forty newborn infants, gestation 27-41 weeks (median 33), age 2-17 days (median 7), undergoing routine venepuncture. METHOD: A 1.5 g portion of 4% (w/w) amethocaine gel (Ametop; Smith and Nephew, Hull, UK) or placebo was applied to the skin under occlusion for one hour, then wiped away. Venepuncture was performed five minutes later. Facial reaction and cry were recorded on videotape. Pain was assessed using a validated adaptation of the neonatal facial coding system. Five features were scored at one second intervals for five seconds before and after venepuncture. No or minimal pain was defined as a cumulative score of below 10 (out of 25) in the five seconds after needle insertion. Each author scored the tapes independently. RESULTS: There was close agreement on scoring of the tapes. One infant was excluded because of restlessness before the venepuncture. Of 19 amethocaine treated infants, 16 (84%) showed little or no pain compared with six of 20 (30%) in the placebo group (p = 0.001). The median cumulative neonatal facial coding system score over five seconds after needle insertion was 3 compared with 16 in the placebo group (p = 0.001). Of the 19 amethocaine treated infants, 15 (79%) did not cry compared with five of 20 (25%) placebo treated infants (p = 0.001). No local reaction to amethocaine was seen. CONCLUSION: Topical amethocaine provides effective pain relief during venepuncture in the newborn.

Cardiovascular effects of an intravenous bolus of morphine in the ventilated preterm infant.

AIM: To examine the cardiovascular effects of an intravenous bolus of morphine, 100 microg/kg, in 17 ventilated preterm infants. METHODS: Heart rate and blood pressure were monitored. Right ventricular output, superior vena caval flow, and the width of the ductus arteriosus were measured by Doppler echocardiography 10 and 60 minutes after the morphine injection, and the values compared with baseline values by the paired t test. RESULTS: There was a small but significant fall in heart rate (2.1% at 10 minutes, 4.3% at 60 minutes) consistent with a sedative effect. There was no effect on systolic, diastolic, or mean blood pressure. There was no significant effect on systemic blood flow as measured by either right ventricular output or superior vena caval flow. Ductal width was significantly reduced by a mean of 16% at 60 minutes, suggesting that normal duct closure was not inhibited. CONCLUSION: No cardiovascular effects of an intravenous bolus of morphine could be detected.

Influence of antenatal steroids and sex on maturation of the epidermal barrier in the preterm infant.

BACKGROUND: The epidermal barrier is well developed in term infants but defective in the immature infant with important clinical consequences. The development of the barrier shares similarities with production of pulmonary surfactant. Studies in the rat have shown that barrier maturation is accelerated by antenatal steroids, both structurally and functionally. Females have a more mature barrier than males at the same gestational age. These factors have not been studied in the human. AIM: To examine the influence of antenatal steroids and sex on maturation of the epidermal barrier in the preterm infant. SUBJECTS: A total of 137 infants born before 34 weeks gestation, 80 boys and 57 girls, were studied: 87 had been exposed to antenatal steroids, and 50 had not; 99 were studied prospectively, and 38 had been studied previously. METHOD: Barrier function was measured as transepidermal water loss from abdominal skin by evaporimetry. Measurements were made within the first 48 hours and corrected to a standard relative humidity of 50% (TEWL(50)). RESULTS: The relation between TEWL(50) and gestation was exponential with very high levels in the most immature infants. No influence of antenatal steroids or sex could be shown. When infants who were optimally exposed to antenatal steroids were considered alone, no effect could be shown. CONCLUSION: Epidermal maturation in the preterm infant does not appear to be influenced by antenatal steroids or sex, suggesting that the mechanism of maturation differs from that of the rat.

Local anaesthetic effect of topical amethocaine gel in neonates: randomised controlled trial.

AIM: To assess the efficacy of amethocaine as a topical local anaesthetic in neonates. METHODS: A randomised, double blind controlled trial compared 4% amethocaine gel (Ametop) with placebo in 60 healthy neonates (29 to 42 weeks of gestation) in the first week after birth. Either 1.5 g 4% w/w amethocaine (gel) or 1.5 g placebo gel were applied to the dorsum of one foot. No gel was applied to the other foot. Each foot was occluded and left for one hour. Local anaesthesia was then assessed by eliciting the cutaneous withdrawal reflex in response to stimulation with a series of graded nylon filaments (von Frey hairs). The reflex was first elicited from the control and then the treated foot. The difference in filament thickness and deforming weight required to elicit the reflex was recorded. RESULTS: In infants treated with amethocaine, 17 of 31 (54. 8%) showed evidence of local anaesthetic action compared with five of 29 (17.2%) in the placebo group (p=0.003). The mean difference in deforming weight required to elicit the reflex was 18.8 g in the amethocaine group compared with 3.9 g in the placebo group (p=0.02). The apparent local anaesthetic action of the placebo can be explained by habituation to repeated stimulation. CONCLUSIONS: It is concluded that topical amethocaine gel has a local anaesthetic action on neonatal skin which merits further investigation. An effective and safe surface local anaesthetic would be valuable for the relief of procedure related pain in neonates.

Ultrasound study of heel to calcaneum depth in neonates.

AIM: To investigate whether it would be safe to extend the currently recommended area of sampling to the whole heel in neonates. METHODS: Eighty newborn infants were studied, weight range 0.56 to 4.34 kg, gestation 24 to 42 weeks. Ultrasound scanning was used to measure the shortest distance between the skin and the perichondrium of the calcaneum. RESULTS: The shortest depth of perichondrium was in the centre of the heel and ranged from 3 to 8 mm. In 78 of the 80 infants the distance was 4 mm or more. There was a small but significant positive correlation with weight. CONCLUSIONS: Standard automated lancets for preterm use that puncture to a depth of 2.4 mm may be safely used anywhere over the plantar surface of the heel. The posterior aspect of the heel should be avoided. Reducing the density of heel pricks should reduce the associated pain.

