Inflammation, sepsis severity and neurodevelopmental outcomes of late-onset sepsis in preterm neonates.

BACKGROUND: The aim of this study was to investigate the association between inflammatory biomarkers (C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6)) and sepsis severity (neonatal-Sequential-Organ-Failure-Assessment (nSOFA)) and neurodevelopmental outcomes at 2 years, among very preterm neonates. METHODS: Data on preterm neonates (gestational age <30 weeks) from 2016 until 2020 were reviewed. Outcomes of interest were NDI (no, mild, severe) and the motor and cognitive score on the Dutch-Bayley-Scales-of-Infant-and-Toddler-Development (Bayley-III-NL) assessed at the corrected age of 2 years. Logistic and linear regression analysis were used for categorical and continuous outcomes, respectively. All analyses were adjusted for gestational age, sex and birthweight-for-gestational-age SD-score. RESULTS: In total 410 patients were eligible for analysis. Maximum CRP concentrations were associated with lower motor and cognitive scores (effect estimate -0.03 points,(95% CI -0.07; -0.00) and -0.03 points,(95% CI -0.06; -0.004), respectively) and increased risk of severe NDI (odds ratio (OR) 1.01, (95% CI 1.00; 1.01)). High nSOFA scores (≥4) during sepsis episodes were associated with an increased risk of mild NDI (OR 2.01, (95% CI 1.34; 3.03)). There were no consistent associations between IL-6, PCT and the outcomes of interest. CONCLUSION: High CRP concentrations and sepsis severity in preterm neonates seem to be associated with neurodevelopmental outcomes in survivors at the age of 2 years. IMPACT STATEMENT: The level of inflammation and sepsis severity are associated with neurodevelopmental outcome in preterm neonates at 2 years of corrected age. Sepsis is a major health issue in preterm neonates and can lead to brain damage and impaired neurodevelopment. Biomarkers can be determined to assess the level of inflammation. However, the relation of inflammatory biomarkers with neurodevelopmental outcome is not known. The level of inflammation and sepsis severity are related to neurodevelopmental outcome in preterm neonates. Maximum CRP concentration and high nSOFA scores are associated with an increased risk of neurodevelopmental impairment in survivors at the corrected age of 2 years.

Knowledge gaps in late-onset neonatal sepsis in preterm neonates: a roadmap for future research.

Late-onset neonatal sepsis (LONS) remains an important threat to the health of preterm neonates in the neonatal intensive care unit. Strategies to optimize care for preterm neonates with LONS are likely to improve survival and long-term neurocognitive outcomes. However, many important questions on how to improve the prevention, early detection, and therapy for LONS in preterm neonates remain unanswered. This review identifies important knowledge gaps in the management of LONS and describe possible methods and technologies that can be used to resolve these knowledge gaps. The availability of computational medicine and hypothesis-free-omics approaches give way to building bedside feedback tools to guide clinicians in personalized management of LONS. Despite advances in technology, implementation in clinical practice is largely lacking although such tools would help clinicians to optimize many aspects of the management of LONS. We outline which steps are needed to get possible research findings implemented on the neonatal intensive care unit and provide a roadmap for future research initiatives. IMPACT: This review identifies knowledge gaps in prevention, early detection, antibiotic, and additional therapy of late-onset neonatal sepsis in preterm neonates and provides a roadmap for future research efforts. Research opportunities are addressed, which could provide the means to fill knowledge gaps and the steps that need to be made before possible clinical use. Methods to personalize medicine and technologies feasible for bedside clinical use are described.

Introducing heart rate variability monitoring combined with biomarker screening into a level IV NICU: a prospective implementation study.

The aim of this study was to investigate the association between the implementation of a local heart rate variability (HRV) monitoring guideline combined with determination of inflammatory biomarkers and mortality, measures of sepsis severity, frequency of sepsis testing, and antibiotic usage, among very preterm neonates. In January 2018, a guideline was implemented for early detection of late-onset neonatal sepsis using HRV monitoring combined with determination of inflammatory biomarkers. Data on all patients admitted with a gestational age at birth of < 32 weeks were reviewed in the period January 2016-June 2020 (n = 1,135; n = 515 pre-implementation, n = 620 post-implementation). Outcomes of interest were (sepsis-related) mortality, sepsis severity (neonatal sequential organ failure assessment (nSOFA)), sepsis testing, and antibiotic usage. Differences before and after implementation of the guideline were assessed using logistic and linear regression analysis for binary and continuous outcomes respectively. All analyses were adjusted for gestational age and sex. Mortality within 10 days of a sepsis episode occurred in 39 (10.3%) and 34 (7.6%) episodes in the pre- and post-implementation period respectively (P = 0.13). The nSOFA course during a sepsis episode was significantly lower in the post-implementation group (P = 0.01). We observed significantly more blood tests for determination of inflammatory biomarkers, but no statistically significant difference in number of blood cultures drawn and in antibiotic usage between the two periods.Conclusion: Implementing HRV monitoring with determination of inflammatory biomarkers might help identify patients with sepsis sooner, resulting in reduced sepsis severity, without an increased use of antibiotics or number of blood cultures.

Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates.

BACKGROUND: Sepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis. METHODS: The study was conducted at the Erasmus University Medical Center-Sophia Children's Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia). RESULTS: A total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64-3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70-5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68-2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support. CONCLUSIONS: Our findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.

Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial).

BACKGROUND: Late onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies. METHODS: The PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics. DISCUSSION: The study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04152980 , Registered November 6th, 2019.

Reconstruction of the Aortic Arch in Neonates and Infants: The Importance of Patch Material.

OBJECTIVES: Restenosis after aortic arch reconstruction is a known complication in neonates and infants. Homograft is the most commonly used patch material for aortic arch reconstructions in our center. Since 2014, tissue-engineered bovine pericardium (CardioCel) has been used as an alternative. The aim of our study was to determine whether the choice of material affected the development of restenosis in these patients. METHODS: Data of all neonates and infants who underwent aortic arch reconstruction with the use of any patch material between 2005 and 2016 were analyzed. Restenosis was defined by the need for reintervention, either percutaneous or surgical. RESULTS: Forty-one patients underwent aortic arch repair. Excluding the 30-day mortality, 36 patients represented the study population. At primary repair, the aortic arch was reconstructed with homograft (n = 26) or CardioCel (n = 10). Restenosis was documented during the first year of life in 13 patients: Six (23%) patients in the homograft group and seven (70%) patients in the CardioCel group (P = .01). In the homograft group, the median time from operation to first intervention for restenosis was 22.0 (range: 14-32) weeks, as compared to 14.0 (range: 7-21) weeks in the CardioCel group (P = .04). CONCLUSION: We conclude that choice of patch material is likely to be an important determinant for the risk of restenosis needing reintervention following reconstruction of the aortic arch in neonates and infants.

Using Classification Tree Analysis to Predict the Type of Infection in Preterm Neonates: Proof of Concept Study.

BACKGROUND: Late-onset neonatal sepsis is a major complication in preterm neonates. Early identification of the type of infection could help to improve therapy and outcome depending on the suspected microorganism by tailoring antibiotic treatment to the individual patient based on the predicted organism. Results of blood cultures may take up to 2 days or may remain negative in case of clinical sepsis. Chemical biomarkers may show different patterns in response to different type of microorganisms. OBJECTIVE: The aim of this study was to develop, as a proof of concept, a simple classification tree algorithm using readily available information from biomarkers to show that biomarkers can potentially be used in discriminating in the type of infection in preterm neonates suspected of late-onset neonatal sepsis. DERIVATION COHORT: A total of 509 suspected late-onset neonatal sepsis episodes in neonates born before less than 32 weeks of gestation were analyzed. To examine model performance, 70% of the original dataset was randomly selected as a derivation cohort (n = 356; training dataset). VALIDATION COHORT: The remaining 30% of the original dataset was used as a validation cohort (n = 153; test dataset). PREDICTION MODEL: A classification tree prediction algorithm was applied to predict type of infection (defined as no/Gram-positive/Gram-negative sepsis). RESULTS: Suspected late-onset neonatal sepsis episodes were classified as no sepsis (80.8% [n = 411]), Gram-positive sepsis (13.9% [n = 71]), and Gram-negative sepsis (5.3% [n = 27]). When the derived classification tree was applied to the test cohort, the overall accuracy was 87.6% (95% CI, 81.3-92.4; p = 0.008). The classification tree demonstrates that interleukin-6 is the most important differentiating biomarker and C-reactive protein and procalcitonin help to further differentiate. CONCLUSION: We have developed and internally validated a simple, clinically relevant model to discriminate patients with different types of infection at moment of onset. Further research is needed to prospectively validate this in a larger population and assess whether adaptive antibiotic regimens are feasible.