Reply to Ghirardello et al Letter to the Editor

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Thromboelastometry parameters for the evaluation of primary hemostasis in neonates

Background: Ill preterm and full-term neonates present increased risk of hemorrhage, with a negative impact on outcome and survival. As bleeding in this setting is multifactorial, an index incorporating both platelet count and functionality to more accurately depict neonatal hemostatic status, would be ideal.Aim: Our aim was to investigate the potential role of certain thromboelastometry (ROTEM) parameters, including maximum clot elasticity (MCE) and platelet component (PLTEM MCE and PLTEM MCF) in early prediction of bleeding events in thrombocytopenic critically ill neonates. Material and methods: This single-centre, prospective, cohort study included 110 consecutive thrombocytopenic neonates with sepsis, suspected sepsis or perinatal hypoxia. On the first day of sepsis or suspected sepsis and/or hypoxia, along with the appropriate workup, the ROTEM EXTEM and FIBTEM assays were conducted on arterial blood samples. The neonatal bleeding assessment tool (NeoBAT) was used for the evaluation of bleeding events on the same day with ROTEM analysis. Results: Most EXTEM and FIBTEM ROTEM parameters significantly differed between neonates with (n = 77) and without bleeding events (n = 33). Neonates with bleeding events had significantly lower PLTEM MCE and PLTEM MCF values compared to those without bleeding events (p <0.001). Platelet count was found to be strongly positively correlated with EXTEM A10 (Spearman rho = 0.64, p <0.001) and EXTEM A5 (rho = 0.61, p <0.001), while a weak positive correlation was shown with EXTEM MCF (rho = 0.40, p <0.001), EXTEM MCE (rho = 0.38, p <0.001), PLTEM MCF (rho = 0.33, p = 0.001) and PLTEM MCE (rho = 0.29, p = 0.004). Adjusted evaluation of the correlation between ROTEM parameters and hemorrhage revealedthat only EXTEM A10 (OR = 0.88, 95% CI:0.81 – 0.95, p = 0.003), PLTEM ΜCE (OR = 0.90, 95% CI:0.82 –0.99, p=0.043) and PLTEM MCF (OR = 0.96, 95% CI:0.92 – 0.99, p=0.039) were significantly correlated with bleeding, while FIBTEM A10 was not associated with hemorrhage (aOR = 0.94, 95% CI 0.87 – 1.02, p = 0.16). EXTEM A10 demonstrated the best prognostic performance (AUC = 0.853) with an optimal cutoffvalue of ≤37mm (sensitivity = 91%, specificity = 76%) for prediction of bleeding events in thrombocytopenic neonates. Similar results emerged for EXTEM A5 (AUC = 0.850) with an optimal cut-off value of ≤28mm (sensitivity = 91%, specificity = 77%). Conclusions: EXTEM A10 and EXTEM A5 parameters were found to be strong predictors of hemorrhage, compared to most ROTEM variables quantifying clot elasticity or platelet component in thrombocytopenic, critically ill neonates.