Surveillance-embedded genomic outbreak resolution of methicillin-susceptible Staphylococcus aureus in a neonatal intensive care unit.

We observed an increase in methicillin-susceptible Staphylococcus aureus (MSSA) infections at a Dutch neonatal intensive care unit. Weekly neonatal MSSA carriage surveillance and cross-sectional screenings of health care workers (HCWs) were available for outbreak tracing. Traditional clustering of MSSA isolates by spa typing and Multiple-Locus Variable number tandem repeat Analysis (MLVA) suggested that nosocomial transmission had contributed to the infections. We investigated whether whole-genome sequencing (WGS) of MSSA surveillance would provide additional evidence for transmission. MSSA isolates from neonatal infections, carriage surveillance, and HCWs were subjected to WGS and bioinformatic analysis for identification and localization of high-quality single nucleotide polymorphisms, and in-depth analysis of subsets of isolates. By measuring the genetic diversity in background surveillance, we defined transmission-level relatedness and identified isolates that had been unjustly assigned to clusters based on MLVA, while spa typing was concordant but of insufficient resolution. Detailing particular subsets of isolates provided evidence that HCWs were involved in multiple outbreaks, yet it alleviated concerns about one particular HCW. The improved resolution and accuracy of genomic outbreak analyses substantially altered the view on outbreaks, along with apposite measures. Therefore, inclusion of the circulating background population has the potential to overcome current issues in genomic outbreak inference.

Effect of early nutritional intake on long-term growth and bone mineralization of former very low birth weight infants.

BACKGROUND: Preterm infants are at risk for impaired bone mineralization and growth in length later in life due to inadequate nutritional intake in the early postnatal period. OBJECTIVE: To investigate whether increased nutritional supplementation of calcium, phosphate and protein in Very Low Birth Weight (VLBW) infants during the first 14days after birth was associated with improvement in length and bone development until 9-10years of age. DESIGN: Observational follow-up study of VLBW infants (birth weight<1500g or gestational age<32weeks) born in two consecutive years (eligible infants: 2004 n: 63 and 2005: n: 66). Cohort 2005 received higher intake of calcium, phosphate and protein with parenteral nutrition compared to Cohort 2004. Anthropometric data were collected during standard follow-up visits until five years, and additionally at 9-10years of age including measurements of bone mineral content, bone mineral density of the whole body and lumbar spine determined by dual-energy X-ray absorptiometry. Long-term growth trajectories of both cohorts were evaluated separately for participants born appropriate (AGA) and small for gestational age (SGA), stratified by gender. Multivariate linear regression was used to examine the effect of nutritional intake and clinical covariates on length and bone mineralization. RESULTS: Both cohorts achieved a catch-up in length to SDS within the normal range by 6months (length SDS: estimated mean (95% confidence interval (CI): 6months: Cohort 2004: -0.7 (-1.1, -0.3) Cohort 2005: -0.5 (-0.8, -0.2)). Bone mineral content and density were within the normal range and not different between the cohorts. SGA children achieved a catch-up in length at 5years with bone mineralization comparable to AGA children. Only for girls birth weight was significantly associated with length SDS (per gram: ß 0.001; 95% CI (0.000, 0.003); p=0.03) There was no evidence of an association between early nutritional intake and bone mineralization. CONCLUSION: Children born as appropriate or small for gestational age preterm infants are able to catch up in length after the postnatal period, and achieve a normal length and bone mineralization at age nine-ten years. An improvement of calcium and phosphate intake during the first 14days after birth was not associated with improvement in length and bone development.

Population Pharmacokinetics of Amoxicillin in Term Neonates Undergoing Moderate Hypothermia.

