Risk factors for Staphylococcus capitis pulsotype NRCS-A colonisation among premature neonates in the neonatal intensive care unit of a tertiary-care hospital: a retrospective case-control study.

BACKGROUND: A S. capitis strain called NRCS-A (S. capitis NRCS-A) has emerged as a cause of bloodstream infections and sepsis in neonatal intensive care units (NICUs) worldwide. AIM: To identify risk factors for S. capitis NRCS-A colonisation among neonates, Dunedin Hospital NICU, Dunedin, New Zealand, from September 2013 through March 2015. METHODS: Weekly axillary swabs categorised eligible neonates as a case or a control. A case was defined as a week ending with a neonate's first positive swab for S. capitis NRCS-A and a control as a week in which a neonate remained negative. Weekly exposures were abstracted from hospital medical records. Analyses were performed using conditional logistic regression. FINDINGS: The median (range) gestational age at birth of participants was 32.7 (23.1-41.3) weeks. Participants contributed 26 weeks of case data and 177 weeks of control data. On adjusted analysis compared with matched controls, cases had higher odds of requiring invasive mechanical ventilation (OR 3.6, 95% CI: 1.1-11.6, p=0.035) and of a patent ductus arteriosus (PDA) (OR 3.0, 95% CI: 1.0-9.0, p=0.044). Cases had lower odds of being part of a multiple birth (OR 0.24, 95% CI 0.08-0.73, p=0.001), having an area of inflamed skin (OR 0.31, 95% CI: 0.13-0.75, p=0.009), and specifically an area of inflamed axillary skin (OR 0.08, 95% CI: 0.01-0.50, p=0.006). CONCLUSIONS: We found that premature neonates with invasive mechanical ventilation and PDA had greater odds for S. capitis NRCS-A colonisation. Transmission may be mediated by increased staff contact, but prospective research is needed to confirm this.

Newborn Vitamin K Prophylaxis: A Historical Perspective to Understand Modern Barriers to Uptake.

Since its initial discovery almost a century ago, vitamin K has been labeled as both lifesaving and malignancy causing. This has led to debate of not only its use in general but also regarding its appropriate dose and route. In this article, we review through a historical lens the past 90 years of newborn vitamin K from its discovery through to its modern use of preventing vitamin K deficiency bleeding (VKDB). Although researchers in surveillance studies have shown considerable reductions in VKDB following intramuscular vitamin K prophylaxis, ongoing barriers to the universal uptake of vitamin K prophylaxis remain. Reviewing the history of newborn vitamin K provides an opportunity for a greater understanding of the current barriers to uptake that we face. Although at times difficult, improving this understanding may allow us to address contentious issues related to parental and health professional beliefs and values as well as improve overall communication. The ultimate goal is to improve and maintain the uptake of vitamin K to prevent VKDB in newborns.

Multi-Locus Next-Generation Sequence Typing of DNA Extracted From Pooled Colonies Detects Multiple Unrelated Candida albicans Strains in a Significant Proportion of Patient Samples.

The yeast Candida albicans is an important opportunistic human pathogen. For C. albicans strain typing or drug susceptibility testing, a single colony recovered from a patient sample is normally used. This is insufficient when multiple strains are present at the site sampled. How often this is the case is unclear. Previous studies, confined to oral, vaginal and vulvar samples, have yielded conflicting results and have assessed too small a number of colonies per sample to reliably detect the presence of multiple strains. We developed a next-generation sequencing (NGS) modification of the highly discriminatory C. albicans MLST (multilocus sequence typing) method, 100+1 NGS-MLST, for detection and typing of multiple strains in clinical samples. In 100+1 NGS-MLST, DNA is extracted from a pool of colonies from a patient sample and also from one of the colonies. MLST amplicons from both DNA preparations are analyzed by high-throughput sequencing. Using base call frequencies, our bespoke DALMATIONS software determines the MLST type of the single colony. If base call frequency differences between pool and single colony indicate the presence of an additional strain, the differences are used to computationally infer the second MLST type without the need for MLST of additional individual colonies. In mixes of previously typed pairs of strains, 100+1 NGS-MLST reliably detected a second strain. Inferred MLST types of second strains were always more similar to their real MLST types than to those of any of 59 other isolates (22 of 31 inferred types were identical to the real type). Using 100+1 NGS-MLST we found that 7/60 human samples, including three superficial candidiasis samples, contained two unrelated strains. In addition, at least one sample contained two highly similar variants of the same strain. The probability of samples containing unrelated strains appears to differ considerably between body sites. Our findings indicate the need for wider surveys to determine if, for some types of samples, routine testing for the presence of multiple strains is warranted. 100+1 NGS-MLST is effective for this purpose.

