The Utility of NATEM Assay in Predicting Bleeding Risk in Critically Ill Neonates.

We aimed to investigate the hemostatic status of diseased neonates using nonactivated rotational thromboelastometry (ROTEM) assay (NATEM) assay and, in addition, to evaluate the discriminative power of NATEM parameters in predicting the risk of bleeding in critically ill neonates and compare it to that of EXTEM (extrinsically activated ROTEM) parameters. This cohort study included 158 consecutive, critically ill neonates with presumed sepsis, perinatal hypoxia, or respiratory distress syndrome. The EXTEM and NATEM assays were performed on the first day of disease onset. The neonatal bleeding assessment tool was used to record and assess clinical bleeding events on the day of ROTEM analysis. Several EXTEM and NATEM ROTEM parameters differed between neonates with and without clinical bleeding events, indicating a hypo-coagulable state in neonates with clinical bleeding. NATEM parameters had comparable predictive performance for clinical bleeding events with EXTEM parameters for clotting time, clot formation time (CFT), A10 (clot amplitude at 10minutes), maximum clot firmness, lysis index at 60minutes, and maximum clot elasticity (p>0.05). However, NATEM A20, A30, and α angle demonstrated better predictive ability than EXTEM A20, A30, and α angle, respectively (p<0.05). A NATEM CFT value ≥147seconds presented 95.2% sensitivity (95% confidence interval [CI]: 76.1-99.8%) and 65.6% specificity (95% CI: 57.1-73.5%) to detect neonates with clinical bleeding, while a NATEM A10 value ≤42mm had 80.8% sensitivity (95% CI: 71.8-85.9%) and 76.0% specificity (95% CI: 52.8-91.7%) to detect neonates with clinical bleeding events. The NATEM assay has shown remarkable sensitivity in predicting bleeding in critically ill neonates, exceeding EXTEM performance in some selected parameters. The incorporation of NATEM test parameters in predictive models for neonatal hemorrhage seems promising.

Subcapsular Liver Hematoma-A Life-Threatening Condition in Preterm Neonates-A Case Series and Systematic Review of the Literature.

The subcapsular hematoma (SLH) of the liver is a rare finding in living infants. The clinical presentation of rupture is non-specific, with the signs of hypovolemic shock dominating. The causes are several, with prematurity, trauma and sepsis playing a leading role in the creation of an SHL. Umbilical vein catheterization and an increased bleeding tendency have also been associated with this usually fatal diagnosis. Abdominal ultrasonography, among other imaging methods, comprises the gold standard examination for early diagnosis. It should be differentiated from other possible causes of shock, such as sepsis and intraventricular hemorrhage, which have similar clinical presentation. We report a case series of three very low birth weight preterms (VLBW), with an SHL, during the first days of life, one of which survived from this usually catastrophic condition. A comprehensive review of the literature regarding this clinical entity was also conducted. A high index of suspicion is essential for early identification of such a case, with conservative or surgical treatment being the way to go.

A fatal neonatal case of fungemia due to Exophiala dermatitidis-case report and literature review.