The pharmacokinetics (PK) of amoxicillin in asphyxiated newborns undergoing moderate hypothermia were quantified using prospective data (N = 125). The population PK was described by a 2-compartment model with a priori birthweight (BW) based allometric scaling. Significant correlations were observed between clearance (Cl) and postnatal age (PNA), gestational age (GA), body temperature (TEMP), and urine output (UO). For a typical patient with GA 40 weeks, BW 3,000 g, 2 days PNA (i.e., TEMP 33.5°C), and normal UO, Cl was 0.26 L/h (interindividual variability (IIV) 41.9%) and volume of distribution of the central compartment was 0.34 L/kg (IIV of 114.6%). For this patient, Cl increased to 0.41 L/h at PNA 5 days and TEMP 37.0°C. The respective contributions of both covariates were 23% and 27%. Based on Monte Carlo simulations we recommend 50 and 75 mg/kg/24h amoxicillin in three doses for patients with GA 36-37 and 38-42 weeks, respectively.

Prenatal (non)treatment decisions in extreme prematurity: evaluation of decisional conflict and regret among parents.

This corrects the article DOI: 10.1038/jp.2017.90.

Prenatal (non)treatment decisions in extreme prematurity: evaluation of Decisional Conflict and Regret among parents.

OBJECTIVE: To evaluate Decisional Conflict and Regret among parents regarding the decision on initiating comfort or active care in extreme prematurity and to relate these to decision-making characteristics. STUDY DESIGN: A nationwide, multicenter, cross-sectional study using an online survey in the Netherlands. Data were collected from March 2015 to March 2016 among all parents with infants born at 24+0/7-24+6/7 weeks gestational age in 2010-2013. The survey contained a Decisional Conflict and Decision Regret Scale (potential scores range from 0 to 100) and decision-making characteristics. RESULTS: Sixty-one surveys were returned (response rate 27%). The median Decisional Conflict score was 28. From the subscores within Decisional Conflict, 'values clarity' revealed the highest median score of 42-revealing that parents felt unclear about personal values for benefits and risks of the decision on either comfort care or active care. The median Decision Regret score was 0. Regret scores were influenced by the actual decision made and by outcome: Decision Regret was lower in the active care group and in the survivor group. CONCLUSION: We found little Decisional Conflict and no Decision Regret among parents regarding decision-making at 24 weeks gestation.

Changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation.

OBJECTIVE: Thyroid hormone concentrations can be disturbed during critical illness. Our aim was to determine changes in thyroid hormone concentrations during neonatal extracorporeal membrane oxygenation (ECMO). STUDY DESIGN: We included 21 ECMO-treated neonates. Age-specific s.d. scores (SDS) of free and total thyroxine (FT4; TT4), reverse and total triiodothyronine (rT3; TT3), thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) were determined at six fixed time-points. Data were analyzed using general linear models. RESULTS: At baseline, mean SDS FT4 (-0.78, 95% CI: -1.37 to -0.19), TT4 (-1.97, 95% CI: -2.76 to -1.18), TT3 (-0.88, 95% CI: -1.13 to -0.63), TSH (-2.14, 95% CI: -2.93 to -1.35) and TBG (-3.52, 95% CI: -4.55 to -2.50) were low with high mean SDS rT3 (0.53, 95% CI: 0.28 to 0.78). One hour after start ECMO, TT4, TSH and TBG had further declined; 12 h after start ECMO TT3 had declined (all P<0.05). After this decline, mean SDS TSH increased to the baseline level 12 h after start ECMO (-2.50, 95% CI: -3.22 to -1.79), and was higher than baseline 48 h after start ECMO (-0.56, 95% CI: -1.29 to 0.17). This TSH increase was followed by increases in TT4 and TT3. FT4 remained constant within the normal range during ECMO. CONCLUSIONS: Thyroid hormone concentrations before ECMO were suggestive of non-thyroidal illness syndrome (NTIS). During ECMO, increases in TSH, TT4 and TT3 after an initial decline possibly reflect spontaneous restoration of the hypothalamic-pituitary-thyroid axis. FT4 remained constant within the normal range. This suggests that thyroxine therapy is not required during ECMO.

Estimation of extravascular lung water using the transpulmonary ultrasound dilution (TPUD) method: a validation study in neonatal lambs.