Hyperglycaemic preterm neonates exhibit insulin resistance and low insulin production.

OBJECTIVES: To explore and compare the relationships between postmenstrual age (PMA), insulin, C-peptide and blood glucose concentrations (BGC) in hyperglycaemic and euglycaemic preterm neonates (PMA <30 weeks). DESIGN: Observational. SETTING: Dunedin Hospital Neonatal Intensive Care Unit, New Zealand. PATIENTS: Preterm neonates were recruited and included nine insulin-treated hyperglycaemic and 20 euglycaemic neonates. Samples for euglycaemic neonates were obtained from leftover blood, and for insulin-treated neonates, additional blood was collected at the same time as the patients' routine 4 hourly blood glucose test over a 24-hour period (six samples). MAIN OUTCOME MEASURES: Blood samples were collected, plasma was analysed for insulin and C-peptide and was measured in temporal association with BGC. RESULTS: The euglycaemic neonates had a mean PMA (SD) of 28 (1.4) weeks and the insulin-treated neonates had 25.5 (1.8) weeks. C-peptide plasma concentrations were significantly lower (p<0.01) in the insulin-treated hyperglycaemic neonates (51.7 (100) pmol/L; 200(208) pmol/L) indicating lower insulin production. Insulin plasma concentrations (r=-0.38), BGC (r=-0.38), C-peptide plasma concentrations (r=0.36) and insulin/C-peptide ratios (r=-0.49) were all significantly affected by PMA (p<0.01). As expected, insulin plasma concentrations were higher in the insulin-treated hyperglycaemic neonates (156 (161) pmol/L; 93.2 (63.1) pmol/L, p<0.01) confirming that intravenous exogenous insulin reached these neonates. CONCLUSIONS: This study demonstrates that preterm neonates exhibit insulin resistance, hyperglycaemic neonates have lower insulin production than euglycaemic neonates and treatment with exogenous insulin did not appear to suppress insulin production in these neonates.

Insulin resistance, glucagon-like peptide-1 and factors influencing glucose homeostasis in neonates.

OBJECTIVES: To explore the relationships between postmenstrual age (PMA), insulin, C-peptide, glucagon and blood glucose concentrations (BGCs) in preterm and term neonates. To compare glucagon-like peptide-1 (GLP-1) concentrations in fed versus never-fed neonates. DESIGN: Observational. SETTING: Dunedin Hospital Neonatal Intensive Care Unit, New Zealand. PATIENTS: Term or preterm euglycaemic neonates (102) receiving routine blood tests (343 samples). INTERVENTIONS: None: plasma was obtained from surplus samples from routine clinical care. MAIN OUTCOME MEASURES: Insulin, C-peptide, GLP-1 and glucagon concentrations were measured in temporal association with BGC. RESULTS: Insulin and C-peptide concentrations were elevated in very preterm infants (PMA≤32 weeks) and decreased to term; this relationship persisted when BGCs were accounted for. Generalised linear mixed models showed that insulin:C-peptide ratio and insulin:BGC ratio decreased significantly with increasing PMA (p<0.001). GLP-1 increased following initial oral feeds regardless of PMA (p<0.001). CONCLUSION: Preterm neonates exhibit insulin resistance in the absence of hyperglycaemia. Enteral feeds result in an increase in GLP-1. These factors are likely to contribute to the increased risk of hyperglycaemia in premature neonates (PMA<32 weeks).

Why do parents decline newborn intramuscular vitamin K prophylaxis?