Εισαγωγή: Πάσχοντα πρόωρα και τελειόμηνα νεογνά έχουν αυξημένο κίνδυνο αιμορραγίας, με αρνητικό αντίκτυπο στην έκβαση και επιβίωσή τους. Καθώς η αιμορραγία σε αυτό το κλινικό πλαίσιο είναι πολυπαραγοντική, θα ήταν χρήσιμος ένας δείκτης που εκτός από τον αριθμό θα ενσωμάτωνε και τη λειτουργικότητα των αιμοπεταλίων, αντικατοπτρίζοντας ακριβέστερα το αιμοστατικό δυναμικό τωννεογνών.Σκοπός: Σκοπός μας ήταν η διερεύνηση του πιθανού ρόλου παραμέτρων της θρομβοελαστομετρίας (ROTEM), όπως η μέγιστη ελαστικότητα του θρόμβου (MCE) και το αιμοπεταλιακό στοιχείο (PLTEM MCE και PLTEM MCF) στην πρώιμη πρόβλεψη αιμορραγικών επεισοδίων σε θρομβοπενικά, πάσχοντα νεογνά.Υλικό και μέθοδοι: Πρόκειται για μια μονοκεντρική, προοπτική, μελέτη κοορτής, που συμπεριέλαβε 110 θρομβοπενικά νεογνά με σήψη, υποψία σήψης, ή περιγεννητική υποξία. Την πρώτη ημέρα της ύποπτης ή επιβεβαιωμένης σήψης και/ ή της υποξίας, οι δοκιμασίες ΕΧΤΕΜ και FIBTEM της ROTEM διενεργήθηκαν σε δείγμα αρτηριακού αίματος. Παράλληλα, την ίδια ημέρα, αξιολογήθηκε η εμφάνιση αιμορραγικώνεπεισοδίων στα νεογνά, με τη χρήση ενός εργαλείου εκτίμησης της αιμορραγίας (NeoBAT).Αποτελέσματα: Οι περισσότερες θρομβοελαστομετρικές παράμετροι των δοκιμασιών EXTEM και FIBTEM διέφεραν σημαντικά μεταξύ των νεογνών με αιμορραγικό επεισόδιο (n = 77) και εκείνων χωρίς αιμορραγία (n = 33). Τα νεογνά που εκδήλωσαν αιμορραγία είχαν σημαντικά μειωμένες τιμές PLTEM MCE και PLTEM MCF σε σύγκριση με νεογνά που δεν εμφάνισαν αιμορραγία (p <0,001). Ο αριθμός των αιμοπεταλίων συσχετίστηκε θετικά και ισχυρά με τις παραμέτρους ΕΧΤΕΜ Α10 και ΕΧΤΕΜ Α5 (Spearman rho = 0,64 και rho = 0,61, p <0,001, αντιστοίχως), ενώ αδύναμη ήταν η θετική συσχέτιση με τις παραμέτρους EXTEM MCF (rho = 0,40, p<0,001), EXTEM MCE (rho = 0,38, p<0,001), PLTEM MCF (rho = 0,33, p = 0,001) και PLTEMMCE (rho = 0,29, p = 0,004). Η σταθμισμένη εκτίμηση της συσχέτισης μεταξύ των παραμέτρων ROTEM και της εκδήλωσης αιμορραγίας αποκάλυψε ότι μόνο το EXTEM A10 (OR = 0,88, 95% CI:0,81 – 0,95, p=0,003), το PLTEM ΜCE (OR = 0,90, 95% CI:0,82 – 0,99, p=0,043) και το PLTEM MCF (OR = 0,96, 95% CI:0,92 – 0,99, p =0,039) συσχετίστηκαν σημαντικά με αιμορραγία, ενώ το FIBTEM A10 δε συσχετίστηκε με αιμορραγικά συμβάματα (aOR = 0,94, 95% CI:0,87 – 1,02, p = 0,16). Η μεταβλητή EXTEM A10 επέδειξε την καλύτερη προγνωστική αξία (AUC=0,853), με βέλτιστη διαχωριστική τιμή ≤37mm (ευαισθησία = 91%, ειδικότητα = 76%) για την πρόβλεψη αιμορραγικών επεισοδίων σε θρομβοπενικά νεογνά. Παρόμοια ήταν τααποτελέσματα και για τη μεταβλητή ΕΧΤΕΜ Α5 (ΑUC = 0,850), με βέλτιστη διαχωριστική τιμή ≤28mm (ευαισθησία = 91%, ειδικότητα = 77%). Συμπεράσματα: Οι παράμετροι EXTEM A10 και ΕΧΤΕΜ Α5 αναδείχτηκαν ισχυροί προγνωστικοί δείκτες αιμορραγίας, συγκρινόμενες με άλλες μεταβλητές της ROTEM που εκφράζουν την ελαστικότητα του θρόμβου ή το αιμοπεταλιακό στοιχείο σε θρομβοπενικά, βαρέως πάσχοντα νεογνά

