An outbreak of meticillin-resistant Staphylococcus aureus colonization in a neonatal intensive care unit: use of a case-control study to investigate and control it and lessons learnt.

AIM: To describe the investigation and management of a meticillin-resistant Staphylococcus aureus (MRSA) outbreak on a neonatal intensive care unit (NICU) and the lessons learnt. METHODS: This was an outbreak report and case-control study conducted in a 40-cot NICU in a tertiary referral hospital and included all infants colonized/infected with gentamicin-resistant MRSA. INTERVENTION: Standard infection-control measures including segregation of infants, barrier precautions, enhanced cleaning, assessment of staff practice including hand hygiene, and increased MRSA screening of infants were implemented. Continued MRSA acquisitions led to screening of all NICU staff. A case-control study was performed to assess staff contact with colonized babies and inform the management of the outbreak. FINDINGS: Eight infants were colonized with MRSA (spa type t2068), one of whom subsequently developed an MRSA bacteraemia. MRSA colonization was significantly associated with lower gestational age; lower birthweight and with being a twin. Three nurses were MRSA colonized but only one nurse (45) was colonized with MRSA spa type t2068. Multivariable logistic regression analysis identified being cared for by nurse 45 as an independent risk factor for MRSA colonization. CONCLUSIONS: Lack of accurate recording of which nurses looked after which infants (and when) made identification of the risk posed by being cared for by particular nurses difficult. If this had been clearer, it may have enabled earlier identification of the colonized nurse, avoiding subsequent cases. This study highlights the benefit of using a case-control study, which showed that most nurses had no association with colonized infants.

Validation of the continuous glucose monitoring sensor in preterm infants.

OBJECTIVE: Recent studies have highlighted the need for improved methods of monitoring glucose control in intensive care to reduce hyperglycaemia, without increasing the risk of hypoglycaemia. Continuous glucose monitoring is increasingly used in children with diabetes, but there are little data regarding its use in the preterm infant, particularly at extremes of glucose levels and over prolonged periods. This study aimed to assess the accuracy of the continuous glucose monitoring sensor (CGMS) across the glucose profile, and to determine whether there was any deterioration over a 7 day period. DESIGN: Prospectively collected CGMS data from the NIRTURE Trial was compared with the data obtained simultaneously using point of care glucose monitors. SETTING: An international multicentre randomised controlled trial. PATIENTS: One hundred and eighty-eight very low birth weight control infants. OUTCOME MEASURES: Optimal accuracy, performance goals (American Diabetes Association consensus), Bland Altman, Error Grid analyses and accuracy. RESULTS: The mean (SD) duration of CGMS recordings was 156.18 (29) h (6.5 days), with a total of 5207 paired glucose levels. CGMS data correlated well with point of care devices (r=0.94), with minimal bias. It met the Clarke Error Grid and Consensus Grid criteria for clinical significance. Accuracy of single readings to detect set thresholds of hypoglycaemia, or hyperglycaemia was poor. There was no deterioration over time from insertion. CONCLUSIONS: CGMS can provide information on trends in glucose control, and guidance on the need for blood glucose assessment. This highlights the potential use of CGMS in optimising glucose control in preterm infants.

Management of hyperglycaemia in the preterm infant.

In the fetus, the predominant energy supply is glucose transported across the placenta from the mother. As pregnancy progresses, the amount of glucose transported increases, with glycogen and fat stores being laid down, principally in the third trimester. In the well-term baby, there is hormonal and metabolic adaptation in the perinatal period to ensure adequate fuel supply to the brain and other vital organs after delivery, but in the preterm infant, abnormalities of glucose homeostasis are common. After initial hypoglycaemia, due to limited glycogen and fat stores, preterm babies often become hyperglycaemic because of a combination of insulin resistance and relative insulin deficiency. Hyperglycaemia is associated with increased morbidity and mortality in preterm infants, but what should be considered optimal glucose control, and how best to achieve it, has yet to be defined in these infants.

The continuous glucose monitoring sensor in neonatal intensive care.