OBJECTIVE: To explore the influencing factors and reasoning of parents who opt out of intramuscular vitamin K prophylaxis for their newborn. DESIGN: We conducted a qualitative study with 15 families from the Otago/Southland region of New Zealand. Semistructured interviews explored their choice to opt out of intramuscular vitamin K prophylaxis and thematic analysis was used to elucidate themes that captured important aspects of this parental decision-making process. RESULTS: Parents opt out of intramuscular vitamin K for a variety of reasons. These were clustered into three main themes: parents' beliefs and values (philosophy and spirituality), concerns about their child's welfare (pain and potential side effects) and external influencing factors (family, friends, media and health professionals). As part of a wider family hesitancy towards medical intervention, the majority of parents also raised concerns regarding other perinatal or childhood interventions. CONCLUSION: Many factors influence parental decision making and lead to a decision to opt out of newborn intramuscular vitamin K prophylaxis. Due to strong parallels with other common childhood interventions, these findings have relevance for vitamin K prophylaxis and for other healthcare interventions in childhood.

Central Venous Catheter-Related Tachycardia in the Newborn: Case Report and Literature Review.

Central venous access is an important aspect of neonatal intensive care management. Malpositioned central catheters have been reported to induce cardiac tachyarrhythmia in adult populations and there are case reports within the neonatal population. We present a case of a preterm neonate with a preexisting umbilical venous catheter (UVC), who then developed a supraventricular tachycardia (SVT). This was initially treated with intravenous adenosine with transient reversion. Catheter migration was subsequently detected, with the UVC tip located within the heart. Upon withdrawal of the UVC and a final dose of adenosine, the arrhythmia permanently resolved. Our literature review confirms that tachyarrhythmia is a rare but recognised neonatal complication of malpositioned central venous catheters. We recommend the immediate investigation of central catheter position when managing neonatal tachyarrhythmia, as catheter repositioning is an essential aspect of management.

Haematocrit influences insulin concentration measurements in dried blood spots.

INTRODUCTION: A major barrier to conducting pharmacokinetic studies in neonates is the relatively large blood volume required by most assays. The use of dried blood spots (DBS) has potential to enable the use of smaller volumes and simplify sample processing and handling. AIM: The aim of this study is to determine the effect of haematocrit on insulin concentrations from DBS. METHODS: DBS of varying haematocrit (0.25-0.65) were prepared at three insulin plasma concentrations (10, 25, and 50 mU/L). DBS were analysed for insulin using the method developed by Butter et al. (2001). DBS and paired plasma samples were obtained from neonates at Dunedin Hospital NICU. RESULTS: Insulin chemiluminescence responses were significantly lower at higher haematocrit values (p < 0.05). All results showed high variability (CV% = 9-61%). Calculated whole blood concentrations were plotted against chemiluminescence and an exponential function [Formula: see text] fitted. Plasma insulin concentrations from neonatal DBS were typically higher than paired plasma samples. CONCLUSIONS: Haematocrit has a significant effect on insulin measurement by chemiluminescence when using DBS. Plasma insulin concentration could be determined when haematocrit was known. DBS insulin concentrations higher than plasma indicate that insulin may be present in red blood cells. However, measuring plasma insulin concentrations with DBS in neonates is not ideal due to high variability.

Effect of gestational age and blood glucose on C-peptide excretion rate and clearance in neonates.

AIMS: The aim of this study was to measure urinary C-peptide concentrations, and then calculate C-peptide clearance (Cl), and excretion rate (UER) in neonates. In addition, the effect of gestational age (GA) and blood glucose levels (BGL) on C-peptide UER were investigated. METHODS: Insulin concentrations in plasma and C-peptide concentrations were measured in plasma and urine, in 20 neonates. Chemiluminescent immunoassays were used for insulin and C-peptide measurements, with urine diluted to 40% with bovine serum albumin 1% in phosphate buffered saline. Urine volume and time of collection were recorded and used to calculate UER and Cl. RESULTS: The mean Cl of C-peptide was 0.309 ± 0.329 mL/min/kg, and UER was 0.0329 ± 0.0342 pmol/min/kg. Correlations between Cl or UER and GA were not significant (P > 0.05). No significant correlation was shown between Cl or UER and BGL (P > 0.05). CONCLUSIONS: Both Cl and UER were highly variable in neonates, but were not correlated with GA. Additionally, BGL did not appear to affect C-peptide UER and Cl. As GA and BGL did not appear to affect Cl and UER, urinary C-peptide may provide a non-invasive method of measuring insulin production in neonates.