Breastfeeding in Neonates Admitted to an NICU: 18-Month Follow-Up

Introduction: The admission of neonates to Neonatal Intensive Care Units (NICUs) has been identified as a primary inhibiting factor in the establishment of breastfeeding. The aims of this study were to (1) estimate the prevalence and duration of breastfeeding in infants/toddlers who had been admitted to an NICU in Greece and (2) to investigate factors, associated with the NICU stay, which affected the establishment and maintenance of breastfeeding in infants/toddlers previously admitted to the NICU. Materials and methods: Data for this cohort study were retrieved from interviews with mothers of infants/toddlers who had been admitted to our NICU as neonates during the period of 2017–2019. Interviews were conducted based on a questionnaire regarding the child’s nutrition from birth to the day of the interview, including previous maternal experience with breastfeeding. Information related to the prenatal period, gestation age, delivery mode, duration of NICU stay, and neonatal feeding strategies during their hospital stay were recorded. Results: The response rate to the telephone interviews was 57%, resulting in 279 mother–infant pairs being included in this study. The results showed that 78.1% of children received maternal milk during their first days of life. Of all infants, 58.1% were exclusively breastfed during their first month, with a gradual decrease to 36.9% and 19.4% by the end of the third and sixth months of life, respectively. The prevalence of breastfed children reached 14.7% and 7.5% at the ages of twelve and eighteen months, respectively. In the multivariate analysis, prematurity emerged as an independent prognostic factor for the duration of exclusive and any breastfeeding (aHR 1.64, 95% CI: 1.03–2.62; and 1.69, 95% CI: 1.05–2.72, respectively; p < 0.05). Additionally, the nationality of the mother, NICU breastfeeding experience, the administration of maternal milk during neonatal hospital stay, and previous breastfeeding experience of the mother were independent prognostic factors for the duration of breastfeeding. Conclusions: Although breastfeeding is a top priority in our NICU, the exclusive-breastfeeding rates at 6 months were quite low for the hospitalized neonates, not reaching World Health Organization (WHO) recommendations. Mothers/families of hospitalized neonates should receive integrated psychological and practical breastfeeding support and guidance

Umbilical Venous Catheters and Peripherally Inserted Central Catheters: Are They Equally Safe in VLBW Infants? A Non-Randomized Single Center Study

Background and Objective: Peripherally inserted central catheters (PICC) and umbilical venous catheters (UVC) are frequently used for vascular access in neonatal intensive care units (NICUs). While there is a significant need for these devices for critically ill neonates, there are many complications associated with their use. We aimed at investigating the incidence of UVC and PICC complications in very low birth weight (VLBW) infants. Materials and Methods: This is an observational study performed with neonates of the tertiary General Hospital of Piraeus, Greece, during an 18 month-period. Seventy-one neonates were recruited and divided into two groups: 34 neonates with PICC and 37 neonates with UVC. We recorded: Catheter dwell time, the causes of catheter removal, other complications, infections, and catheter tip colonization rates. Results: No significant statistical differences were noticed between the 2 study groups with regards to demographic characteristics, causes for catheter removal, catheter indwelling time or the incidence of nosocomial infection. Eleven UVC tips and no PICC tips were proved colonized (p = 0.001) following catheter removal. Conclusions: The incidence of complications associated with the use of UVCs and PICCs in VLBW infants did not significantly differ in our study. Their use seems to be equally safe. Further studies, with larger samples, are necessary to confirm our results

The Non-Activated Thromboelastometry (NATEM) Assay’s Application among Adults and Neonatal/Pediatric Population: A Systematic Review

The non-activated thromboelastometry (NATEM) assay is a point-of-care assay that can provide a comprehensive insight into the actual hemostatic mechanism. However, there are very limited data about its use in clinical practice. The aim of this study was to systematically review the literature for any data regarding the use of NATEM in several clinical settings. A systematic review of PubMed and Scopus databases was conducted through 20 January 2022 for studies evaluating the use of the NATEM assay in different clinical settings. The literature search yielded a total of 47 publications, 30 of which met the eligibility criteria for this review. Evaluation of NATEM’s detecting ability for hemostasis disorders is limited in the literature. The results of the included studies indicate that NATEM seems to be a sensitive method for the detection of hyperfibrinolysis and may have an advantage in the diagnosis of hemostatic disorders. It could be more informative than the other ROTEM assays for detecting changes in coagulation parameters in patients who receive anticoagulants. However, the reported outcomes are highly varying among the included studies. NATEM has a high sensitivity to detect hypo- or hypercoagulability and provides a detailed insight into the whole hemostatic process from clot formation to clot breakdown. It could be a useful technique in variable fields of medicine, not only in adults, but also in pediatric and neonatal populations, to guide different hemostatic treatments and predict coagulation disorders or mortality/morbidity; this issue remains to be further investigated