OBJECTIVE: To determine the feasibility of continuous glucose monitoring in the very low birthweight baby requiring intensive care, as these infants are known to be at high risk of abnormalities of glucose control. METHOD: Sixteen babies were studied from within 24 hours of delivery and for up to seven days. RESULTS: The subcutaneous glucose sensors were well tolerated and readings were comparable to those on near patient whole blood monitoring devices. CONCLUSION: Continuous glucose monitoring is practical in neonates, giving detailed information about glucose control.

Neonatal thyroid disorders.

Hypothyroxinaemia, which is common in the preterm infant, and thyrotoxicosis, which is rare, are important neonatal thyroid disorders. Their causes and treatment are discussed.

Hypoglycemia and resistance to ketoacidosis in a subject without functional insulin receptors.

Humans with congenital absence of the islets of Langerhans and mice rendered null for the insulin receptor rapidly develop severe hyperglycemia and ketoacidosis and, if untreated, die in the early neonatal period. In contrast, children with homozygous or compound heterozygous mutations of the insulin receptor gene, although hyperglycemic postprandially, survive for many months without developing ketoacidosis. Paradoxically, they often develop hypoglycemia. The rarity of the condition and the difficulties of undertaking metabolic studies in ill infants have limited the physiological information that might explain the clinical features. We studied a boy with Donohue's syndrome who represents a further example of the null phenotype, with two different and novel nonsense mutations in the alpha-subunit of the receptor. He survived for 8 months without developing ketoacidosis, and fasting hypoglycemia was a frequent problem. Despite the complete absence of insulin receptors, evidence for persistent insulin-like effects on fat and liver was seen; fasting plasma beta-hydroxybutyrate and nonesterified fatty acid levels were low, fell further during the early postprandial period, and failed to rise in response to hypoglycemia. The inverse relationships between plasma insulin and insulin-like growth factor-binding protein-1 levels were maintained, suggesting persistent hepatic effects of insulin. GH levels measured over a 6.5-h period were low throughout. Thus, the differences between congenital insulin deficiency vs. insulin receptor deficiency in humans may be explained by persistent insulinomimetic activity of the grossly elevated plasma insulin presumably being mediated through the type 1 insulin-like growth factor receptor. As GH plays a critical role in the regulation of ketogenesis during insulinopenia in humans, but not in rodents, this may contribute to the distinct phenotype of human vs. mouse insulin receptor knockouts.

Insulin, insulin-like growth factor I (IGF-I), IGF-binding protein-1, growth hormone, and feeding in the newborn.

The relationship between GH, insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin may be critical to the understanding of variation in early growth, especially in the small for gestational age (SGA) baby. To investigate these relationships, we have undertaken 12-h hormone profiles in 26 babies (13 SGA) at a median of 4.5 days of age. GH levels were measured every 10 min; insulin and IGFBP-1 were measured every 20 min. Mean levels of these hormones and IGF-I levels (from a single sample) were related to size at birth. The GH data were analyzed by Pulsar and time series analysis to characterize hormone pulsatility and relationship with feeds. IGF-I levels correlated with birth weight and length (r2 = 0.47; P = 0.004, and r2 = 0.5; P = 0.0005, respectively, after allowing for gestation), whereas mean GH levels were negatively related to birth size (r2 = -0.18; P = 0.04 and r2 = -0.2; P = 0.03 for weight and length, respectively). No direct relationship between mean GH levels and IGF-I was identified. IGF-I levels were higher in appropriate for gestational age (AGA; mean +/- SD, 82+/-61 ng/mL) than in SGA (34+/-22 ng/mL; P = 0.03) babies. Baseline (mean +/- SD, 25.9+/-11.9), mean (33.9+/-14.0), and peak (45.0+/-18.1 microg/L) GH levels were higher in SGA than in AGA babies [17.1+/-8.2 (P = 0.04), 22.5+/-10.4 (P = 0.03), and 30.7+/-15.4 microg/L (P = 0.04), respectively]. Mean IGFBP-1 levels were also higher in SGA than AGA babies (157.4+/-90.7 vs. 62.7+/-43.8 ng/mL; P = 0.01). A positive correlation was identified between changes in insulin and coincident pulses of GH (r = 0.147; P < 0.01), whereas there was an inverse relationship between insulin and IGFBP-1, with a lag time 120 min (r = -0.33; P < 0.0001). In conclusion, these studies indicate that the GH-IGF-I axis is closely related to feeding in the newborn. In SGA babies, low IGF-I and elevated IGFBP-1 reflect the slow growth, but elevated GH and rapid GH pulsatility may be a signal for lipolysis.

