Paracetamol treatment for patent ductus arteriosus: practice and attitudes in Australia and New Zealand.

Aim: To describe the current clinical practices and attitudes of neonatologists towards paracetamol treatment of PDA in Australia (AU) and New Zealand (NZ). Method: A web-based survey of all neonatologists registered under the 2017 Australia New Zealand Neonatal Network (ANZNN) was conducted. Results: The response rate for the survey was 67%, (141/210). Of those respondents, 37% stated their unit had a written policy outlining how to treat patent ductus arteriosus (PDA). Of the written policies, 53% mentioned paracetamol treatment. The majority of the respondents (70%) have prescribed paracetamol for PDA closure. When comparing between countries, 79% of AU respondents had compared with 44% of NZ respondents. Successful ductal closure in the infants who received paracetamol was anecdotally reported by 61% of respondents. The main reasons for clinicians not prescribing paracetamol were due to preferential NSAID use (61%) and lack of evidence to indicate efficacy (49%). Conclusion: Many neonatologists in AU and NZ have prescribed paracetamol for PDA closure. However, considerable practice variations exist. The results from this study suggest there may be a role for paracetamol in the treatment of PDA, however, further research is required to clarify the optimal use and provide evidence of efficacy.

The effect of sepsis upon gentamicin pharmacokinetics in neonates.

AIM: To investigate the effect of sepsis upon the volume of distribution (Vd) of gentamicin in neonates. METHODS: A retrospective chart review was conducted of neonates admitted to Dunedin Hospital who had gentamicin concentrations performed between 1st January 2000 and 30th October 2003. Data from 277 neonates, including a total of 576 gentamicin concentrations, were included in the pharmacokinetic analysis. Fifteen (5.4%) of the neonates had confirmed sepsis. Pharmacokinetic analyses were performed with NONMEM using a one compartment first order elimination model. Duration of infusion (D) was included as a parameter in the model. Covariates included sepsis (SEP), chronological age, gestational age (GA), birth weight, current weight, gender, Apgar score at 1 (AP1) and 5 (AP2) minutes, plasma C-reactive protein and serum creatinine. RESULTS: The initial model provided a mean estimates of clearance (CL) of 0.0460 l kg(-1) h(-1), volume of distribution (Vd) of 0.483 l kg(-1) and D of 0.748 h. The magnitudes of interpatient variability, expressed as CV%, were 29.2% for CL, 20.8% for Vd and 71.5% for D. The magnitude of residual variability in gentamicin concentrations was 88.0%. The final pharmacokinetic model was: CL = (0.0177 + 0.00147.(GA-20) + 0.000635.AP2) l kg(-1) h(-1), Vd = (0.483 +0.0656. sepsis) l kg(-1), D = 0.672 h. The interpatient variability (CV%) was 22.8% for CL, 22.8% for Vd and 97.7% for D. The magnitude of residual variability in gentamicin concentrations was 83.3%. CONCLUSIONS: The 14% increase in Vd in septic neonates implies that larger doses may be required to achieve peak therapeutic concentrations in the presence of sepsis. D is an important parameter in neonatal pharmacokinetic models.

Predicting iron status in low birthweight infants.

OBJECTIVE: To determine the iron status of a selected group of low birthweight infants at approximately 9 months of age, and examine the feasibility of predicting iron status by examining the history of supplementary iron intake. METHODS: All live low birthweight infants recorded in the Dunedin Hospital Queen Mary Maternity Unit birth register who reached 9 months of age between November 1995 and September 1996 were eligible to participate. Infants were categorized into 'high' or 'low' iron intake groups depending on their consumption of infant formula or medicinal iron for one month prior to the study, and their iron status compared. RESULTS: Eighty-one infants of 73 mothers, with an average age of 10 months (range 8-13 months), participated. Thirty-three per cent (n = 27) were iron deficient: 19% (n = 15) had latent iron deficiency and 15% (n = 12) had iron deficiency anaemia. Those with a 'low' iron intake were 13-fold more likely to be iron deficient than infants with a 'high' iron intake (95% confidence interval: 4.4-41.5). Screening for iron deficiency using categories based on supplementary iron intake had a positive predictive value of 66% and a negative predictive value of 88%. CONCLUSIONS: The risk of iron deficiency was considerably greater for infants who had not received supplementary iron daily over the course of the previous month. Current preventative methods for avoiding poor iron status in this group of high risk infants are not effective. Screening for iron deficiency in low birthweight infants on the basis of iron intake from infant formula or medicinal iron provides a useful method for identifying infants whose iron status should be investigated.

