Continuous Glucose Monitoring in the Management of Neonatal Hypoglycaemia

A quality improvement project was carried out in a Level 3 Neonatal Intensive Care Unit (NICU) which aimed to successfully implement the use of continuous glucose monitoring systems (CGMS) in hypoglycaemic infants. Piloting of the device revealed several potential practical barriers to its reliably successful implementation. Five Plan-Do-Study-Act (PDSA) cycles followed, tackling these problems and other issues inductively identified throughout the project. Parents and multi-professional stakeholders were involved and consulted throughout. Change was measured on a runchart using qualitative and quantitative feedback. Problem rate per patient was reduced to zero by the end of a one-month study period. This study used basic quality improvement methodologies to implement a change intervention in a structured manner and elucidated aspects of its use that need to be adapted for its successful incorporation into real-life clinical practice.

The Prolonged Neonatal Admission: Implications for our National Children's Hospital.

A significant number of neonates are admitted to tertiary paediatric units for prolonged stays annually, despite limited availability of neonatal beds. As the three Dublin paediatric hospitals merge, this pressure will be transferred to our new National Children's Hospital. We analysed epidemiological trends in prolonged neonatal admissions to the 14-bed neonatal unit in The Children's University Hospital, Temple Street, Dublin. This was with a view to extrapolating this data toward the development of a neonatal unit in the National Children's Hospital that could accommodate for this complex, important, and resource-heavy patient population. Four hundred and thirty-six babies between 0 and 28 days of life were admitted to our neonatal unit for prolonged stays (three cohorts: >1 month and <3months, >3months and <6months, and >6months), between 2000-2014. Mean number of prolonged admissions >1 month was 29.1 per year (range 18-43). Median length of stay (LOS) was 42 days (range 29-727). 363 babies were admitted for >1month but <3months with a median LOS 38 days (range 28-90); 54 babies were admitted for >3months but <6months with a median LOS 111 days (range 91-179); 19 babies were admitted for >6months with a median LOS 331 (range 196-727). There has been a statistically significant upward trend in the number of prolonged admissions over last fifteen years (Spearman's rho p=0.01, correlation coefficient 0.848). There has been no significant increase in the median length of stay over time. It can be extrapolated, that in the new children's hospital must be capable of dealing with at least 80 neonatal long-stay patients annually.

Prevention Across the Spectrum: a randomized controlled trial of three programs to reduce risk factors for both eating disorders and obesity.

BACKGROUND: A randomized controlled trial of three school-based programs and a no-intervention control group was conducted to evaluate their efficacy in reducing eating disorder and obesity risk factors. METHOD: A total of 1316 grade 7 and 8 girls and boys (mean age = 13.21 years) across three Australian states were randomly allocated to: Media Smart; Life Smart; the Helping, Encouraging, Listening and Protecting Peers (HELPP) initiative; or control (usual school class). Risk factors were measured at baseline, post-program (5 weeks later), and at the 6- and 12-month follow-ups. RESULTS: Media Smart girls had half the rate of onset of clinically significant concerns about shape and weight than control girls at the 12-month follow-up. Media Smart and HELPP girls reported significantly lower weight and shape concern than Life Smart girls at the 12-month follow-up. Media Smart and control girls scored significantly lower than HELPP girls on eating concerns and perceived pressure at the 6-month follow-up. Media Smart and HELPP boys experienced significant benefit on media internalization compared with control boys and these were sustained at the 12-month follow-up in Media Smart boys. A group × time effect found that Media Smart participants reported more physical activity than control and HELPP participants at the 6-month follow-up, while a main effect for group found Media Smart participants reported less screen time than controls. CONCLUSIONS: Media Smart was the only program to show benefit on both disordered eating and obesity risk factors. Whilst further investigations are indicated, this study suggests that this program is a promising approach to reducing risk factors for both problems.

The evolving course of HNF4A hyperinsulinaemic hypoglycaemia--a case series.

BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4A) gene mutations have a well-recognized role in maturity-onset diabetes of the young and have recently been described in congenital hyperinsulinism. A biphasic phenotype has been postulated, with macrosomia and congenital hyperinsulinism in infancy, and diabetes in young adulthood. In this case series, we report three children with HNF4A mutations (two de novo) and diazoxide-responsive congenital hyperinsulinism, highlighting the potential for ongoing diazoxide requirement and the importance of screening for these mutations even in the absence of family history. CASE REPORTS: All patients presented with macrosomia (mean birthweight 4.26 kg) and hyperinsulinaemic hypoglycaemia soon after birth (median age 1 day). All three (age range 7 months to 11 years 10 months) remain on diazoxide therapy, with dose requirements increasing in one patient. There was no prior family history of diabetes, neonatal hypoglycaemia or macrosomia. Parents were screened for HNF4A mutations post-diagnosis and one father was subsequently found to have maturity-onset diabetes of the young. CONCLUSIONS: This case series follows the evolving course of three patients with confirmed HNF4A-mediated congenital hyperinsulinism, highlighting (1) the variable natural history of these mutations, (2) the potential for prolonged diazoxide requirement, even into adolescence, and (3) the need for screening, regardless of family history.

Difficulties associated with diabetes management during the Junior Certificate examination.

The aim of this study was to describe the adherence to recommended diabetes care during the Junior Certificate, and the utilisation of available allowances for children with type 1 diabetes. Questionnaires were sent within 3 months of the examination to all adolescents and their families attending our service completing the Junior Certificate in June of 2012. Fifteen of the 25 (60%) patients/parents completed the questionnaires. Five (33%) had higher than usual glucose readings during the examination period and three (20%) experienced hypoglycaemia during at least one exam. Nine (60%) never checked capillary glucose levels during the exams. No patients left the examination area to perform diabetes related tasks. Thirteen (86%) brought fast acting glucose into the examination centre while only six (40%) brought a glucometer. Just four (27%) patients availed of the rest breaks allowed and six (40%) felt that their diabetes affected their examination performance.

Is the NHS best practice tariff for type 1 diabetes applicable in the Irish context?

The National Health Service in the UK has identified thirteen key standards of paediatric diabetes care. Funding depends on services meeting these standards. The aim of this study was to determine if these standards are applicable in an Irish setting. All patients attending the diabetes service during 2012 were included. Patient charts, electronic appointments, nursing notes and computerised results were used to ascertain relevant information for comparison with the NHS standards. Patients attended a mean 2.97 (SD 0.7) medical and 2.2 (SD 2.9) nursing appointments per year, with a median additional contacts of 8 nurse phone calls (range 0 - 125). Most standards were met by this service. In comparing our service to the NHS standard, we have identified a number of areas for improving our service provision. Limited resources and staff shortages make a number of these standards unachievable, namely annual dietetic review and three monthly outpatient appointments.

Short stature in child with early-onset diabetes.

We present a girl who initially presented at 12 weeks of age with antibody negative diabetes. Genetic screening for common mutations of monogenic diabetes was negative. She was noted to have short stature at 8 years of age (height <0.4 centile), as well as overlapping toes and distal abnormalities of her fingers. On reevaluation, further investigation revealed an EIF2AK3 mutation, and a diagnosis of Wolcott Rallison syndrome was made. This case highlights the importance of close follow up of patients with neonatal diabetes for the development of syndromic features that may lead to a unifying diagnosis.

Dietary intake in population-based adolescents: support for a relationship between eating disorder symptoms, low fatty acid intake and depressive symptoms.