The use of an automated microsampling system for the characterization of growth hormone pulsatility in newborn babies.

To overcome the difficulties of studying hormone pulsatility in the newborn, we have developed an automated microsampling system that permits the measurement of hormones in small prediluted samples of blood (40 microL) taken at 10-min intervals over 12 h. The system has been validated in adult volunteers, and the error attributable to the dilution was <4%. Using this method in 10 preterm babies, we have been able to describe pulsatile changes in GH and have demonstrated a clear postprandial elevation in GH levels peaking 60 min after a feed. Fourier transform analysis indicated a pulse periodicity of 180 min in babies who were appropriate for gestational age (n = 6), but faster, co-dominant pulse periodicities of 90-100 and 140 min in babies who were small for gestational age (weight and length below the 10th centile) (n = 4). There was no significant difference between mean, peak, and baseline GH levels between the two groups.

Treatment of radiation-induced growth hormone deficiency with growth hormone-releasing hormone.

UNLABELLED: In children with hypothalamic causes for GH deficiency there are theoretical reasons why a GHRH analogue might be better than conventional GH therapy in promoting growth. OBJECTIVE: We have aimed to determine the efficacy and safety of growth hormone-releasing hormone (GHRH) (1-29)-NH2 given as a twice daily subcutaneous injection in the treatment of growth failure in children with radiation-induced GH deficiency. DESIGN: A multicentre study comparing growth before and after 1 year of treatment with GHRH (1-29)-NH2, 15 micrograms/kg twice daily, by subcutaneous injection in children with radiation-induced GH deficiency. On completion of the study year all children were treated with GH (0.5 U/kg/week) and growth parameters were documented over the next year. PATIENTS: Nine children (six boys) with radiation-induced GH deficiency following cranial (n = 4) or craniospinal (n = 5) irradiation for a brain tumour distant from the hypothalamic-pituitary axis (n = 8) or prophylaxis against central nervous system leukaemia (n = 1) were studied. All were prepubertal when the study commenced, which was at least 2 years from radiotherapy. MEASUREMENTS: Anthropometry and pubertal staging were carried out at 3-monthly intervals and bone age estimations at 6-monthly intervals (TW2 method). Pretreatment standing height velocities were compared with values during the year of GHRH treatment and then after the first year of GH therapy. In those that had received craniospinal irradiation, a change in leg-length Standard deviation score (SDS) was noted before and after GHRH therapy. Changes in skin-fold thickness and bone age during the GHRH study year were documented. Adverse events and 3-monthly measurements of clinical chemistry, haematology, lipid profile and thyroid function were recorded. RESULTS: There was a significant increase in height velocity from 3.3 (SD 1.1) cm/year before treatment, to 6.0 (SDS 1.5) cm/year after 1 year of GHRH treatment (P = 0.004). GHRH maintained or improved the leg length SDS in children who had received craniospinal irradiation. Bone age increased by a mean of 1.1 years/chronological year during treatment with GHRH. Subsequent height velocity during 1 year of GH therapy was 7.5 (SD 1.5)cm/year. No adverse changes in biochemical or hormonal analyses were noted or adverse events that could be attributed to GHRH therapy. One child went into puberty during the GHRH study year and three were pubertal during the first year of GH therapy. CONCLUSION: In cranially irradiated children, GHRH was effective in increasing growth velocity but this was less than that seen in response to GH therapy, although it matched that in children with isolated idiopathic GH deficiency treated with the same dose and schedule of GHRH administration.