Palivizumab prophylaxis of respiratory syncytial virus infection in high-risk infants.

Palivizumab prophylaxis significantly reduces hospitalization for respiratory syncytial virus (RSV) disease in preterm infants. However, palivizumab is very expensive. Data from a New Zealand cost-effectiveness analysis were considered by representatives of the Infectious Diseases and Immunisation, Fetus and Newborn, and Respiratory Committees of the Paediatric Society of New Zealand. Prophylaxis in all high-risk groups was associated with net cost. The consensus panel recommends that the priority for palivizumab be given to babies discharged on home oxygen with chronic lung disease, followed by babies born at 28 weeks or less gestation.

Mannan mucin-1 peptide immunization: influence of cyclophosphamide and the route of injection.

The mucin MUC1 is greatly increased in breast cancer and is a potential target for immunotherapy. In mice, MUCI conjugated to oxidized mannan (MUC1-mannan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this basis, three phase I trials were performed in patients with adenocarcinoma to evaluate the toxicity and the immunologic responses to mannan MUCI. Forty-one patients with metastatic or locally advanced carcinoma of the breast (trial 1), colon (trial 2), and various adenocarcinomas (trial 3) received increasing doses of M-FP (1 to 300 microg). The immunizations were given at weekly intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide (to increase cellular immunity) was given on weeks 1 and 4. M-FP was given intramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effects occurred, and delayed-type hypersensitivity responses were present only as a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with the intraperitoneal route yielding approximately 10-fold higher responses. Cellular responses (proliferation, cytotoxic T cells, or CD8 T cells secreting tumor necrosis factor-alpha alphand interferon-gamma in response to MUC1 stimulation in vitro) were found in 28% of the patients, which was similar to that seen without cyclophosphamide. In most patients, disease progressed, but in five it remained stable. In addition, there were no objective responses. M-FP is not toxic and induces immune responses that were amplified by the intraperitoneal route of immunization. Cyclophosphamide was of no benefit.

Interacting quantitative trait loci control phenotypic variation in murine estradiol-regulated responses.

The steroid hormone estradiol (E2) elicits a spectrum of systemic and uterotropic responses in vivo. For example, E2 treatment of ovariectomized adult and sexually immature rodents leads to uterine leukocytic infiltration, cell proliferation, and organ growth. E2-regulated growth is also associated with a variety of normal and pathological phenotypes. Historically, the uterine growth response has been used as the key model to understand the molecular and biochemical mechanisms underlying E2-dependent growth. In this study, genome exclusion mapping identified two quantitative trait loci (QTL) in the mouse, Est2 and Est3 on chromosomes 5 and 11, respectively, that control the phenotypic variation in uterine wet weight. Both QTL are linked to a variety of E2-regulated genes, suggesting that they may represent loci within conserved gene complexes that play fundamental roles in mediating the effects of E2. Interaction and multiple trait analyses using the uterine leukocyte response and wet weight suggest that Est4, a QTL on chromosome 10, may encode an interacting factor that influences the quantitative variation in both responses. Our results show that E2-dependent responses can be genetically controlled and that a genetic basis may underlie the variation observed in many E2-dependent phenotypes.

Staphylococcal neonatal necrotising fasciitis: survival without radical debridement.

Necrotising fasciitis is a serious infection associated with high morbidity and mortality. The conventional treatment is radical resection of the involved area with antibiotic as well as intensive supportive therapy. We describe a case of extensive truncal necrotising fasciitis in a neonate, secondary to Staphylococcus aureus infection successfully treated with intensive antibiotic therapy and multi-organ support, followed by fasciotomies, drainage and betadine irrigation. The successful outcome without radical resection could be due to the viability of superficial skin, S aureus as the causative organism and the excellent blood supply of cutaneous neonatal tissue.

Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-MUC1 fusion protein.

Mucin 1 (MUC1) is a large complex glycoprotein that is highly expressed in breast cancer, and as such could be a target for immunotherapy. In mice, human MUC1 is highly immunogenic, particularly when conjugated to mannan, where a high frequency of CD8(+) MHC-restricted cytotoxic T lymphocytes is induced, accompanied by tumor protection. On this basis, a clinical trial was performed in which 25 patients with advanced metastatic carcinoma of breast, colon, stomach, or rectum received mannan-MUC1 in increasing doses. After 4 to 8 injections, large amounts of IgG1 anti-MUC1 antibodies were produced in 13 out of 25 patients (with antibody titers by ELISA of 1/320-1/20,480). Most of the antibodies reacted to the epitopes STAPPAHG and PAPGSTAP. In addition, T cell proliferation was found in 4 out of 15 patients, and CTL responses were seen in 2 out of 10 patients. Mannan-MUC1 can immunize patients, particularly for antibody formation, and to a lesser extent, cellular responses. It remains to be seen whether such responses have antitumor activity.

