Cerebral Hemodynamics and Regional Oxygen Metabolism during Ductus Arteriosus Ligation in Preterm Infants.

INTRODUCTION: Neurodevelopmental impairment is a growing concern for preterm infants who received surgical ligation of patent ductus arteriosus (PDA). We aimed to explore the cerebral hemodynamics during the critical period of PDA ligation. METHODS: Very-low-birth-weight (VLBW) preterm infants who underwent PDA ligation were prospectively enrolled. Patients were monitored preoperatively and until 72 h post-ligation. Middle cerebral artery (MCA) flow, regional cerebral oxygen saturation (rcSO2), and cardiac output were measured through Doppler ultrasound, near-infrared spectroscopy, and electrical cardiometry, respectively. Using rcSO2 <55% indicating cerebral hypoxia, the duration (% of time) and burden (cumulative negative quantity of rsSO2 <55% × the period [minutes]) were estimated. An abnormal MCA was defined as an MCA flow of <10th percentile of flow velocity or >90th percentile of pulsatility or resistance index. Poor outcomes were defined as in-hospital death or neurologic disorders, either neuroimaging or functional abnormalities, upon discharge. RESULTS: Thirty-two VLBW infants were examined, and 15 (46.9%) had poor outcomes. Infants with poor outcomes had significantly longer duration of cerebral hypoxia (5.4 [2.2-32.3] vs. 1.8 [0.4-5.6] %, p = 0.033) and worse hypoxic burden (2,118 [684-13,549] vs. 622 [88-1,669] %minutes, p = 0.027). In a linear mixed model, rcSO2 was positively correlated with arterial saturation (ß 0.860, 95% CI: 0.649-1.070) and negatively correlated with abnormal MCA flow (ß -5.287, 95% CI: -8.238 to -2.335). CONCLUSION: Longer duration of cerebral hypoxia and worse hypoxic burden post-ligation was associated with an increased risk of in-hospital mortality or neurologic disorders upon discharge in VLBW preterm infants.

Protective factors against preterm infants to develop significant patent ductus arteriosus.

BACKGROUND: Identifying preterm infants with a higher likelihood of spontaneous patent ductus arteriosus (PDA) closure would be desirable. This study aimed to examine daily PDA status during the first week of life for very low birthweight (VLBW, <1500 g) preterm infants and to develop a scoring system to predict spontaneous PDA closure. METHODS: We enrolled VLBW infants admitted between January 2016 and January 2017 and performed daily echocardiographic screening for PDA existence. Oxygen index (OI, mean airway pressure × fraction of inspired oxygen/partial pressure of arterial oxygen) was applied to represent the respiratory condition. RESULTS: A total of 215 VLBW infants were enrolled, and the accumulative incidence of spontaneous PDA closure by age 1 week was 80%, 70%, and 34% for infants born of gestational age (GA) ≥30, 28-29, and ≤27 weeks, respectively. Of these 215 infants, 184 infants entered the second phase to establish the scoring system. Infants with spontaneous PDA closure were more mature (GA 29.2 ± 2.3 vs. 26.9 ± 2.3 weeks, p < 0.001), had lower OI (2.8 ± 2.2 vs. 5.6 ± 5.3, p < 0.001) and were less likely to need endotracheal intubation (23% vs. 68%, p < 0.001). Using the receiver operating characteristics curve, OI <2.5 was determined favoring higher PDA closure incidence. The score was calculated based on the odds ratio generated in multiple regression: 4, 3 and 1 points for GA ≥30, 28-29 and ≤27 weeks, 2 and 1 points for OI <2.5 and ≥2.5, and 3 and 1 points for without and with endotracheal intubation. Using score ≥6 to predict PDA closure, the sensitivity and specificity were 0.77 and 0.72. CONCLUSION: A score made up of GA, OI and need for intubation was proposed to predict spontaneous PDA closure by age 1 week, which could be helpful to clinicians in the management of PDA in preterm infants.

Middle cerebral artery velocity is associated with the severity of MRI brain injury in neonates received therapeutic hypothermia.