BACKGROUND: Relatively little is known about the dietary intake and nutritional status of community-based individuals with eating disorders. This research aimed to: (i) describe the dietary intake of population-based adolescents with an eating disorder and (ii) examine associations between eating disorder symptoms, fatty acid intake and depressive symptoms in adolescents with and without an eating disorder. METHODS: Data were drawn from the Western Australian Pregnancy Cohort (Raine) Study, a population-based cohort study that has followed participants from birth to young adulthood. This research utilised self-report data from the 17-year Raine Study assessment. Participants comprised 429 female adolescents who completed comprehensive questionnaire measures on dietary intake, eating disorder symptoms and depressive symptoms. RESULTS: Adolescents with an eating disorder (n = 66) reported a significantly lower intake of total fat, saturated fat, omega-6 fatty acid, starch, vitamin A and vitamin E compared to adolescents without an eating disorder (n = 363). Adolescents with an eating disorder and pronounced depressive symptoms (n = 23) also reported a significantly lower intake of polyunsaturated fat and omega-3 and omega-6 fatty acid than adolescents with an eating disorder but no marked depression (n = 43). In the eating disorder sample but not the control sample, omega-3 and omega-6 fatty acid correlated significantly and negatively with eating disorder symptoms and with depressive symptoms. CONCLUSIONS: Support is provided for a relationship between low omega-3 and omega-6 fatty acid intake and depressive symptoms in adolescents with eating disorders. Research is needed to examine the feasibility and effectiveness of fatty acid supplementation in this high-risk group.

Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer.

BACKGROUND: Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways. METHODS: Microarray experiments identified genes regulated by COX-2 in HCA7 CRC cells. In vitro and in vivo regulation of DRAK2 (DAP kinase-related apoptosis-inducing kinase 2 or STK17beta, an apoptosis-inducing kinase) by COX-2 was validated by qRT-PCR. RESULTS: Inhibition of COX-2 induced apoptosis and enhanced DRAK2 expression in HCA7 cells (4.4-fold increase at 4 h by qRT-PCR, P=0.001), an effect prevented by co-administration of PGE(2). DRAK2 levels were suppressed in a panel of human colorectal tumours (n=10) compared to normal mucosa, and showed inverse correlation with COX-2 expression (R=-0.68, R2=0.46, P=0.03). Administration of the selective COX-2 inhibitor rofecoxib to patients with CRC (n=5) induced DRAK2 expression in tumours (2.5-fold increase, P=0.01). In vitro silencing of DRAK2 by RNAi enhanced CRC cell survival following COX-2 inhibitor treatment. CONCLUSION: DRAK2 is a serine-threonine kinase implicated in the regulation of apoptosis and is negatively regulated by COX-2 in vitro and in vivo, suggesting a novel mechanism for the effect of COX-2 on cancer cell survival.

Failure of oral penicillin as secondary prophylaxis for rheumatic heart disease: a lesson from a low-prevalence rheumatic fever region.

Our patient is an 18-year-old Caucasian woman from the UK who developed severe mitral stenosis on a history of childhood acute rheumatic fever (ARF) and rheumatic heart disease (RHD). She had been reporting of her oral penicillin secondary prophylaxis regimen since diagnosis. At the age of 15 years, a new murmur was discovered during routine cardiac follow-up. An echocardiogram confirmed moderate-severe mitral stenosis. One year later, her exercise tolerance significantly deteriorated and she subsequently underwent balloon valvuloplasty of her mitral valve to good effect. Our case emphasises the evidence base supporting the use of monthly intramuscular penicillin injection to prevent ARF recurrence and RHD progression; it also emphasises the reduced efficacy of oral penicillin prophylaxis in this context. It particularly resonates with regions of low rheumatic fever endemicity. The long-term cardiac sequelae of ARF can be devastating; prescribing the most effective secondary prophylaxis regimen is essential.

Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis.