Increased extravascular lung water (EVLW) may contribute to respiratory failure in neonates. Accurate measurement of EVLW in these patients is limited due to the lack of bedside methods. The aim of this pilot study was to investigate the reliability of the transpulmonary ultrasound dilution (TPUD) technique as a possible method for estimating EVLW in a neonatal animal model. Pulmonary edema was induced in 11 lambs by repeated surfactant lavages. In between the lavages, EVLW indexed by bodyweight was estimated by TPUD (EVLWItpud) and transpulmonary dye dilution (EVLWItpdd) (n = 22). Final EVLWItpud measurements were also compared with EVLWI estimations by gold standard post mortem gravimetry (EVLWIgrav) (n = 6). EVLWI was also measured in two additional lambs without pulmonary edema. Bland-Altman plots showed a mean bias between EVLWItpud and EVLWItpdd of -3.4 mL/kg (LOA ± 25.8 mL/kg) and between EVLWItpud and EVLWIgrav of 1.7 mL/kg (LOA ± 8.3 mL/kg). The percentage errors were 109 and 43 % respectively. The correlation between changes in EVLW measured by TPUD and TPDD was r2 = 0.22. Agreement between EVLWI measurements by TPUD and TPDD was low. Trending ability to detect changes between these two methods in EVLWI was questionable. The accuracy of EVLWItpud was good compared to the gold standard gravimetric method but the TPUD lacked precision in its current prototype. Based on these limited data, we believe that TPUD has potential for future use to estimate EVLW after adaptation of the algorithm. Larger studies are needed to support our findings.

The enigma to achieve normal postnatal growth in preterm infants--using parenteral or enteral nutrition?

AIM: To evaluate whether increasing the amount of amino acids and energy in parenteral nutrition combined with rapid increment of enteral feeding improves postnatal growth in preterm infants. METHODS: Observational study; two consecutive year-cohorts of preterm infants; Cohort 2 received higher supplementation of parenteral amino acids and energy with more rapid enhancement of enteral feeding than Cohort 1. Nutritional intake, weight and head circumference (HC) were compared. RESULTS: Cohort 2 [N: 79, gestational age (GA): 29.8 ± 2.2 weeks, birth weight (BW): 1248 ± 371 g] achieved full enteral feeds earlier (p < 0.001) and had a higher protein/energy intake during the first week (p < 0.001) than Cohort 1 (N: 68, GA: 29.5 ± 2.3 weeks, BW: 1261 ± 339 g). Both cohorts developed cumulative protein/energy deficits, but less in Cohort 2 (p < 0.01). Appropriate for gestational age infants (AGA) of Cohort 2 improved weight gain until week 5 (p < 0.01) compared to AGA of Cohort 1, nevertheless all infants demonstrated a decline in mean standard deviation score (>1) for weight at term. Small for GA infants failed to improve HC. CONCLUSION: Improved parenteral intake may lead to improved short-term postnatal weight gain. Faster increase of enteral nutrition was well tolerated but failed to prevent nutritional deficits. Practising early enteral feeding with higher supplementation of nutrients may be needed and requires further study.

Influence of lung injury on cardiac output measurement using transpulmonary ultrasound dilution: a validation study in neonatal lambs.