BACKGROUND: No previous study has investigated the relationship between middle cerebral artery (MCA) flow velocity and the severity of hypoxic ischemic encephalopathy (HIE) evaluated by magnetic resonance imaging (MRI). The aim of this study was to assess the correlation between cerebral blood flow as assessed by transcranial Doppler sonography and the severity of MRI brain injury in asphyxiated neonates with clinical HIE who received therapeutic hypothermia. METHODS: This retrospective cohort study was conducted in the neonatal intensive care unit at Chang Gung Memorial Hospital between April 2011 and May 2014. All neonates with HIE who received therapeutic hypothermia, transcranial Doppler examinations, and brain MRI were eligible. Brain MRI was performed at 11 days of age (interquartile range: 8.5-15 days) and the severity of MRI brain injuries was evaluated using the MR scoring system proposed by Barkovich et al. Serial transcranial Doppler examinations were performed in pre-hypothermia, hypothermia, and post-hypothermia phases. RESULTS: Twenty-six neonates met the eligibility criteria for this study. Neonates with an abnormal MCA mean flow velocity (MFV) during the hypothermia phase had a higher risk of brain MRI abnormalities (77.8% vs. 22.2%, p = 0.017) and neonates with abnormal high MFV of MCA had higher MR scores of basal ganglia (p = 0.022). However, there were no statistical differences between abnormal MFV of MCA and brain MRI abnormalities during pre- and post-hypothermia phases. CONCLUSIONS: During therapeutic hypothermia, mean cerebral blood flow velocity of the MCA was associated with the severity of MRI brain injury in the neonates with clinical HIE.

Baseline cardiac output and its alterations during ibuprofen treatment for patent ductus arteriosus in preterm infants.

BACKGROUND: Infants with hemodynamically significant patent ductus arteriosus (PDA) may physiologically compensate with a supranormal cardiac output (CO). As such, a supranormal CO may be a surrogate marker for a significant PDA or indicate a failed response to PDA closure by ibuprofen. Electrical cardiometry (EC) is an impedance-based monitor that can continuously and non-invasively assess CO (COEC). We aimed to trend COEC through ibuprofen treatment for PDA in preterm infants. METHODS: We reviewed our database of preterm infants receiving ibuprofen for PDA closure. Response to ibuprofen was defined as no ductal flow in echocardiography ≤24 h after treatment. Responders were compared with gestational age (GA) and postnatal age matched non-responders and their trends of COEC were compared. Both groups' baseline COEC were further compared to the reference infants without PDA. RESULTS: Eighteen infants (9 responders and 9 non-responders) with median (interquatile range) GA 27.5 (26.6-28.6) weeks, birthweight 1038 (854-1218) g and age 3.5 (3.0-4.0) days were studied. There were positive correlations between COEC and ductal diameter and left atrium/ aortic root ratio (r = 0.521 and 0.374, p < 0.001, respectively). Both responders and non-responders had significantly higher baseline COEC than the reference. Although there was no significant within-subject alteration of COEC during ibuprofen treatment, there was a between-subject difference indicating non-responders had generally higher COEC. CONCLUSIONS: The changes of COEC during pharmacological closure of PDA is less drastic compared to surgical closure. Infants with PDA had higher baseline COEC compared to those without PDA, and non-responders had higher COEC especially at baseline compared to responders.

Risk Factors and Outcomes of Recurrent Candidemia in Children: Relapse or Re-Infection?

In this paper, our aim was to investigate the incidence, clinical characteristics, risk factors, and outcomes of recurrent candidemia in children. We retrospectively reviewed all children with candidemia from a medical center in Taiwan between 2004 and 2015. Two episodes of candidemia ≥30 days apart with clinical and microbiological resolution in the interim were defined as "late recurrence", and those that had 8⁻29 days apart from previous episodes were defined as "early recurrence". 45 patients (17.2%) had 57 episodes of recurrent candidemia, and 24 had 28 episodes of late recurrent candidemia. The median time between recurrences was 1.8 months (range: <1 month to 13 months). Of those, 29 had relapsed candidemia and 28 were re-infected by different Candida species (n = 24) or by different strains (n = 4). Recurrent candidemia patients were more likely to require echinocandins treatment, had a longer duration of candidemia, and higher rate of treatment failure (p = 0.001, 0.014, and 0.012, respectively). Underlying gastrointestinal diseases (Odds ratio (OR) 3.84; 95% Confidence interval (CI) 1.81⁻8.12) and neurological sequelae (OR 2.32; 95% CI 1.15⁻4.69) were independently associated with the development of recurrent candidemia. 17.2% of pediatric patients with candidemia developed recurrent candidemia, and approximately half were re-infected. Underlying gastrointestinal diseases and neurological sequelae were the independent risk factors for recurrent candidemia.

Characterization of group B Streptococcus colonization in full-term and Late-Preterm neonates in Taiwan.