BACKGROUND: Systemic infections caused by the black yeast-like fungus Exophiala dermatitidis are rare, but are associated with high mortality especially in immunocompromised patients. We report the first case of E. dermatitidis fungemia in a premature extremely low birth weight (ELBW) neonate who succumbed despite antifungal therapy with liposomal amphotericin (AMB) and fluconazole. A systematic review of all fungemia cases due to E. dermatitidis was also conducted aiming for a better understanding of the risk factors, treatment strategies and outcomes. CASE PRESENTATION: A male, ELBW premature neonate, soon after his birth, developed bradycardia, apnoea and ultimately necrotizing enterocolitis with intestinal perforation requiring surgical intervention. Meanwhile, he had also multiple risk factors for developing bloodstream infection, such as intubation, mechanical ventilation, central venous catheter (CVC), parenteral nutrition, empirical and prolonged antibiotic use. His blood cultures were positive, firstly for Acinetobacter junii and then for Klebsiella pneumoniae together with E. dermatitidis while on fluconazole prophylaxis and antibiotic empiric therapy. Despite the treatment with broad spectrum antibiotics, liposomal AMB and fluconazole, the newborn succumbed. A literature review identified another 12 E. dermatitidis bloodstream infections, mainly in patients with hematologic malignancies and solid organ transplant recipients (61%), with overall mortality 38% despite CVC removal and antifungal therapy. CONCLUSIONS: Due to the rarity of E. dermatitidis infections, little is known about the characteristics of this yeast, the identification methods and the optimal therapy. Identification by common biochemical tests was problematic requiring molecular identification. Resolution of neonatal fungemia is difficult despite proper antifungal therapy especially in cases with multiple and severe risk factors like the present one. Therapeutic intervention may include CVC removal and treatment for at least 3 weeks with an azole (itraconazole or fluconazole after susceptibility testing) or AMB monotherapy but not echinocandins or AMB plus azole combination therapy.

Fungemia due to Moesziomyces aphidis (Pseudozyma aphidis) in a premature neonate. Challenges in species identification and antifungal susceptibility testing of rare yeasts.

Premature neonates are at particularly increased risk to develop invasive infections with excessive case fatality due to their low birth weight, enteral malabsorbtion, insufficient microbial defenses and underdeveloped anatomic barriers. We present a case of Moesziomyces aphidis (syn. Pseudozyma aphidis) fungemia in a newborn with severe morbidity and prolonged hospital stay. Phenotypic tests failed to identify the isolate whereas commercial antifungal susceptibility tests failed to detect resistance to fluconazole. To the best of our knowledge, this is the first case of M. aphidis fungemia in a premature neonate in whom complete clinical resolution occurred after liposomal amphotericin B administration. Our case is the third Pseudozyma spp. infection described in Europe. Twenty-one cases have been described globally. Common risk factors were central venus catheter (80%), previous antibiotic treatment (80%), hematologic malignancies (27%) and solid tumors (20%) with 3 cases reported in neonates. The most commonly used antifungal therapy was amphotericin B followed by oral voriconazole or itraconazole. Our report highlights the clinical importance of rare yeasts species in neonates, emphasizes the roles of prematurity and lower birth weight as major risk factors for invasive infections with high morbidity. Reliable identification and susceptibility testing of these rare yeasts is a key issue for an adequate therapy and better outcome.

"Aggressive" Feeding of Very Preterm Neonates and Body Mass Index at School Age.

INTRODUCTION: The effects of "aggressive" neonatal feeding policies of very preterm neonates (VPN) and the risk of metabolic syndrome later in life remain questionable. We aimed to evaluate the effect of our "aggressive" nutrition policies of VPN during hospitalisation on body mass index (BMI) at ages 2 and 8 years. MATERIALS AND METHODS: Eighty four VPN, who received "aggressive" nutrition during hospitalisation in an effort to minimise postnatal growth restriction (PGR) (group A), and 62 term neonates, as controls (group B), were enrolled in the study. Group A was further divided in four subgroups depending on the type (A1: fortified expressed breast milk and preterm formula; A2: exclusively preterm formula) and quantity of milk received (A3: maximum feeds 180-210 mL/kg/day; A4: maximum feeds 210 and up to 260 mL/kg/day). BMI was calculated at ages 2 and 8 years and plotted on the centile charts. RESULTS: There was no significant difference in BMI between groups A and B at 2 and 8 years, respectively, in both absolute BMI values and their centile chart distribution. There was no significant difference in BMI at 2 and 8 years either between subgroups A1 and A2 or between subgroups A3 and A4. CONCLUSIONS: "Aggressive" and individualised feeding policy for VPN did not affect the BMI and obesity rates at ages of 2 and 8 years in our study population. The type and quantity of milk feeds had no impact on their BMI at school age. Further larger studies are needed to confirm our results.