The childhood scars of newborn intensive care.

Many of the techniques used in newborn intensive care damage the skin and may lead to scarring. We have investigated a cohort of consecutive survivors of newborn intensive care for the presence of scars. Ninety of the original 100 children between the ages of 8 and 9 years were examined in detail by a single observer--the number, site and severity of the scars were noted and compared with the findings when the children were 2 years old. There was an overall reduction in the number of scars with time, regardless of gestational age. Scars from needlemarks were reduced by 41% and those from intravenous accidents by 70%, compared with those seen at 2 years. Scars from chest drains were still visible, in two cases requiring corrective surgery. Nine children and their families found that the scars caused them embarrassment. The only scars which did not usually improve with time and which were often judged to be worse cosmetically were those caused by surgery.

Urinary excretion of 5-L-oxoproline (pyroglutamic acid) during early life in term and preterm infants.

Urinary 5-L-oxoproline was measured in term and preterm infants from shortly after birth until 6 weeks of postnatal age to determine their ability to synthesise glycine. In term infants the excretion was five to 10 times that seen in normal adults, increasing from 105 mumol/mmol creatinine in the first 72 hours after birth to 170 mumol/mmol creatinine at 6 weeks of age. There was a significant inverse linear correlation between the excretion of 5-L-oxoproline and length of gestation or birthweight. By 6 weeks of age there was no longer a significant difference in 5-L-oxoproline between term and preterm infants. There was no difference in the excretion of 5-L-oxoproline between boys and girls, or between infants fed on human milk or an artificial formula. If, in part, variability in the excretion of 5-L-oxoproline is determined by the extent to which the endogenous formation of glycine is adequate, then glycine formation may be marginal during early life, more so in preterm than in term infants, providing additional evidence that glycine is a conditionally essential amino acid in the neonate.

Stress, severity of illness, and outcome in ventilated preterm infants.

AIM: To determine physiological and hormonal stress responses in ventilated preterm infants. METHODS: Physiological and hormonal stress responses were studied in 47 ventilated preterm infants who were judged clinically to require sedation. The correlation between the stress response and severity of illness was examined, and responses were compared between infants with different clinical outcomes. RESULTS: Stress hormone concentrations were significantly correlated with severity of illness, assessed using the arterial: alveolar oxygen partial pressure ratio. Noradrenaline showed the strongest correlation, with an exponential pattern of increased secretion. Catecholamine concentrations before sedation were significantly higher among infants who subsequently died (n = 15, at a median age of 6 days) than among survivors: median noradrenaline 4.31 vs 2.16 nmol/l, median adrenaline 0.69 vs 0.31 nmol/l. The observed fall in noradrenaline with sedation was lower among those who died than survivors (median fall 2% vs 40%). CONCLUSION: Preterm infants are capable of hormonal stress responses appropriate for the severity of their illness. Extreme catecholamine responses, in the sickest infants, are associated with the worst outcome.

The immature skin.

The skin of the extremely preterm infant is structurally and functionally immature at birth, although there is rapid postnatal maturation. The consequences of this immaturity are a high transepidermal water loss (leading to hypothermia and difficulty in fluid balance) accidental percutaneous absorption and toxicity, and skin trauma (leading to infection). Neonatologists must be aware of these and take measures to limit them.

Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions.

1. The pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were studied in 19 ventilated newborn infants (24-41 weeks gestation) who were given a loading dose of 50 micrograms kg-1 or 200 micrograms kg-1 of diamorphine followed by an intravenous infusion of 15 micrograms kg-1 h-1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady-state and at steady state of the diamorphine infusion. 2. Following both the 50 micrograms kg-1 or 200 micrograms kg-1 loading doses the mean steady-state plasma concentration (+/- s.d.) of morphine, M3G and M6G were 86 +/- 52 ng ml-1, 703 +/- 400 ng ml-1 and 48 +/- 28 ng ml-1 respectively and morphine clearance was found to be 4.6 +/- 3.2 ml min-1 kg-1. 3. M3G formation clearance was estimated to be 2.5 +/- 1.8 ml min-1 kg-1, and the formation clearance of M6G was estimated to be 0.46 +/- 0.32 ml min-1 kg-1. 4. M3G metabolite clearance was 0.46 +/- 0.60 ml min-1 kg-1, the elimination half-life was 11.1 +/- 11.3 h and the volume of distribution was 0.55 +/- 1.13 l kg-1. M6G metabolite clearance was 0.71 +/- 0.36 ml min-1 kg-1, the elimination half-life was 18.2 +/- 13.6 h and the volume of distribution was 1.03 +/- 0.88 l kg-1. 5. No significant effect of the loading dose (50 micrograms kg-1 or 200 micrograms kg-1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found. 6. We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters. 7. M3G: morphine and M6G: morphine steady-state plasma concentration ratios were 11.0 +/- 10.8 and 0.8 +/- 0.8, respectively. 8. The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults.

Capillary blood sampling: should the heel be warmed?

The hypothesis that capillary blood sampling is made easier by warming the heel was examined in a randomised, controlled trial of healthy newborn infants. Sampling was performed using an automated lancet with or without prior warming. The time taken to collect a standard volume of blood, the number of repeat procedures needed, and the infants' behavioural responses were measured. Eighty one procedures were studied in 57 infants. Warming produced a median rise in heel skin temperature of 4.7 degrees C. However, there were no significant differences between the warmed and unwarmed groups in any of the outcome measures. Heel skin temperature is not an important factor in capillary blood sampling. Attention should be directed towards improving sampling devices and technique.