BACKGROUND: Group B streptococcus (GBS) infections can be life-threatening in newborns. This study aimed to analyze GBS carriage status and genotypic diversity in healthy neonates after implementation of intrapartum antibiotic prophylaxis (IAP) in Taiwan. METHODS: Newborns carrying GBS were identified from a screen of 500 newborns and followed up until their cultures turned negative. Their mothers' GBS screening data were reviewed. Molecular methods, including capsular serotyping, multilocus sequence typing and pulsed-field gel electrophoresis (PFGE), were used to analyze GBS isolates. RESULTS: GBS colonization was detected at either the nose or anus in 11 of 500 healthy neonates (2.2%). In this group of 11 neonates, 4 had GBS serotypes II and III for 4-6 months, 1 had serotype V for 2 months, 6 had serotypes Ia, II, V, and VI for less than 1 month, and 1 had 2 different serotypes (serotypes V and II) at different times. The most prevalent serotype was II (33.3%), followed by Ia (25.0%), III (16.7%), V (16.7%), and VI (8.3%). The main sequence type was ST1 (50.0%), followed by ST19 (16.7%), ST23 (8.3%), ST24 (8.3%), ST103 (8.3%), and ST 231 (8.3%). All isolates were grouped into 5 PFGE clusters F, G, J, X, and Y, and all were susceptible to ß-lactam antimicrobial agents. CONCLUSIONS: GBS was carried in 2.2% (11/500) healthy newborns and persisted for 6 months in 3 neonates. This study makes clearer our understanding of GBS colonization, serotype distribution, and genotype distribution in healthy neonates.

Factors and outcomes associated with candidemia caused by non-albicans Candida spp versus Candida albicans in children.

BACKGROUND: Candidemia in children caused by non-albicans Candida (NAC) spp is increasing in prevalence, but the relevant information is limited. METHODS: All isolates of pediatric candidemia from a medical center in Taiwan between 2003 and 2015 were enrolled. The characteristics of patients with NAC and Candida albicans candidemia (CAC) were compared. RESULTS: Among the 319 episodes of candidemia occurring in 262 patients, C albicans accounted for 46.4%. The NAC and CAC groups had no significant differences in demographics, underlying diseases, most risk factors, and clinical characteristics. Patients in the NAC group were significantly more likely to have fluconazole exposure (14.0% vs 6.8%, respectively; P = .045), and NAC species accounted for 70.2% of all recurrent episodes. NAC candidemia had a longer duration of candidemia (median, 3.0 vs 1.0 days after effective antifungal treatment, respectively; P = .001), slower responses to antifungal treatment, and a higher rate of treatment failure than CAC. However, the 2 groups had similar 30-day candidemia-attributable mortality rates. After multivariate logistic regression, longer duration of central venous catheter was the independent risk factor for NAC candidemia in children (odds ratio, 1.21; 95% confidence interval, 1.08-1.35 for every 10-day increment). CONCLUSIONS: NAC species collectively have emerged as the predominant pathogens of candidemia in children. Prolonged use of a central venous catheter is associated with an increased risk of candidemia caused by NAC species.

Comparison of the incidence, clinical features and outcomes of invasive candidiasis in children and neonates.

BACKGROUND: Invasive candidiasis differs greatly between children and neonates. We aimed to investigate the different therapeutic approaches and their effects on treatment outcomes of these two groups. METHODS: Episodes of neonatal invasive candidiasis were compared with non-neonatal pediatric episodes during a 12-year cohort study. Clinical isolates were documented by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and DNA sequencing, and antifungal susceptibility testing was performed. RESULTS: A total of 342 episodes of invasive candidiasis (113 neonatal and 229 non-neonatal pediatric episodes) in 281 pediatric patients (96 neonates and 185 children) were identified. Candida albicans was the most common pathogen causing invasive candidiasis in neonates and children (47.8% vs. 44.1%). The antifungal susceptibility profiles were not significantly different between neonates and children. More neonates received amphotericin B as therapy, whereas more children received fluconazole or caspofungin. Compared with children, neonates had a significantly longer duration of fungemia, higher rates of septic shock (34.5% vs. 21.8%; P = 0.013), sepsis-attributable mortality (28.3% vs. 17.5%; P = 0.024) and in-hospital mortality (42.7% vs. 25.4%; P = 0.004) than children. Independent risk factors for treatment failure of invasive candidiasis were septic shock (odds ration [OR] 16.01; 95% confidence interval [CI] 7.64-33.56; P <  0.001), delayed removal of intravenous catheter (OR 6.78; 95% CI 2.80-17.41; P <  0.001), renal failure (OR 5.38; 95% CI 1.99-14.57; P = 0.001), and breakthrough invasive candidiasis (OR 2.99; 95% CI 1.04-8.67; P = 0.043). CONCLUSIONS: Neonatal invasive candidiasis has worse outcomes than non-neonatal pediatric candidiasis. Neonatologists and pediatricians must consider age-specific differences when developing treatment and prevention guidelines, or when interpreting studies of other age groups.