Rotational Thromboelastometry in Neonates Admitted to a Neonatal Intensive Care Unit: A Large Cross-sectional Study.

The aim of the present study was to assess the coagulation profile in neonatal critical illness using rotational thromboelastometry (ROTEM), and to investigate its association with disease severity and its potential prognostic role in this clinical setting. Over a period of 67 months (July 2014-February 2020) 423 critically ill neonates with confirmed or suspected sepsis, perinatal hypoxia, or respiratory distress syndrome, hospitalized in our neonatal intensive care unit were included in the study. Demographic, clinical, and laboratory data were recorded on admission day and arterial blood was analyzed on ROTEM analyzer using the standard extrinsically activated rotational thromboelastometry assay (EXTEM). Neonatal illness severity scores (Modified NEOMOD [Neonatal Multiple Organ Dysfunction] and SNAPPE [Score for Neonatal Acute Physiology with Perinatal Extension]) were calculated at the same time as ROTEM analysis. Mortality during in-hospital stay was the main outcome measure. Multivariable analyses showed that a 10 mm decrease in EXTEM clot amplitude recorded at 10 minutes (A10) is significantly associated with a higher mortality (odds ratio [OR] = 1.69, 95% confidence interval [CI]: 1.33-2.08). Higher modified NEOMOD (OR = 1.36, 95% CI: 1.26-1.47) and higher SNAPPE scores (OR = 1.06, 95% CI: 1.04-1.08) were also associated with increased mortality. The CT and A10 variables demonstrated the best prognostic performance among the EXTEM parameters for mortality (area under the curve [AUC] = 0.78; 95% CI: 0.69-0.86 and AUC = 0.76; 95% CI: 0.66-0.85, respectively), showing an optimal cut-off CT ≥63 seconds and A10 ≤37 mm. Using optimal cut-off values of the EXTEM parameters for prediction of mortality, neonates with CT ≥63 seconds were 7.4 times more likely to die (OR = 7.40, 95% CI: 3.50-15.65), while neonates with A10 ≤37 mm were 5.8 times more likely to die (OR = 5.88, 95% CI: 2.94-12.50). An EXTEM hypocoagulable profile on disease onset was shown to be an independent risk factor for in-hospital mortality in neonatal critical illness.

Idiopathic scrotal hematoma in a neonate.

Background: Neonatal scrotal hematoma is considered a surgical emergency in the neonatal period. Up to recently, immediate surgical exploration was considered the gold standard for the diagnosis and treatment in the underlying causes. Objective: In this article, we present a case of idiopathic scrotal hematoma in a neonate. Method: It was managed conservatively with clinical and ultrasonographic follow-up. Result: The hematoma had gradually subsided, and any surgical intervention was avoided to the neonate. Conclusion: With good clinical and imaging follow-up, some cases could be managed nonoperatively.

Reference Values of Thrombolastometry Parameters in Healthy Term Neonates.

BACKGROUND: Thromboelastometry (ROTEM), as a point of care test, is an attractive tool for rapid evaluation of hemostasis. Currently, no reference ranges exist for all ROTEM assays in neonates, limiting its use in this vulnerable population. The aim of the present study was: (1) to establish reference ranges for standard extrinsically activated (EXTEM), intrinsically activated (INTEM), and fibrinogen polymerization (FIBTEM) ROTEM assays in whole blood samples of healthy term neonates; (2) to determine the impact of gender, delivery mode, and hematocrit on ROTEM parameters. METHODS: EXTEM, INTEM, and FIBTEM ROTEM assays were performed simultaneously with complete blood count in 215 healthy term neonates. RESULTS: Reference ranges (2.5th and 97.5th percentiles) were obtained for clotting time (CT), clot formation time (CFT), α-angle, clot firmness at 10 min (A10), maximum clot firmness (MCF), and lysis index at 60 min (LI60, %). Reference ranges for EXTEM were CT 38-78 s, CFT 49-148 s, A10 40-65 mm, and MCF 47-69 mm, LI60 83-98%. For INTEM, CT 134-270 s, CFT 50-142 s, A10 41-63 mm, and MCF 48-67 mm, LI60 85-97%, and finally, for FIBTEM: CT 36-85 s, A10 9-25 mm and MCF 10-26 mm, LI60 92-100%. Hematocrit values were positively correlated with CT, CFT and negatively with A10, MCF values. CONCLUSION: This study provides, for the first time, reference ranges for ROTEM EXTEM/INTEM/FIBTEM values simultaneously in healthy term neonates. The combined evaluation of ROTEM tests increases its diagnostic accuracy, contributing to the expansion of ROTEM use in the neonatal population.