Comparative Performance of Four Established Neonatal Disease Scoring Systems in Predicting In-Hospital Mortality and the Potential Role of Thromboelastometry

Background: To compare the prognostic accuracy of the most commonly used indexes of mortality over time and evaluate the potential of adding thromboelastometry (ROTEM) results to these well-established clinical scores. Methods: The study population consisted of 473 consecutive term and preterm critically-ill neonates. On the first day of critical illness, modified Neonatal Multiple Organ Dysfunction (NEOMOD) scoring system, Score for Neonatal Acute Physiology (SNAP II), Perinatal extension of SNAP (SNAPPE), and SNAPPE II, were calculated and ROTEM standard extrinsically activated (EXTEM) assay was performed simultaneously. Time-to-event methodology for competing-risks was used to assess the performance of the aforementioned indexes in predicting in-hospital mortality over time. Time-dependent receiver operator characteristics curves for censored observation were compared across indexes. The addition of EXTEM parameters to each index was tested in terms of discrimination capacity. Results: The modified NEOMOD score performed similarly to SNAPPE. Both scores performed significantly better than SNAP II and SNAPPE II. Amplitude recorded at 10 min (A10) was the EXTEM parameter most strongly associated with mortality (A10 &lt; 37 mm vs. ≥37 mm; sHR = 5.52; p &lt; 0.001). Adding A10 to each index apparently increased the prognostic accuracy in the case of SNAP II and SNAPPE II. However, these increases did not reach statistical significance. Conclusion: Although the four existing indexes considered showed good to excellent prognostic capacity, modified NEOMOD and SNAPPE scores performed significantly better. Though larger studies are needed, adding A10 to well-established neonatal severity scores not including biomarkers of coagulopathy might improve their prediction of in-hospital mortality

Comparative Performance of Four Established Neonatal Disease Scoring Systems in Predicting In-Hospital Mortality and the Potential Role of Thromboelastometry

Background: To compare the prognostic accuracy of the most commonly used indexes of mortality over time and evaluate the potential of adding thromboelastometry (ROTEM) results to these well-established clinical scores. Methods: The study population consisted of 473 consecutive term and preterm critically-ill neonates. On the first day of critical illness, modified Neonatal Multiple Organ Dysfunction (NEOMOD) scoring system, Score for Neonatal Acute Physiology (SNAP II), Perinatal extension of SNAP (SNAPPE), and SNAPPE II, were calculated and ROTEM standard extrinsically activated (EXTEM) assay was performed simultaneously. Time-to-event methodology for competing-risks was used to assess the performance of the aforementioned indexes in predicting in-hospital mortality over time. Time-dependent receiver operator characteristics curves for censored observation were compared across indexes. The addition of EXTEM parameters to each index was tested in terms of discrimination capacity. Results: The modified NEOMOD score performed similarly to SNAPPE. Both scores performed significantly better than SNAP II and SNAPPE II. Amplitude recorded at 10 min (A10) was the EXTEM parameter most strongly associated with mortality (A10 &lt; 37 mm vs. &amp; GE;37 mm; sHR = 5.52; p &lt; 0.001). Adding A10 to each index apparently increased the prognostic accuracy in the case of SNAP II and SNAPPE II. However, these increases did not reach statistical significance. Conclusion: Although the four existing indexes considered showed good to excellent prognostic capacity, modified NEOMOD and SNAPPE scores performed significantly better. Though larger studies are needed, adding A10 to well-established neonatal severity scores not including biomarkers of coagulopathy might improve their prediction of in-hospital mortality

Sepsis-Induced Coagulopathy: An Update on Pathophysiology, Biomarkers, and Current Guidelines