BACKGROUND: Transpulmonary ultrasound dilution (TPUD) is a promising method for cardiac output (CO) measurement in severely ill neonates. The incidence of lung injury in this population is high, which might influence CO measurement using TPUD because of altered lung perfusion. We evaluated the influence of lung injury on the accuracy and precision of CO measurement using TPUD in an animal model. METHODS: In nine neonatal lambs, central venous and arterial catheters were inserted and connected to the TPUD monitor. Repeated lavages with warmed isotonic saline were performed to gradually induce lung injury. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe around the main pulmonary artery (COufp). An increase in oxygenation index was used as an indicator of induced lung injury during the experiment. Post-mortem lung injury was confirmed by histopathological examination. RESULTS: Fifty-five sessions of three paired CO measurements were analysed. The mean COufp was 1.53 litre min(-1) (range 0.66-2.35 litre min(-1)), and the mean COtpud was 1.65 litre min(-1) (range 0.78-2.91 litre min(-1)). The mean bias (standard deviation) between the two methods was 0.13 (0.15) litre min(-1) with limits of agreement of ±0.29 litre min(-1). The overall percentage error was 19.1%. The accuracy and precision did not change significantly during progressive lung injury. Histopathological severity scores were consistent with heterogeneous lung injury. The capability to track changes in CO using TPUD was moderate to good. CONCLUSIONS: The accuracy and precision of CO measurement using TPUD is not influenced in the presence of heterogeneous lung injury in an animal model.

Cardiac output measurement with transpulmonary ultrasound dilution is feasible in the presence of a left-to-right shunt: a validation study in lambs.

BACKGROUND: Cardiac output (CO) monitoring remains complex in newborns as most of the current technologies fail to accurately measure systemic blood flow in the presence of shunts. We validated CO measurements using transpulmonary ultrasound dilution (TPUD) in a neonatal lamb model with a left-to-right shunt. METHODS: Regular arterial and central venous catheters were inserted into seven lambs (3.5-8.3 kg). A surgically constructed left-to-right aorto-pulmonary Gore-Tex(®) shunt was intermittently opened and closed, while CO was manipulated by creating haemorrhagic hypotension. CO measurements with TPUD (COtpud) were compared with those obtained by an ultrasonic transit-time flow probe positioned around the main pulmonary artery (COufp). RESULTS: We performed 72 sessions of three paired CO measurements. The mean COufp was 1.00 litre min(-1) (range 0.47-1.75 litre min(-1)) and mean COtpud 1.05 litre min(-1) (range 0.54-1.87 litre min(-1)). With an open shunt, the mean Qp/Qs ratio was 1.8 (range 1.3-2.6). A comparison between COufp and COtpud showed a mean bias (sd) of 0.03 (0.09) and 0.07 (0.10) litre min(-1), respectively, for measurements with a closed and an open shunt. The percentage error was 18% and 20% for measurements with a closed and an open shunt. Polar plot analysis showed good trending ability for both closed and open shunt groups. CONCLUSIONS: TPUD is a reliable technology to measure CO in the presence of a left-to-right shunt.

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus.

Congenital diaphragmatic hernia (CDH) is associated with high mortality and morbidity. To date, there are no standardized protocols for the treatment of infants with this anomaly. However, protocols based on the literature and expert opinion might improve outcome. This paper is a consensus statement from the CDH EURO Consortium prepared with the aim of achieving standardized postnatal treatment in European countries. During a consensus meeting between high-volume centers with expertise in the treatment of CDH in Europe (CDH EURO Consortium), the most recent literature on CDH was discussed. Thereafter, 5 experts graded the studies according to the Scottish Intercollegiate Guidelines Network (SIGN) Criteria. Differences in opinion were discussed until full consensus was reached. The final consensus statement, therefore, represents the opinion of all consortium members. Multicenter randomized controlled trials on CDH are lacking. Use of a standardized protocol, however, may contribute to more valid comparisons of patient data in multicenter studies and identification of areas for further research.

Region-specific adaptations in determinants of rat skeletal muscle oxygenation to chronic hypoxia.