Pubertal growth in young adult survivors of childhood leukemia.

PURPOSE: To determine the effect of cranial irradiation (18 Gy and 24 Gy) on pubertal growth in young adult survivors of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Final height (FH) and pubertal growth were retrospectively examined in 142 young adult survivors of childhood ALL. All were in first remission and had received either 18 or 24 Gy of cranial irradiation. Eighty-four children (48 girls) were treated with 24 Gy and 58 (35 girls) with 18 Gy. None had received either testicular or spinal irradiation. Timing and duration of puberty were studied in 110 patients. RESULTS: Significant reduction in height standard deviation score (SDS) from diagnosis to FH was seen in both sexes and in both dose groups. In girls, in both dose groups, mean age at peak height velocity (PHV) and mean age at menarche occurred significantly earlier than in the normal population. In boys, there was a normal timing of PHV. The amplitude of PHV was significantly reduced in both sexes and in both dose groups. Parameters of pubertal duration (PHV to menarche, PHV to FH, and menarche to FH) were not significantly different from normal population values. CONCLUSION: In conclusion, puberty occurred early in girls, but not in boys. Amplitude of PHV was reduced in both sexes, with no reduction in the duration of puberty. It is likely that disturbances of both timing and quality of growth during puberty contribute to the loss of standing height and body disproportion seen in these children.

Endocrinology of the neonate.

Endocrine disease in the neonate is uncommon, but, if it is not promptly recognised and treated, may be life-threatening or have profound long-term consequences. This article covers congenital adrenal hyperplasia, hypothyroidism, neonatal thyrotoxicosis and hypopituitarism. Other endocrine problems with which the MRCP(Paeds) candidate should be familiar are also listed.

Effect of chemotherapy on growth.

Growth restriction has been demonstrated clearly following the treatment of childhood malignancies, even in the absence of irradiation to the hypothalamic-pituitary axis. The use of CT and spinal irradiation in the original treatment of brain tumours has a marked effect on growth. This effect is most profound in children who have received both treatments and cannot be overcome using GH therapy at conventional doses.

Growth and puberty after growth hormone treatment after irradiation for brain tumours.

The impact of treatment with either cranial or craniospinal irradiation with or without cytotoxic chemotherapy for a brain tumour distant from the hypothalamic-pituitary axis was assessed in 29 children who had reached final height. All had received growth hormone treatment for radiation induced growth hormone deficiency. Final height, segmental growth during puberty, and duration of puberty were studied. Both craniospinal irradiation and the use of chemotherapy resulted in a significant and equal reduction in final height; this effect in those children who received both craniospinal irradiation and chemotherapy was additive. The degree of height loss was related to the age at irradiation, the most profound effect on final height occurring in the youngest at irradiation. The mean duration of puberty from G2-G4/B2-B4 (1.97 years) was not significantly different from the duration of puberty in normal children. Growth hormone increases growth velocity in children with radiation induced growth hormone deficiency but their final height is significantly less than their mid-parental height. The use of spinal irradiation and chemotherapy in the original treatment of brain tumours has a marked effect on growth which is not overcome with the use of growth hormone treatment in current doses. Early puberty of normal duration contributes to poor growth.

High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia in childhood.

To determine whether obesity complicated the treatment of childhood acute lymphoblastic leukemia, we studied the body mass index (BMI) of 63 female when and 51 male patients from the time of diagnosis of acute lymphoblastic leukemia to the time when final height was attained. The BMI z score was calculated for each patient at diagnosis, at end of treatment, and at attainment of final height. Obesity at attainment of final height was defined as a BMI greater than the 85th percentile of the normal reference population. At final height 23 of 51 male (45%) and 30 of 63 female patients (47%) were obese. Girls became obese between diagnosis and the end of chemotherapy (p = 0.02), after which they had no further increase, indicating that chemotherapy may have played a role in their obesity. Boys had a progressive and gradual increase in BMI z score through to attainment of final height. Obesity did not appear to be associated with growth hormone insufficiency, disproportionate growth, or abnormal timing of puberty. We conclude that approximately half the survivors of leukemia in childhood become obese young adults. Many of those treated with the more recent regimens studied are still only in their mid or preteen years and should be advised regarding a more active lifestyle and a healthy diet in an attempt to reduce the incidence of obesity.