Significant cross talk occurs between inflammation and coagulation. Thus, coagulopathy is common in sepsis, potentially aggravating the prognosis. Initially, septic patients tend to exhibit a prothrombotic state through extrinsic pathway activation, cytokine-induced coagulation amplification, anticoagulant pathways suppression, and fibrinolysis impairment. In late sepsis stages, with the establishment of disseminated intravascular coagulation (DIC), hypocoagulability ensues. Traditional laboratory findings of sepsis, including thrombocytopenia, increased prothrombin time (PT) and fibrin degradation products (FDPs), and decreased fibrinogen, only present late in the course of sepsis. A recently introduced definition of sepsis-induced coagulopathy (SIC) aims to identify patients at an earlier stage when changes to coagulation status are still reversible. Nonconventional assays, such as the measurement of anticoagulant proteins and nuclear material levels, and viscoelastic studies, have shown promising sensitivity and specificity in detecting patients at risk for DIC, allowing for timely therapeutic interventions. This review outlines current insights into the pathophysiological mechanisms and diagnostic options of SIC

Table1_Development and validation of a sepsis diagnostic scoring model for neonates with suspected sepsis.docx

BackgroundWe aimed to develop and validate a diagnostic model for sepsis among neonates evaluated for suspected sepsis, by incorporating thromboelastometry parameters, maternal/neonatal risk factors, clinical signs/symptoms and laboratory results.MethodsThis retrospective cohort study included 291 neonates with presumed sepsis, hospitalized in a NICU, from 07/2014 to 07/2021. Laboratory tests were obtained on disease onset and prior to initiating antibiotic therapy. Τhromboelastometry extrinsically activated (EXTEM) assay was performed simultaneously and Tοllner and nSOFA scores were calculated. Sepsis diagnosis was the outcome variable. A 10-fold cross-validation least absolute shrinkage and selection operator logit regression procedure was applied to derive the final multivariable score. Clinical utility was evaluated by decision curve analysis.ResultsGestational age, CRP, considerable skin discoloration, liver enlargement, neutrophil left shift, and EXTEM A10, were identified as the strongest predictors and included in the Neonatal Sepsis Diagnostic (NeoSeD) model. NeoSeD score demonstrated excellent discrimination capacity for sepsis and septic shock with an AUC: 0.918 (95% CI, 0.884–0.952) and 0.974 (95% CI, 0.958–0.989) respectively, which was significantly higher compared to Töllner and nSOFA scores.ConclusionsThe NeoSeD score is simple, accurate, practical, and may contribute to a timely diagnosis of sepsis in neonates with suspected sepsis. External validation in multinational cohorts is necessary before clinical application.</p

DataSheet1_Development and validation of a sepsis diagnostic scoring model for neonates with suspected sepsis.docx

BackgroundWe aimed to develop and validate a diagnostic model for sepsis among neonates evaluated for suspected sepsis, by incorporating thromboelastometry parameters, maternal/neonatal risk factors, clinical signs/symptoms and laboratory results.MethodsThis retrospective cohort study included 291 neonates with presumed sepsis, hospitalized in a NICU, from 07/2014 to 07/2021. Laboratory tests were obtained on disease onset and prior to initiating antibiotic therapy. Τhromboelastometry extrinsically activated (EXTEM) assay was performed simultaneously and Tοllner and nSOFA scores were calculated. Sepsis diagnosis was the outcome variable. A 10-fold cross-validation least absolute shrinkage and selection operator logit regression procedure was applied to derive the final multivariable score. Clinical utility was evaluated by decision curve analysis.ResultsGestational age, CRP, considerable skin discoloration, liver enlargement, neutrophil left shift, and EXTEM A10, were identified as the strongest predictors and included in the Neonatal Sepsis Diagnostic (NeoSeD) model. NeoSeD score demonstrated excellent discrimination capacity for sepsis and septic shock with an AUC: 0.918 (95% CI, 0.884–0.952) and 0.974 (95% CI, 0.958–0.989) respectively, which was significantly higher compared to Töllner and nSOFA scores.ConclusionsThe NeoSeD score is simple, accurate, practical, and may contribute to a timely diagnosis of sepsis in neonates with suspected sepsis. External validation in multinational cohorts is necessary before clinical application.</p