Perinatal influences on the uptake of newborn Vitamin K prophylaxis--a retrospective cohort study.

OBJECTIVES: To describe rates of newborn vitamin K prophylaxis uptake according to method of administration (intramuscular [IM], oral, refused) and identify predictors for the choice of oral administration and for refusal of vitamin K prophylaxis. METHODS: A retrospective cohort study examined the relationship between method of vitamin K administration and various exposure factors (infant, maternal, socio-demographic and healthcare professional). Written and electronic data for births from a single tertiary birthing unit in New Zealand (NZ) were examined over a four-year period from January 2009 to December 2012. RESULTS: Records for 7,089 mothers/babies were examined. Of these, 92.9% of infants received IM and 5.4% oral vitamin K. Refusal of vitamin K was associated with (OR [95%CI]): Asian ethnicity (5.87 [3.61 to 9.53] p<0.001); vaginal delivery (2.85 [1.83 to 4.43] p<0.001); and gestational age, per additional week, (1.24 [1.10 to 1.39) p<0.001). Oral vitamin K was associated with (OR [95%CI]): Asian ethnicity (2.61 [1.80 to 3.79] p<0.001); obstetric nurse as the Lead Maternity Carer (LMC) (2.65 [1.73 to 4.06] p<0.001); vaginal delivery (2.34 [1.84 to 2.96] p<0.001); gestational age, per week, (1.14 [1.07 to 1.21] p<0.001); and LMC experience, per decade (0.61 [0.51 to 0.74] p<0.001). CONCLUSIONS: This study reveals several important and novel associations with mode of administration of newborn vitamin K prophylaxis. IM vitamin K uptake was also lower than international data, largely due to increased oral uptake. IMPLICATIONS: Uptake of vitamin K is associated with ethnicity and also factors in the infant that might imply a perceived protection against vitamin K deficiency bleeding. Further investigation is required for a fuller understanding of the motivations for choosing differing routes of vitamin K administration in newborns, with particular emphasis on factors influencing parental choice.

Declining newborn intramuscular vitamin K prophylaxis predicts subsequent immunisation refusal: A retrospective cohort study.

AIM: Low rates of childhood immunisation are linked to outbreaks of infectious disease. Identifying and addressing barriers to immunisation may lead to improved immunisation rates. Immunisation and newborn vitamin K prophylaxis have many similarities. We aimed to investigate whether parents who decline newborn vitamin K are also more likely to decline subsequent childhood immunisations. METHODS: We undertook a retrospective cohort study, examining the relationship between vitamin K administration and immunisation uptake by parents of babies born over a 2-year period (January 2010-December 2011) in Dunedin, New Zealand (NZ). Both written and electronic data from a single birthing unit and the NZ National Immunisation Register (NIR) were analysed to ascertain the relationship between declining newborn vitamin K prophylaxis and subsequent immunisation uptake. RESULTS: Records for 3575 babies were examined. Ninety-two per cent of infants received intramuscular, and 5% received oral vitamin K. An increased risk ratio for non-immunisation of 14.1 (95% confidence interval 7.8-25.9) for babies whose parents declined vitamin K was identified. Receiving oral vitamin K was also associated with subsequent non-immunisation, with a risk ratio of 3.5 (95% confidence interval 1.7-7.3). CONCLUSIONS: Parents who decline newborn vitamin K are more likely to decline immunisation for their child. These parents, as well as those that elect for oral vitamin K, are a small but easily identifiable group to whom additional education about the benefits of immunisation could be offered. This is especially pertinent at a time when there is a resurgence of immunisation preventable diseases.

Medical and midwifery attitudes towards vitamin K prophylaxis in New Zealand neonates.