Safety of growth hormone after treatment of a childhood malignancy.

The use of growth hormone therapy in children with radiation-induced growth hormone (GH) deficiency is widely accepted, but the safety of this mitogenic hormone, particularly in children previously treated for cancer, continues to cause concern. A variety of malignant tumours have been induced in animals exposed to supraphysiological doses of GH, whereas hypophysectomised animals appear protected from carcinogen-induced neoplasms. Growth hormone and insulin-like growth factor-1 have been shown to stimulate both proliferation and transformation of normal and leukaemic human lymphocytes in vitro when used in supraphysiological doses. Despite the theoretical arguments, there is no evidence of an increased risk of tumour recurrence following GH therapy in replacement dosage in children previously treated for a malignancy.

Radiation and neuroregulatory control of growth hormone secretion.

OBJECTIVE: Cranial irradiation frequently results in growth hormone (GH) deficiency. Patients with radiation-induced GH deficiency usually remain responsive to exogenous growth hormone releasing hormone, implying radiation damages the hypothalamus rather than the pituitary. Little is known about the effect of cranial irradiation on the neuroendocrine control of GH secretion. This study was to determine the effect of cranial irradiation on somatostatin tone. DESIGN: Somatostatin tone was examined by manipulating cholinergic tone in young adults with radiation-induced GH deficiency and a control population. Each individual underwent three separate studies: the GH response to 100 micrograms GHRH-(1-29)-NH2 was assessed alone, and 60 minutes after pyridostigmine or pirenzepine. PATIENTS: Eight young male adults with radiation induced GH deficiency following treatment in childhood for a brain tumour or acute lymphoblastic leukaemia, and ten healthy adult men were studied. MEASUREMENTS: Serum growth hormone was measured at 15-minute intervals throughout each of the three study periods. RESULTS: One of 10 controls and four of eight irradiated subjects had a peak GH level to GHRH analogue of less than 20 mU/l. After pretreatment with pyridostigmine, all subjects except one irradiated subject had a peak GH level of greater than 20 mU/l. Pretreatment with pyridostigmine and pirenzepine significantly modified the GH response to GHRH analogue within both groups (P < 0.0005). Pretreatment with pyridostigmine significantly enhanced the GH response to GHRH analogue (median (range) area under the curve, 9029 (1956-20940) mU/l/min in controls vs 1970 (628-3608) mU/l/min in the irradiated group) compared with GHRH analogue alone (1953 (512-16140) mU/l/min in control group vs 997 (266-3488) mU/l/min in the irradiated group). Pretreatment with pirenzepine significantly attenuated the GH response to GHRH analogue (552 (64-1274) mU/l/min in controls vs 305 (134-2726) mU/l/min in irradiated group). Between the groups there was no significant difference in GH area under the curve (AUC) after GHRH analogue alone. There was a significantly (P = 0.0014) greater increment of GH secretion after pyridostigmine and GHRH analogue compared with GHRH analogue alone (difference in AUC of pyridostigmine+GHRH analogue and GHRH analogue alone 6348 (696-12856) mU/l controls vs 542 (120-1340) mU/l in the irradiated group) and significantly (P = 0.033) greater suppression of GH secretion after pirenzepine and GHRH analogue compared with GHRH analogue alone (difference in AUC of GHRH analogue alone and pirenzepine+GHRH analogue 1644 (222-15205) mU/l in controls vs 479 (469-1623) mU/l in the irradiated group) in the control population compared with those who had received cranial irradiation in childhood. CONCLUSIONS: These data suggest that cranial irradiation reduces but does not abolish somatostatin (SRIH) tone and also reduces endogenous GHRH secretion. Although SRIH tone is reduced, it can be increased by cholinergic manipulation and is therefore not irreversibly fixed. This has possible implications if GHRH analogues were used to treat children with radiation induced GH deficiency.