Chronic exposure to hypoxia is associated with muscle atrophy (i.e., a reduction in muscle fiber cross-sectional area), reduced oxidative capacity, and capillary growth. It is controversial whether these changes are muscle and fiber type specific. We hypothesized that different regions of the same muscle would also respond differently to chronic hypoxia. To investigate this, we compared the deep (oxidative) and superficial (glycolytic) region of the plantaris muscle of eight male rats exposed to 4 wk of hypobaric hypoxia (410 mmHg, Po(2): 11.5 kPa) with those of nine normoxic rats. Hematocrit was higher in chronic hypoxic than control rats (59% vs. 50%, P < 0.001). Using histochemistry, we observed 10% fiber atrophy (P < 0.05) in both regions of the muscle but no shift in the fiber type composition and myoglobin concentration of the fibers. In hypoxic rats, succinate dehydrogenase (SDH) activity was elevated in fibers of each type in the superficial region (25%, P < 0.05) but not in the deep region, whereas in the deep region but not the superficial region the number of capillaries supplying a fiber was elevated (14%, P < 0.05). Model calculations showed that the region-specific alterations in fiber size, SDH activity, and capillary supply to a fiber prevented the occurrence of anoxic areas in the deep region but not in the superficial region. Inclusion of reported acclimatization-induced increases in mean capillary oxygen pressure attenuated the development of anoxic tissue areas in the superficial region of the muscle. We conclude that the determinants of tissue oxygenation show region-specific adaptations, resulting in a marked differential effect on tissue Po(2).

Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study.

OBJECTIVES: To investigate the value of the observed to expected fetal lung area to head circumference ratio (o/e LHR) and liver position in the prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia (CDH). METHODS: Neonatal morbidity was recorded in 100 consecutive cases with isolated CDH diagnosed in fetal medicine units, which were expectantly managed in the prenatal period, were delivered after 30 weeks and survived until discharge from hospital. Regression analysis was used to identify the significant predictors of morbidity, including prenatal and immediate neonatal findings. RESULTS: The o/e LHR provided significant prediction of the need for prosthetic patch repair, duration of assisted ventilation, need for supplemental oxygen at 28 days, and incidence of feeding problems. An additional independent prenatal predictor of the need for patch repair was the presence of fetal liver in the chest. CONCLUSIONS: In isolated CDH the prenatally assessed size of the contralateral lung is a significant predictor of the need for prosthetic patch repair, the functional consequences of impaired lung development and occurrence of feeding problems.

[A right-sided congenital diaphragmatic hernia masked by pneumonia]. / Een rechtszijdige congenitale hernia diaphragmatica gemaskeerd door een pneumonie.

A 1-day-old premature newborn (34 weeks and 6 days) presented with respiratory insufficiency due to a group B haemolytic streptococcal (GBS) pneumonia. She recovered after temporary treatment with mechanical ventilation and antibiotics. At the time of discharge there was a slight increased fogging on the right side of the chest X-ray, interpreted as residual pleural effusion. Three days later the patient was readmitted with respiratory failure and a need for respiratory support. A chest CT scan revealed a right-sided congenital diaphragmatic hernia (CDH) with a large part of the liver and intestine in the chest. The diaphragmatic defect was closed during a surgical procedure. After an uneventful recovery the patient was discharged in good clinical condition. The combination of delayed presentation of right-sided CDH and neonatal GBS infection occurs rarely but has been described. Its pathogenesis is still unclear.

Disturbed cerebral circulation during opening of the venoarterial bypass bridge in extracorporeal membrane oxygenation.

PURPOSE: To describe the effects on cerebral blood flow velocity (CBFV) of intermittent opening of the venoarterial bridge (VA bridge) during venoarterial extracorporeal membrane oxygenation (VA-ECMO). STUDY DESIGN: Prospective study in 22 newborns during VA ECMO. CBFV was measured in the pericallosal artery by Doppler ultrasound. Changes in peak systolic flow velocity (PSV), end diastolic flow velocity (EDV) and time-averaged mean flow velocity (TAM) on day 1, 2, 3, and 5 and at low ECMO flow (50- 150 ml/min) were analyzed (mean percentage+/-standard deviation (t-tests, p<0.05)). Changes >25% were considered relevant. The relationship between changes in CBFV and ECMO flow rate (Pearson correlation, p<0.01) was studied. RESULTS: Opening of the VA bridge resulted in statistically significant and relevant decreases in PSV (35 +/- 18%), EDV (93 +/- 15%) and TAM (68 +/- 13%), persisting during the consecutive days of treatment. Smaller changes in CBFV at low ECMO flow were statistically significant and mostly relevant: PSV (15 +/- 7%), EDV (76 +/- 21%) and TAM (40 +/- 12%). Changes in CBFV were positively correlated to the ECMO flow. CONCLUSION: Use of the VA bridge results in significant and relevant ECMO flow-dependent changes in CBFV, persisting during the treatment. The VA bridge should be used in such a way as to allow regular unclamping to be omitted.