AIM: Neonates are at risk for potentially life-threatening vitamin K deficiency bleeding. This can be readily prevented with prophylactic vitamin K following delivery. In this context, most vitamin K-deficiency bleeding occurs in those whose parents decline newborn vitamin K. One factor influencing parental decision-making is information received from health professionals. This study examined attitudes and perceptions towards newborn vitamin K in relevant health-care professionals. METHODS: A literature review and one-on-one semi-structured interviews were conducted to inform questionnaire design. Midwives and selected medical staff employed in the South Island of New Zealand were then invited to complete an anonymous survey exploring attitudes and perceptions towards vitamin K prophylaxis in newborns. RESULTS: The survey achieved an overall response rate of 57%. Almost all responding medical staff and 76% of midwives agreed with the current New Zealand Ministry of Health vitamin K guideline. All medical staff but only 55% of midwives feel that all babies should receive vitamin K. Differences were also seen between professionals with respect to vitamin K education and risks. CONCLUSION: This is the first study to examine attitudes and perceptions of midwives and doctors to vitamin K prophylaxis in neonates. Considerable discrepancies in attitude are evident, and in some midwives, a lack of confidence in this intervention is apparent. How this affects education to families is unknown. Increased understanding of this phenomenon, along with improved education and communication to professionals and families, is required.

Randomized controlled trial of oxygen saturation targets in very preterm infants: two year outcomes.

OBJECTIVE: To assess whether an oxygen saturation (Spo2) target of 85%-89% compared with 91%-95% reduced the incidence of the composite outcome of death or major disability at 2 years of age in infants born at <28 weeks' gestation. STUDY DESIGN: A total 340 infants were randomized to a lower or higher target from <24 hours of age until 36 weeks' gestational age. Blinding was achieved by targeting a displayed Spo2 of 88%-92% using a saturation monitor offset by ±3% within the range 85%-95%. True saturations were displayed outside this range. Follow-up at 2 years' corrected age was by pediatric examination and formal neurodevelopmental assessment. Major disability was gross motor disability, cognitive or language delay, severe hearing loss, or blindness. RESULTS: The primary outcome was known for 335 infants with 33 using surrogate language information. Targeting a lower compared with a higher Spo2 target range had no significant effect on the rate of death or major disability at 2 years' corrected age (65/167 [38.9%] vs 76/168 [45.2%]; relative risk 1.15, 95% CI 0.90-1.47) or any secondary outcomes. Death occurred in 25 (14.7%) and 27 (15.9%) of those randomized to the lower and higher target, respectively, and blindness in 0% and 0.7%. CONCLUSIONS: Although there was no benefit or harm from targeting a lower compared with a higher saturation in this trial, further information will become available from the prospectively planned meta-analysis of this and 4 other trials comprising a total of nearly 5000 infants.

Intravenous drug delivery in neonates: lessons learnt.

Intravenous drug administration presents a series of challenges that relate to the pathophysiology of the neonate and intravenous infusion systems in neonates. These challenges arise from slow intravenous flow rates, small drug volume, dead space volume and limitations on the flush volume in neonates. While there is a reasonable understanding of newborn pharmacokinetics, an appreciation of the substantial delay and variability in the rate of drug delivery from the intravenous line is often lacking. This can lead to difficulties in accurately determining the pharmacokinetic and pharmacodynamic relationship of drugs in the smallest patients. The physical variables that affect the passage of drugs through neonatal lines need to be further explored in order to improve our understanding of their impact on the delivery of drugs by this route in neonates. Through careful investigation, the underlying causes of delayed drug delivery may be identified and administration protocols can then be modified to ensure predictable, appropriate drug input kinetics.

Delayed delivery of intravenous gentamicin in neonates: impact of infusion variables.

OBJECTIVE: To investigate infusion variables that delay delivery of gentamicin through neonatal infusion lines. METHODS: Infusions were set up to simulate administration of gentamicin to neonates. The primary infusion was 10% dextrose (Baxter Colleague pump). A syringe driver was used to deliver a coloured marker via the T-connection over 35 min followed by a 1 ml normal saline flush over 35 min. Effects of dextrose concentration, primary infusion rate, dose volume and angle of the primary line were investigated. Gentamicin adsorption to in-line filters (Poisdyne Neo) and administration protocols from different neonatal intensive care units were also investigated. KEY FINDINGS: Low dose volumes (<0.4 ml) infused into slow-flowing glucose (dextrose) lines (3.8-4 ml/h) did not mix well at the T-connection. Coloured solutions formed an upper layer that moved in a retrograde direction towards the primary infusion bag. Gentamicin did not adsorb onto Posidyne Neo filters. Comparison of infusion protocols for gentamicin administration showed that slow infusion (30 min) into slow-flowing lines (4 ml/h) containing 10% glucose gave low recovery of drug during the infusion (<30% of intended dose). CONCLUSIONS: Poor mixing at the T-connection appears to be the cause of delayed and/or incomplete gentamicin delivery for low dose volumes and slow infusion rates.