BACKGROUND: Hepatic stellate cells (HSCs) are a major fibrogenic cell type that contributes to collagen accumulation during chronic liver disease. With increasing interest in developing antifibrotic therapies, there is a need for cell lines that preserve the in vivo phenotype of human HSCs to elucidate pathways of human hepatic fibrosis. We established and characterised two human HSC cell lines termed LX-1 and LX-2, and compared their features with those of primary human stellate cells. METHODS AND RESULTS: LX-1 and LX-2 were generated by either SV40 T antigen immortalisation (LX-1) or spontaneous immortalisation in low serum conditions (LX-2). Both lines express alpha smooth muscle actin, vimentin, and glial fibrillary acid protein, as visualised by immunocytochemistry. Similar to primary HSCs, both lines express key receptors regulating hepatic fibrosis, including platelet derived growth factor receptor beta (betaPDGF-R), obese receptor long form (Ob-RL), and discoidin domain receptor 2 (DDR2), and also proteins involved in matrix remodelling; matrix metalloproteinase (MMP)-2, tissue inhibitor of matrix metalloproteinase (TIMP)-2, and MT1-MMP, as determined by western analyses. LX-2 have reduced expression of TIMP-1. LX-2, but not LX-1, proliferate in response to PDGF. Both lines express mRNAs for alpha1(I) procollagen and HSP47. Transforming growth factor beta1 stimulation increased their alpha1(I) procollagen mRNA expression, as determined by quantitative reverse transcription-polymerase chain reaction. LX-2, but not LX-1, cells are highly transfectable. Both lines had a retinoid phenotype typical of stellate cells. Microarray analyses showed strong similarity in gene expression between primary HSCs and either LX-1 (98.4%) or LX-2 (98.7%), with expression of multiple neuronal genes. CONCLUSIONS: LX-1 and LX-2 human HSC lines provide valuable new tools in the study of liver disease. Both lines retain key features of HSCs. Two unique advantages of LX-2 are their viability in serum free media and high transfectability.

Six git genes encode a glucose-induced adenylate cyclase activation pathway in the fission yeast Schizosaccharomyces pombe.

An important eukaryotic signal transduction pathway involves the regulation of the effector enzyme adenylate cyclase, which produces the second messenger, cAMP. Previous genetic analyses demonstrated that glucose repression of transcription of the Schizosaccharomyces pombe fbp1 gene requires the function of adenylate cyclase, encoded by the git2 gene. As mutations in git2 and in six additional git genes are suppressed by exogenous cAMP, these 'upstream' git genes were proposed to act to produce a glucose-induced cAMP signal. We report here that assays of cAMP levels in wild-type and various mutant S. pombe cells, before and after exposure to glucose, show that this is the case. The data suggest that the cAMP signal results from the activation of adenylate cyclase. Therefore these 'upstream' git genes appear to encode a glucose-induced adenylate cyclase activation pathway. Assays of cAMP on a strain carrying a mutation in the git6 gene, which acts downstream of adenylate cyclase, indicate that git6 may function to feedback regulate adenylate cyclase activity. Thus git6 may encode a cAMP-dependent protein kinase.

A comparison of anaesthetic tensions in arterial blood and oxygenator exhaust gas during cardiopulmonary bypass.

This study evaluates the usefulness of the analysis of gas sampled from the exhaust port of a membrane oxygenator in the estimation of anaesthetic tension in arterial blood. Sixty-seven arterial blood samples were drawn from patients undergoing hypothermic cardiopulmonary bypass with anaesthesia maintained by either isoflurane or desflurane. Anaesthetic tensions in the oxygenator exhaust gas were measured using an infrared analyser and in arterial blood using a two-stage headspace technique with a gas chromatograph. Both measurement systems were calibrated with the same standard gas mixtures. There was no difference in anaesthetic tension measured in arterial blood and gas leaving the oxygenator exhaust (isoflurane: n = 29, range: 0.3-0.8%, 95% limits of agreement: -0.08% to 0.09%; desflurane: n = 38, range: 1.5-5.4%; 95% limits of agreement -0.65% to 0.58%). We conclude that anaesthetic tensions in arterial blood can be accurately monitored by analysis of the gas emerging from the exhaust port of a membrane oxygenator.