Major sacrococcygeal teratoma in an extreme premature infant: a multidisciplinary approach.

Antenatally diagnosed, large sacrococcygeal teratomas in very premature infants are associated with a very poor outcome. We present an extreme premature infant with cardiac decompensation, diagnosed at 27 weeks and 1 day of gestational age. A positive outcome could be achieved with intensive multidisciplinary planning of the delivery, postnatal stabilization and surgical resection, as demonstrated in this case report.

Neonatal screening for congenital hypothyroidism based on thyroxine, thyrotropin, and thyroxine-binding globulin measurement: potentials and pitfalls.

CONTEXT: The Dutch T(4)-TSH-TBG-based neonatal screening program detects patients with congenital hypothyroidism (CH) of thyroidal (CH-T) as well as central (CH-C) origin. The numbers and characteristics of true-positive and false-positive referrals will differ from other, predominantly TSH-based, screening methods. OBJECTIVE: The present study describes the characteristics of the referred neonates, both CH patients and false positives, and of the reported CH patients with a false-negative screening result born in the study period. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE: For each referred child born between April 1, 2002, and May 31, 2004, screening results and first venous sample results were recorded and classified as transient or permanent CH-T or CH-C or as no CH. RESULTS: In the study period, 430,764 children were screened. Of the 772 children with abnormal screening results, 224 (29%) had CH; another 13 CH patients did not have abnormal screening results, giving an overall CH incidence of 1:1800. Incidences of permanent CH, permanent CH-T, permanent CH-C, and transient CH were 1:2200, 1:2500, 1:21,000, and 1:12,000, respectively. The most frequent explanations for the 548 false-positive referrals (71% of the referred cohort) were severe illness and TBG deficiency (occurring in 198 and 200 children, respectively). CONCLUSIONS: The Dutch incidence figures for CH belong to the highest worldwide, suggesting that the T(4)-TSH-TBG screening program is an efficient method to detect CH of variable etiology and severity. Still, a small percentage of children with CH escaped detection via this screening approach. Severe illness and TBG deficiency appear to be responsible for the majority of false-positive referrals.

[Results of extracorporeal membrane oxygenation following cardiac surgery in 16 children in the St Radboud University Medical Centre, 1996-2004]. / Resultaten van extracorporele membraanoxygenatie na een hartoperatie bij 16 kinderen in het Universitair Medisch Centrum St Radboud, 1996-2004.

OBJECTIVE: Description of the results with extracorporeal membrane oxygenation (ECMO) in infants with cardiorespiratory failure after open-heart surgery. DESIGN: Prospective observational study. METHOD: Data on the indications, survival, and complications were collected from all infants treated with ECMO for cardiorespiratory failure after open-heart surgery in the period 1996-2004 in the St Radboud University Medical Centre in Nijmegen, the Netherlands. RESULTS: 17 ECMO treatments were carried out in 16 paediatric patients: 7 girls and 9 boys. All patients had severe circulatory failure, sometimes combined with respiratory insufficiency. The patients' average age was 8 months (range: 1 day-3 years and 10 months). The average duration of treatment was 137 hours (range: 8-433). In 12 of the 17 ECMO treatments, the patient was successfully weaned from ECMO and 7 patients were discharged home. 5 patients died in hospital after successful ECMO treatment. 10 of the 16 patients died. A functional univentricular heart was associated with a high mortality. Haemorrhage, renal insufficiency and; sepsis were the most frequent complications. Major causes of death were sepsis, multi-organ failure and pulmonary hypertension.