Surfactant aerosol treatment of respiratory distress syndrome in the spontaneously breathing premature rabbit.

Surfactant deficiency in premature neonates is a major factor in the development of respiratory distress syndrome (RDS), which is still a significant cause of mortality and morbidity. The aim of this study was to test a noninvasive method of administering surfactant as treatment for RDS. The animal model used was the premature neonatal rabbit of 27-d gestation (full-term being 31 d) primed with an initial oropharyngeal dose of surfactant. The animals were divided into three groups that received either no supplemental surfactant (n = 20), undried nebulized surfactant (n = 21), or dried nebulized surfactant (n = 24). Drying of the surfactant solution was undertaken to create a hygroscopic aerosol that would facilitate surfactant deposition in the lower respiratory tract. The group treated with dried surfactant aerosol showed superior survival (66.7%) and less evidence of RDS. The control and undried aerosol groups each had similar low survival rates (23.8 and 45.0%, respectively). The results indicate that a dried, hygroscopic aerosol is an effective means of administration of surfactant to spontaneously breathing premature rabbit neonates.

Pathophysiology of overheating in a piglet model: findings compared with sudden infant death syndrome.

OBJECTIVE: To examine the nature of hyperthermia-induced pathophysiological changes in an animal model including effects on lung compliance. METHODOLOGY: Piglets were randomly assigned to heated or non-heated groups. Heated animals were warmed to 4 degrees C above normal body temperature while sedated and breathing spontaneously. Cardiorespiratory variables were recorded serially and haematological assessments and blood cultures taken at 0 and 6 h. After 6 h the animals were killed and a limited postmortem was performed. Control animals had all procedures without heating. RESULTS: Heated piglets developed tachycardia, hypotension and a metabolic acidosis in addition to tachypnoea, hypocapnic alkalosis and a neutrophil leucocytosis. Rectal temperature after death fell at the same rate in both groups. Lung histology revealed an excess of lung haemorrhage and alveolar oedema in the heated group. No significant group differences in dynamic lung compliance were demonstrated. CONCLUSIONS: The pathological changes that occur during hyperthermia are non-specific but not incompatible with those found in sudden infant death syndrome. There was no confirmation of the thesis that hyperthermia causes death by altering lung compliance.

New Zealand hospital records insufficient for vitamin K study.

AIMS: To assess the availability and completeness of existing hospital records, required for a proposed case-control study of vitamin K administration to neonates and childhood cancer. METHODS: We surveyed 44 hospitals, to see whether they had kept records for children born during 1962-87. Additionally, we sought the neonatal records of 44 Dunedin-born people who would be in the proposed study if it went ahead. We abstracted details of vitamin K administration from the records found. RESULTS: There were 36 responses to our survey (82%). For two-thirds of the hospitals, neonatal records were not available for all of the period 1962-87. The commonest reason for unavailability of records was that they had been destroyed. Neonatal records could be found for 34 (77%) of those born in Dunedin. Although 30 records indicated that vitamin K had been given, only 17 gave the route of administration. CONCLUSIONS: Our proposed study is not feasible because of the poor availability of records and the lack of details recorded. We support the introduction of regulations requiring hospitals to retain health information for a specified time, and we argue that the minimum period for hospitals should be longer than has been proposed.

Chest position and pulmonary deposition of surfactant in surfactant depleted rabbits.

AIMS: To investigate the correlation between chest position and the distribution of surfactant in the lungs of surfactant depleted rabbits, to corroborate current guidelines on the intratracheal instillation of exogenous surfactant in newborns. METHODS: Twelve tracheotomised rabbits, depleted of pulmonary surfactant by saline bronchoalveolar lavage, were given intratracheal 99m Technetium labelled Exosurf in three positions (prone, right side down, and left side down) (n = 4 in each group). They were monitored for 10 minutes using dynamic gamma scintigraphy monitoring. Instillation completed, the lateral lying animals were turned to the opposite side to determine whether redistribution of the surfactant had taken place. The amount of radiolabelled surfactant deposited at the peripheral, central, dorsal and ventral parts of the lungs was then estimated by gamma counting of the lung sections at necropsy. RESULTS: Both gamma scintigraphy and gamma counting showed similar rates and total amount of surfactant accumulation in both lungs of the prone animals. In the lateral lying animals surfactant accumulated at a significantly faster rate in the dependent lungs: the amount of surfactant deposition was three to 14-fold that in the raised lungs (p = 0.017; nested ANOVA). Changing the chest position immediately after instillation did not redistribute the surfactant. In all three groups of animals there was no significant difference in deposition between the peripheral, central, ventral and dorsal parts of the lungs. CONCLUSIONS: Pulmonary distribution of intratracheally instilled surfactant is largely determined by gravity, and changing the chest position after instillation does not result in any redistribution of the surfactant. During the instillation of exogenous surfactant to newborn infants, keeping the chest in the horizontal position may therefore result in the most even distribution of the surfactant in the two lungs. Further deposition studies are required to evaluate the validity of the current recommendations on surfactant administration.