Effects of enflurane and halothane on carbohydrate metabolism in isolated perfused rabbit lungs.

Isolated, perfused rabbit lungs were used to investigate the effects of enflurane and halothane on pulmonary carbohydrate metabolism. The development of oedema in the preparation was assessed by continuous measurement of pulmonary artery pressure, airway pressure and lung weight. Ventilation of the lungs with 2% enflurane for 3 h had no effect on the rates of glucose utilization and lactate production and there were only small changes in the indices of oedema. Likewise, ventilation with 1% halothane for 1 h had no effect on the rates of glucose utilization and lactate production, and did not change significantly the concentrations of glycogen, glucose, glycolytic intermediates and high-energy phosphate compounds in lung tissue. Enflurane and halothane, at clinically relevant concentrations, probably do not influence carbohydrate metabolism in the lung.

Effect of sevoflurane on spontaneous sympathetic activity and baroreflexes in rabbits.

Sevoflurane causes a decrease in mean arterial pressure (MAP). We have studied in anaesthetized rabbits its interactive effects on MAP, the autonomic nervous system and baroreflexes. During sevoflurane administration changes in renal sympathetic nerve activity (RSNA) and heart rate (HR) were observed: (1) when the normal decrease in MAP occurred; (2) when this was prevented by angiotensin II; (3) during a similar decrease in MAP induced by infusion of sodium nitroprusside (SNP) without sevoflurane administration; and (4) during pressor and depressor responses to phenylephrine and SNP. There was a reduction in MAP from 80 to 40 mm Hg after 1-4% sevoflurane without changes in HR, while RSNA remained unchanged only up to concentrations of 3% and was depressed by 37% (P < 0.05) with 4% sevoflurane. When MAP was maintained constant with angiotensin II, both HR and RSNA decreased, by 12% and 69%, respectively, after 4% sevoflurane (P < 0.05). A decrease in MAP of 40 mm Hg during infusion of SNP increased HR and RSNA by 22% (P < 0.05) and 150% (P < 0.01), respectively. At 2% sevoflurane, baroreflex sensitivity (i.e. delta RSNA/delta MAP and delta HR/delta MAP) was depressed by 36% and 57%, respectively, for the pressor effects of pherylephrine, and by 89% and 81%, respectively, for the depressor effects of SNP. We conclude that the baroreflexes continued to compensate for the effects of sevoflurane on sympathetic and cardiomotor activity with concentrations up to 3% and 4%, respectively.

Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits.

BACKGROUND: It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e.g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic. METHODS: PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 microgram.kg-1 i.v. or midazolam 0.05 mg.kg-1 i.v. on the effects of propofol and fentanyl respectively on PNA were studied. RESULTS: Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg.kg-1 i.v. and 32 micrograms.kg-1 i.v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg.kg-1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg.kg-1. The mean ED50s, calculated from dose-response curves, were 5.4 mg.kg-1, 3.9 micrograms.kg-1 and 0.4 mg.kg-1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 microgram.kg-1 i.v. or midazolam 0.05 mg.kg-1 i.v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg.kg-1 and 8 micrograms.kg-1, respectively. CONCLUSION: Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.

Synergism between sevoflurane and intravenous fentanyl on A delta and C somatosympathetic reflexes in dogs.