Caffeine and Gastric Emptying Time in Very Preterm Neonates.

BACKGROUND: Caffeine has been commonly used for prevention and treatment of apnea-related symptoms in premature infants. However, its side effects have not been thoroughly studied. We investigated whether caffeine affects gastric motility in very-preterm (VP) neonates. METHODS: The study is a randomized crossover clinical trial. Twenty-two neonates with mean birth weight (BW) (standard deviation-SD) 1077 (229) g and mean gestational age (GA) (SD) 28.6 (2.1) weeks were recruited. Each neonate had its gastric emptying time checked twice with ultrasound assessment of changes in antral cross sectional area (ACSA). All neonates were sequentially allocated to the caffeine group (A) and the control group (B). Complications from the gastrointestinal tract were documented throughout the study. RESULTS: Statistically significant difference was found with regards to the gastric emptying time [median, (range)] between caffeine and control group (p = 0.040). Additionally, in the neonates with BW 1000-1500 g and GA ≥ 28 weeks, the gastric emptying time (minutes) was significantly longer during caffeine treatment [44.5 (36-68.2)] and [40 (34.5-66.5)] respectively, as compared to the gastric emptying time during no caffeine treatment [27 (24.2-30)] (p = 0.002) and [27 (24.5-30)] (p = 0.001). The incidence of gastrointestinal (GI) complications was significantly greater in neonates receiving caffeine [6 (27.%)] as compared with those without caffeine treatment [1 (4.6%)] (p = 0.039). CONCLUSIONS: During caffeine treatment, a significantly delayed gastric emptying time was noted in all study neonates, especially in these with BW 1000-1500 g and those with GA ≥ 28 weeks. Further larger studies are necessary in order to confirm this interesting finding.

ROTEM diagnostic capacity for measuring fibrinolysis in neonatal sepsis.

BACKGROUND: Hypofibrinolysis has been demonstrated in several studies in adult sepsis. Although fibrinolysis is an important and integral part of the hemostatic system, few data are available regarding its role in neonatal sepsis. Our purpose was to define fibrinolytic profiles across neonatal sepsis spectrum using rotational thromboelastometry (ROTEM). MATERIAL AND METHODS: This study was performed in a Greek tertiary General Hospital during an 18 month-period and included 44 neonates with confirmed sepsis and 22 with suspected sepsis; 110 healthy neonates served as controls. Whenever sepsis was suspected, EXTEM and APTEM assays were performed, clinical findings and laboratory data were recorded. RESULTS: Although most EXTEM parameters were significantly different among the 3 groups, Maximal Lysis (ML) and Lysis Index at 60 min (LI60) levels were similar (p = 0.11 and p = 0.20, respectively). Hyperfibrinolysis, as defined by ROTEM parameters, did not significantly differ among the study populations (p = 0.41). On the contrary, fibrinolysis shutdown, defined as an EXTEM LI60 ≥98%, was more common in septic neonates than in healthy (p < 0.001) and neonates with suspected sepsis (p = 0.042). A weak to moderate correlation of LI60 and ML with mortality (Spearman rho = 0.43 and - 0.40, p = 0.005 and 0.007, respectively) and SNAPE score (Spearman rho = 0.35 and - 0.33, p = 0.02 and 0.03, respectively) was noticed in sepsis group. CONCLUSIONS: ROTEM, based on fibrinolytic parameters, showed a more frequent fibrinolysis shutdown in neonatal sepsis, but it could neither effectively discriminate septic neonates, nor predict their clinical outcome. The considerable overlap among numerical ROTEM values probably compromises their diagnostic clinical utility in neonatal sepsis.