Electrical Cardiometry to Monitor Cardiac Output in Preterm Infants with Patent Ductus Arteriosus: A Comparison with Echocardiography.

BACKGROUND: Electrical cardiometry (EC) is an impedance-based monitoring that provides noninvasive cardiac output (CO) assessment. Through comparison to transthoracic echocardiography (Echo), the accuracy of EC has been verified. However, left-to-right patent ductus arteriosus (PDA) shunting is a concern because PDA shunts aortic flow to the pulmonary artery and may interfere with EC in measuring CO. OBJECTIVE: To determine the agreement between EC and Echo in preterm infants with a hemodynamically significant PDA (hsPDA). METHODS: We reviewed our hemodynamic database in which simultaneous CO measurements by Echo and EC (Aesculon®) were recorded. Preterm infants with left-to-right shunting hsPDA were enrolled. RESULTS: A total of 105 paired measurements in 36 preterm infants were compared. Infants' median (range) age and weight at measurement were 27+2 weeks (24+0-33+1) and 1,015 g (518-1,880), with mean (95% CI) ductal diameter 2.11 mm (1.99-2.22) or 2.15 mm/kg (2.00-2.30). Mean COEC and COEcho were 252 ± 32 and 258 ± 45 mL/kg/min, respectively, which demonstrated a moderate correlation and without a significant between-measurement difference. Bland-Altman analysis showed a bias, limits of agreement, and error percentage of -5.3 mL/kg/min, -78.3 to 67.7 mL/kg/min, and 28.6%, respectively. There was a trend of increased bias and error percentage of infants with high CO ≥280 mL/kg/min and supported with high-frequency ventilator. CONCLUSIONS: EC and Echo have a wide but clinically acceptable agreement in measuring CO in preterm infants with hsPDA. However, for infants with high CO or ventilated by high-frequency ventilation, interpretation of COEC should be approached with caution.

Incidence, clinical features, and implications on outcomes of neonatal late-onset sepsis with concurrent infectious focus.

BACKGROUND: Neonatal bloodstream infection (BSI) is the most important cause of morbidity and mortality in the neonatal intensive care unit (NICU). Although most neonatal BSIs are primary bacteremia, some are associated with a focus of infection. This distinction is not well characterized. METHODS: All patients with neonatal late-onset sepsis (LOS) between January 2006 and December 2013 were enrolled. LOS was categorized as a BSI with a concurrent focus of infection if LOS occurred before or within 24 h after the diagnosis of a specific infectious entity, and as "primary bacteremia" if no concurrent focus of infection was identified. Data concerning demographics, hospital course, microbiology, and outcomes were compared via univariate and multivariate analyses. RESULTS: Of 948 episodes of neonatal LOS, 781 (82.4%) were primary bacteremia, whereas 167 (17.6%) were associated with a known focus of infection, including meningitis (n = 51, 5.4%), ventilator-associated pneumonia (VAP) (n = 36, 3.8%), catheter-related bloodstream infections (n = 57, 6.0%), and necrotizing enterocolitis (NEC) (n = 21, 2.2%). The majority of NEC-associated BSIs were caused by gram-negative bacilli (85.7%). Group B streptococcus accounted for nearly one-third of all meningitis cases (29.4%). Although sepsis-attributable mortality was comparable between primary bacteremia and neonatal BSIs with a focus of infection, neonatal BSIs with meningitis, VAP, and NEC had significantly higher rates of infectious complications. The independent risk factors of sepsis-attributable mortality were infectious complications (Odds ratio [OR] 6.98; 95% confidence interval [CI] 3.64-13.39, P < 0.001); history of one or more than one previous episode(s) of BSI (OR 2.40 and 7.40; 95% CI 1.21-4.74 and 3.70-14.78, P = 0.012 and <0.001, respectively); and underlying secondary pulmonary hypertension in neonates (OR 4.77; 95% CI 1.91-11.96, P = 0.001). CONCLUSIONS: A considerable proportion of neonatal LOS can be associated with known infectious foci in the NICU. The microbiologic etiology of neonatal LOS with a concurrent focus of infection is significantly different from that of primary bacteremia. Neonatal BSIs with concurrent meningitis, VAP, or NEC are significantly more likely to have infectious complications. This association independently leads to sepsis-attributable mortality.