UNLABELLED: In this study, we defined the nature of the interactions between sevoflurane and fentanyl on spontaneous and reflex-evoked sympathetic activity, resting heart rate (HR), and mean arterial pressure (MAP). Spontaneous renal sympathetic nerve activity (RSNA) and A delta- and C-fiber-mediated somatosympathetic reflexes, evoked by electrical stimulation of radial nerves, and HR and MAP were recorded in anesthetized dogs. In one group, the effects of incremental doses of 2-64 micrograms/kg fentanyl i.v. were observed. It had a greater inhibitory effect on C than on A delta reflexes, which were abolished by mean cumulative doses of 64 micrograms/kg and approximately 128 micrograms/kg, respectively. Although 1.5% sevoflurane reduced C reflexes by 28% and A delta reflexes by only 12%, it reduced the total doses of fentanyl required for their abolition to 32 micrograms/kg and 64 micrograms/kg, respectively. Mean RSNA, HR, and MAP values were reduced by 46%, 54%, and 30%, respectively, by fentanyl alone and by 23%, 11%, and 17%, respectively, in response to 1.5% sevoflurane. The combination of fentanyl and sevoflurane caused reductions of 44%, 54%, and 41%, respectively, which indicates a less than additive effect. These results indicate that sevoflurane interacts synergistically with fentanyl to depress A delta and C somatosympathetic reflexes, whereas for RSNA, HR, and MAP, their effects were less than the additive. IMPLICATIONS: Although fentanyl caused a greater depression of C than of A delta reflexes to the point of abolition, the maximal depression of spontaneous sympathetic activity, heart rate, and arterial pressure occurred at smaller doses. The combined depressant effects of sevoflurane and fentanyl were synergistic on somatosympathetic reflexes but were less than additive on spontaneous sympathetic activity, heart rate, and arterial pressure.

A new method for measurement of anaesthetic partial pressure in blood.

We have developed a simple, reliable method for rapid analysis of the partial pressure of volatile anaesthetic agents, based on a two-stage, head-space analysis. It is designed to solve the problems associated with reduced solubility of modern anaesthetics. After equilibration and analysis of a 2-ml sample of blood at 37 degrees C, 1 ml is transferred to another vial for a second equilibration. This ensures that there is no vapour in the headspace before the second equilibration. Measurements were performed on human blood samples equilibrated with 1% sevoflurane, 2.5% isoflurane or 3% desflurane in a tonometer. The mean error in the sample measurements was -2.3% of the tonometer reading and the 95% confidence interval for an individual measurement was +/- 8.5%. Blood samples may be stored overnight without any significant change in the results.

Effect of temperature on the solubility of desflurane, sevoflurane, enflurane and halothane in blood.

We have investigated the effect of temperature on the blood-gas solubility of desflurane, sevoflurane, enflurane and halothane. Blood was equilibrated with gas mixtures of known composition in open cuvette or closed flask tonometers over a temperature range of 29-39 degrees C, and the concentration of each anaesthetic in blood was measured at 37 degrees C by repeated headspace analysis using a gas chromatograph. Solubility increased by 5.4% of the solubility at 37 degrees C for each degree that equilibration temperature was reduced. This result was true for all anaesthetics in all blood samples, and is in keeping with results for other volatile anaesthetics.

Arterial to inspired partial pressure ratio of halothane, isoflurane, sevoflurane and desflurane in rats.

The inspired partial pressure of an anaesthetic is often used as an index of arterial partial pressure in small animal experiments. We have investigated the influence of anaesthetic solubility on the ratio of arterial to inspired partial pressure in 24 rats, allocated randomly to receive halothane, isoflurane or desflurane at four different inspired concentrations. The arterial partial pressure of the volatile agent was measured by two-stage headspace analysis using a gas chromatograph calibrated with the same gas used to calibrate the Datex Capnomac that measured the inspired concentration. Mean values of arterial to inspired ratio at the lowest concentrations were 0.60 (95% confidence intervals 0.50, 0.71) for 0.8% halothane, 0.54 (0.38, 0.69) for 0.8% isoflurane, 0.72 (0.59, 0.86) for 1.5% sevoflurane and 0.71 (0.54, 0.87) for 4% desflurane. Analysis of variance showed a significant effect of anaesthetic agent (P = 0.008) on the arterial to inspired ratio. Thus volatile anaesthetic agents do not demonstrate a fixed arterial to inspired ratio in rats.