Reference ranges of thromboelastometry in healthy full-term and pre-term neonates.

BACKGROUND: Rotational thromboelastometry (ROTEM) is an attractive method for rapid evaluation of hemostasis in neonates. Currently, no reference values exist for ROTEM assays in full-term and pre-term neonates. Our aim was to establish reference ranges for standard extrinsically activated ROTEM assay (EXTEM) in arterial blood samples of healthy full-term and pre-term neonates. METHODS: In the present study, EXTEM assay was performed in 198 full-term (≥37 weeks' gestation) and 84 pre-term infants (<37 weeks' gestation) using peripheral arterial whole blood samples. RESULTS: Median values and reference ranges (2.5th and 97.5th percentiles) for the following main parameters of EXTEM assay were determined in full-term infants: clotting time (seconds), 41 (range, 25.9-78); clot formation time (seconds), 70 (range, 40-165.2); maximum clot firmness (mm), 66 (range, 41-84.1); lysis index at 60 min (LI60, %), 97 (range, 85-100). The only parameter with a statistically significant difference between full-term and pre-term neonates was LI60 (p=0.006). Furthermore, it was inversely correlated with gestational age (p=0.002) and birth weight (p=0.016) in pre-term neonates. CONCLUSIONS: In conclusion, an enhanced fibrinolytic activity in pre-term neonates was noted. For most EXTEM assay parameters, reference ranges obtained from arterial newborn blood samples were comparable with the respective values from studies using cord blood. Modified reagents, small size samples, timing of sampling, and different kind of samples might account for any discrepancies among similar studies. Reference values hereby provided can be used in future studies.

Successful therapy of Candida pulcherrima fungemia in a premature newborn with liposomal amphotericin B and micafungin.

New Candida species may cause bloodstream infections challenging current therapeutic approaches because of unpredictable susceptibility and virulence. In the present report, we describe a fungemia case due to Candida pulcherrima in a premature neonate. After full in vitro diagnostic workup, the neonate was successfully treated with liposomal amphotericin B and micafungin achieving rapid fungal eradication from blood.

Linoleic and arachidonic acid in perinatal asphyxia and prematurity.

OBJECTIVES: Long-chain polyunsaturated fatty acids (LC-PUFA) are important for fetal and infant growth and development. The effects of prematurity and perinatal asphyxia on the levels of linoleic acid (LA) and arachidonic acid (AA) in plasma and red blood cell (RBC) membranes were investigated. METHODS: Fifty-five neonates were studied: 18 full term neonates with perinatal asphyxia (group A), nine preterm neonates (group B), and 28 healthy term neonates (group C). Non-esterified and total levels of LA and AA in plasma and RBC membranes were estimated using gas chromatography within the first day of life. Malondialdehyde (MDA) levels were measured using the thiobarbituric acid (TBA) reactivity method. RESULTS: Compared to group C, statistically significant lower levels of plasma free and total AA and free LA were observed in group A, whereas statistically significant higher levels of RBC total LA and AA were observed in RBC membranes of group B. A negative correlation between MDA and LC-PUFA levels was found. CONCLUSION: Perinatal asphyxia is associated with a reduction in LC-PUFA levels, most likely as a result of increased oxidative stress. Premature infants soon after birth have higher LC-PUFA levels than term neonates, probably reflecting the overall metabolic activity and/or intrauterine transport of LC-PUFA.