Respiratory distress syndrome in New Zealand: evidence from the OSIRIS trial of exogenous surfactant (Exosurf).

AIMS: To assess the impact, mortality, morbidity and economic costs, of respiratory distress syndrome severe enough to warrant ventilation in one year in New Zealand. METHODS: Review of data from all five New Zealand regional neonatal intensive care units' participation in the international OSIRIS trial of exogenous surfactant (Exosurf) treatment for respiratory distress syndrome (involving 6700 infants in 21 countries), and extrapolation of these data to a full year. RESULTS: There were 265 New Zealand infants entered in the OSIRIS trial; the mean birthweight was 1335 g and mean gestation 29 weeks; 61% of infants were less than 30 weeks gestation. Forty-seven infants (17.7%) died prior to discharge from hospital, 40 deaths being attributed to prematurity or respiratory distress syndrome. One hundred and two infants (38.5% of the cohort; 45% of surviving infants) were oxygen dependent and 36 infants (13.6%) were dead at 28 days of age. Thirty-four infants (12.8% of the cohort; 15% of surviving infants) were oxygen dependent and 40 infants (15%) were dead at the expected date of delivery. Infants were intubated for a mean 12.5 days, with surviving infants of less than 27 weeks gestation intubated for a disproportionately long period of time. Seventy-two infants (29% of the 246 infants examined) had an abnormality detected by cranial ultrasound scan at 1 or 6 weeks of age and in 23 (9%) this was a major abnormality. Of surviving infants 16 (7.5% of 213 examined) had a major abnormality on cranial ultrasound scan. Amongst infants at high risk for respiratory distress syndrome (gestation less than 30 weeks) 53% received antenatal steroids, compared with 22% in the OSIRIS trial overall. In a full year the cost of caring for infants with respiratory distress syndrome sufficiently severe enough to warrant ventilation is estimated to be NZ$12.5 million. The average cost of caring for a surviving infant was roughly NZ$52,500 and a nonsurviving infant was NZ$24,500. CONCLUSIONS: In a full year (total births 60,000) approximately 350 New Zealand infants may require ventilation for respiratory distress syndrome. Increasing the percentage of infants who receive antenatal steroids is likely to be extremely cost effective. In the era of antenatal steroids and exogenous surfactant, 85% of infants with respiratory distress syndrome requiring ventilation survive to discharge home and over 90% of survivors are likely to be healthy normal adults.

Endoscopically Assisted Gastric Stomal Dilation for Reflux and Vomiting after Gastric Banding.

Stomal stenosis after gastric banding is one the troublesome problems that can lead to eventual reoperation. Several publications refer to this complication and to reoperation. The author describes a method of dealing a short or long-term basis by dilatation of the stoma. Stomal stenosis is probably more common with non-rigid gastric bands such as Dacron; the author postulates this is due to contracture of the pseudo-capsule which develops over the band in time. By repeated dilatations, this capsule can be stretched, and thereby the stenosis managed. The passage of regulated dilators, placed over an endoscopically guided wire, facilitates this. The author further hypothesizes that rigid bands do not contract after the inevitable pseudo-capsule formation.

Lessons Learned from Laparoscopic Gastric Banding.

The author reviews 27 laparoscopic gastric banding operations, of which 19 cases were completed. Of the 27 operations, eight were revisions of earlier laparoscopic banding. The lessons learned from these cases are highlighted.

A Simple Band for Gastric Banding.

The author has noted that flexible gastric bands have occasionally stenosed the gastric stoma or allowed it to dilate. A band was developed using a soft outer silicone rubber tube over a holding mechanism made out of a nylon cable tie passed within the silicone tube. This simple, easily applied band is rigid, resisting scar contracture and dilatation.