Evaluation of the effect of intravenous volume expanders upon the volume of distribution of gentamicin in septic neonates.

Sepsis has been reported to increase the volume of distribution of gentamicin in neonates. To determine whether this was caused by the use of intravenous volume expanders a retrospective nested case-control study was performed comparing confirmed septic neonates with non-septic controls. Data were collected on intravenous administration of 0.45% saline/10% dextrose, 0.45% saline/5% dextrose, 0.9% normal saline, red blood cells, platelets, immunoglobulin (Intragam P) and albumin. A population pharmacokinetic analysis was performed using NONMEM for 116 neonates (29 confirmed septic) from which 363 gentamicin serum concentrations were available. The final covariate model was CL=0.097x(current weight/2)(1.3)x(postnatal age/7)(0.29) and V=1.07x(current weight/2)(0.8)+(confirmed sepsis)x0.13. The gentamicin volume of distribution was not significantly influenced by the cumulative intravenous volume expanders. The principal covariates that affected the gentamicin volume of distribution were current body weight and confirmed sepsis.

Discrepancies between predicted and observed rates of intravenous gentamicin delivery for neonates.

OBJECTIVES: This study aimed to investigate intravenous infusions as used in the neonatal intensive care setting, to determine the effect of gentamicin dose (mg), gentamicin concentrations (mg/ml), flow rate (ml/h) and flush volume (ml) upon the length of infusion time. METHODS: Intravenous infusions were set up to simulate administration of gentamicin to neonates. Dextrose (10%, w/v) was administered as the primary intravenous fluid at 3.8 or 18.7 ml/h. Gentamicin doses (0.5 mg/0.2 ml, 2 mg/0.2 ml, 2.5 mg/1.0 ml, or 10 mg/1.0 ml) were delivered into the intravenous line at a T-connection using a Graseby pump over 35 min. This was followed by a saline flush of 1 or 2 ml over a further 35 min. At the end of each experiment a 2 ml 0.9% saline bolus was given. Analysis of gentamicin collected at 5-min intervals was by an HPLC method. KEY FINDINGS: The experiment demonstrated that under the infusion conditions neonates weighing 2.5 kg would receive only 80% of the drug at 60 min, increasing to 90-95% by 75 min. In extremely low birth weight neonates (0.5 kg), even lower percentage of gentamicin recovery occurred. At 60 min only 60% of the intended gentamicin dose had been delivered and this increased to only 70% by 75 min. CONCLUSIONS: The delivery of gentamicin administered by intravenous infusion is substantially extended in extremely low birth weight neonates. This appeared to be primarily due to the small volumes and low infusion rates used in these patients.

Individualised dosing of amikacin in neonates: a pharmacokinetic/pharmacodynamic analysis.

PURPOSE: To examine the pharmacokinetics of amikacin and its pharmacokinetic pharmacodynamic (PKPD) relationship in neonates. To develop an alternative dosing strategy for amikacin in neonates. METHODS: A population PKPD analysis was performed using data collected from 80 neonates with gestational ages from 24 to 41 weeks. The final pharmacokinetic model analysed 358 amikacin concentrations. All neonates were > 72 hours postnatal age. Simulations were performed to develop a new dosing strategy. RESULTS: The final covariate model was clearance = 0.23 x (current weight/2)(0.691) x (postmenstrual age/40)(3.23) and volume of distribution = 0.957 x (current weight/2)(0.89). Following the logistic regression analysis of treatment failure, new amikacin target concentrations were estimated and used in development of an alternative dosing strategy. CONCLUSION: Simulation of a new dosing regimen yielded the following recommendations: 15 mg/kg at 36-h intervals, 14 mg/kg at 24-h intervals and 15 mg/kg at 24-h intervals for neonates < or = 28 weeks, 29-36 weeks and > or = 37 weeks postmenstrual age respectively.