Clinical and microbiological characteristics, and impact of therapeutic strategies on the outcomes of children with candidemia.

We aimed to determine the clinical and microbiological characteristics of Candida bloodstream infections in children and the impact of therapeutic strategies on outcomes. All pediatric patients with candidemia from a medical center in Taiwan over a 13-year period (2003-2015) were included and a total of 262 patients with 319 episodes of candidemia were analyzed. Overall susceptibility to fluconazole was 86.1%. Cumulative mortality at 7 and 30 days after the first episode of candidemia was 13.4% and 25.2%, respectively. The overall in-hospital mortality rate was 35.1%. The treatment outcomes did not change over the study period. Multivariate analysis showed that delayed catheter removal (odds ratio [OR], 5.52; 95% confidence interval [CI]: 2.97-10.25), septic shock (OR, 5.49; 95% CI: 2.85-10.57), and breakthrough candidemia (OR, 3.66; 95% CI: 1.43-9.35) were independently associated with clinical treatment failure. In children with candidemia, underlying renal insufficiency and hematological/oncological malignancy, delayed catheter removal, and septic shock at onset were independently associated final in-hospital mortality. Analyzing the subgroup of non-neonatal children did not change the findings. We concluded overall mortality of pediatric candidemia remains high during the past decade. Prompt early catheter removal and aggressive treatment strategy in patients with septic shock would be critical to improve outcomes.

Breakthrough candidemia in children: clinical and microbiological characteristics, therapeutic strategies and impact on outcomes.

AIM: To assess the characteristics, treatments, risk factors and outcomes of breakthrough candidemia in children. MATERIALS & METHODS: Episodes of breakthrough candidemia in children were compared with the remaining episodes in a 13-year cohort study. RESULTS: Out of 319 episodes, 45 (14.1%) were breakthrough candidemia. Breakthrough candidemia occurred in patients with more acutely ill conditions, and the majority was caused by non-albicans Candida species (73.3%; 33 episodes). A total of 79.1% of breakthrough candidemia were caused by antifungal-susceptible Candida isolates and emergence of resistance was the mechanism in five cases of patients receiving fluconazole. Episodes of breakthrough candidemia had significantly higher illness severity and higher rates of fungemia-attributable mortality. CONCLUSION: Breakthrough candidemia independently contributed to unfavorable outcomes, and more aggressive treatment strategies are warranted when breakthrough candidemia is encountered.

Neonatal gram-negative bacillary late-onset sepsis: A case-control-control study on a prospectively collected database of 5,233 admissions.

BACKGROUND: Gram-negative bacillary (GNB) bloodstream infections account for 20%-30% of neonatal late-onset sepsis (LOS). We aimed to identify the incidence, clinical characteristics, and risk factors for adverse outcomes in neonates with GNB LOS. METHODS: All patients with GNB LOS admitted to the neonatal intensive care units (NICUs) of a university-affiliated teaching hospital in Taiwan from January 1, 2004-December 31, 2011, were enrolled. A case-control-control study was performed to evaluate risk factors for acquisition of neonatal GNB LOS. RESULTS: Of the 5,010 neonates, 290 (5.8%) had a total of 346 episodes of GNB LOS (36.7% of total LOS), with an incidence rate of 13.6 per 10,000 neonate hospital days. The overall mortality rate was 17.6% (51/290), and the sepsis attributable mortality rate was 9.8% (34/346 episodes). After multivariate logistic regression analysis, neonates with prolonged use of total parenteral nutrition (adjusted odds ratio [OR] = 1.53; 95% confidence interval [CI], 1.02-2.29; P = .041) were independently associated with acquisition of GNB LOS. The independent predictors of in-hospital mortality were Pseudomonas aeruginosa etiology (OR = 11.45; 95% CI, 2.83-46.24) and underlying secondary pulmonary hypertension (OR = 18.02; 95% CI, 3.28-98.89), renal disease (OR = 17.16; 95% CI, 2.96-99.38), and neuromuscular comorbidities (OR = 2.72; 95% CI, 1.06-7.00). CONCLUSION: Given the higher illness severity and sepsis-attributable mortality rate of neonatal GNB LOS in the NICU, strategies to reduce the incidence need to be addressed urgently.