Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator

Study Overview
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Brief Summary
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Newborns are at risk for early-onset sepsis (EOS), which occurs within 72 hours after birth. The incidence of proven EOS is 0.5-2.0 per 1000 live births. The annual birth rate in the Netherlands is around 170.000, consequently the number of EOS cases varies between 85 to 340. However, about 5%, thus 8500, of late preterm and term newborns receive empiric antibiotic therapy in compliance with the current Dutch guideline. An alternative is the CE certified EOS calculator application, which calculates an individual EOS risk with treatment advice. In this prospective cluster-randomized multicenter trial the current Dutch guideline will be compared with the EOS calculator in newborns at risk for EOS. The primary objectives of this study are: To investigate whether the use of the EOS calculator reduces antibiotic exposure in newborns with suspected EOS in the first 24 hours after birth. To investigate the presence of one or more of the following four predefined safety criteria, namely 1) the need for any respiratory support, and/or 2) the need for an intravascular fluid bolus for hemodynamic instability due to sepsis, and/or 3) referral to a Neonatal Intensive Care Unit for sepsis treatment, and/or 4) proven EOS. Secondary objectives of the study are: To investigate if the use of the EOS calculator decreases the total duration of antibiotic therapy in newborns with suspected EOS. To investigate if the use of the EOS calculator decreases the percentage of antibiotic therapy started for suspected and, or proven EOS if symptoms started between 24-72 hours after birth. To study the impact of (suspected) EOS on parents/guardians.

Detailed Description
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Suspicion of EOS is often based on risk factors and nonspecific clinical symptoms, such as maternal fever during labor or rapid breathing in the newborn. The combination of the difficulty to recognize EOS in time and the risk of serious consequences of EOS not treated timely has resulted in a low threshold for the start of empirical antibiotic therapy. This has led to significant overtreatment. The current standard of care in the Netherlands is the Dutch Society of the Nederlands (NVK) guideline Prevention and treatment of early-onset neonatal infections, which is an adaptation of the 2012 version of the National Institute for Health and Care Excellence (NICE) guideline Antibiotics for early-onset neonatal infection: antibiotics for the prevention and treatment of early-onset neonatal infection. The NVK guideline uses risk factors and symptoms to categorically indicate which newborns need antibiotic therapy. Evaluating its use in 9 Dutch hospitals, limited adherence was found, especially when antibiotics were recommended by the guideline but withheld by the clinicians. This limited adherence indicates that it is desirable to amend the current guideline or to investigate the use of an alternative method. A new method for determining which newborns need antibiotic therapy is the EOS calculator. Developed in the United States, this method uses a combination of detailed information about 5 maternal risk factors and the presence of clinical neonatal symptoms to calculate an individual EOS risk and treatment advice. For the Dutch situation, equipoise between the current NVK guideline and the EOS calculator can be established given balance of risk for both over- and undertreatment of EOS for both strategies. A large body of evidence now supports the safety of the EOS calculator approach, but validation outside of the North-American setting is limited, especially for safety outcomes. A prospective cluster-randomized Dutch validation study of the EOS calculator is needed before implementation because of the following reasons: Multicenter validation of actual EOS calculator use has not been performed in the Netherlands. To date, no randomized prospective study of EOS calculator use with safety as an outcome measure has been performed. Specifically, there are no studies that take into account the potential effects of a treatment delay due to EOS calculator use. This especially holds true for cases that are clinically suspect for EOS, but not culture-confirmed.

Official Title
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Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator: a Cluster Randomized Study (EOS Calculator RCT)

Conditions
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Early-Onset Sepsis, Neonatal, EOS

Intervention / Treatment
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* Device: EOS calculator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: postmenstrual age of 34 weeks or more; age between 0-24 hours; at least one EOS risk factor or clinical sign of infection (suspected of EOS) present within the first 24 hours of life; parental/guardian consent. Exclusion Criteria: major congenital anomalies; language barrier (lack of effective communication or whenever it hinders understanding).

Ages Eligible for Study
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Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A prospective, cluster-randomized trial will be conducted; five hospitals will be randomized to NVK guidelines use, five hospitals will be randomized to EOS calculator use. After randomization, the assigned protocol is considered standard care for newborns with suspected EOS within 0-24 hours after birth during the study period in that hospital. This means that the NVK guidelines or the EOS calculator (depending on randomization) will be used for all newborns at risk for EOS (within 0-24 hours after birth) in the assigned hospital, independent of study participation. It is noteworthy that attending physicians have the option to choose for clinical management according to another protocol instead of the assigned protocol.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: NVK Guidelines<br>The NVK guidelines use 8 maternal and 15 neonatal risk factors, each categorized as either red flag or non-red flag. These criteria guide clinicians on the management in case of suspected EOS. Briefly, antibiotic treatment is recommended if at least one red flag and, or, two or more non-red flags are present. An observation period of at least 12 hours is recommended if one non-red flag is present. Antibiotics are recommended when an infection is suspected during this observation. Newborns without EOS risk factors, with a good clinical condition, and a gestational age of more than 36 weeks will be discharged. If the guidelines recommend an observation period, the newborn with a good clinical condition is discharged after repeating physical examination. In case antibiotic treatment is started, discharge depends on the duration of treatment and the clinical course. At discharge, parents are instructed to call the hospital in case of signs of infection within the first 14 days of life. | |
| Experimental: EOS Calculator<br>Using the EOS calculator application between 0-24 hours after birth, maternal EOS risk factors combined with the physical examination of the newborn are used to assign a risk category and accompanying clinical recommendation based on estimated EOS incidence for each newborn at-risk for an infection. The EOS calculator results are used to guide clinical management on performing either a diagnostic work-up and start of antibiotics for (suspected) EOS, or a conservative approach with routine controls of vital parameters every 3 hours. In case of routine controls, re-evaluation of physical appearance by a pediatric resident or pediatrician will take place within 24 hours postpartum. Newborns will be observed for at least 24 hours. In case antibiotics are started, the need for further treatment is depending on blood culture results, infection parameters, and clinical condition of the newborn. Discontinuation of antibiotics and discharge is at the discretion of the treating physician. | Device: EOS calculator<br>* For this study the EOS calculator was developed as a mobile application (by everywhereIM), including CE marking. It is concerned a medical device for health care professionals.<br>* Other names: neonatal EOS calculator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Co-primary superiority outcome: antibiotic therapy started within 24 hours after birth | The proportion of patients that started antibiotic therapy for suspected and, or proven EOS in the first 24 hours after birth. | 0-24 hours after birth | 
| First co-primary non-inferiority outcome (safety): proportion of patients with respiratory support | A composite non-inferiority outcome regarding the presence of one or more of the following four predefined safety criteria, namely 1) the need for any respiratory support, and/or 2) the need for an intravascular fluid bolus for hemodynamic instability due to sepsis, and/or 3) referral to a Neonatal Intensive Care Unit (NICU) for sepsis treatment, and/or 4) proven EOS. - Respiratory support is defined as any form of respiratory support (invasive ventilation, continuous positive airway pressure (CPAP), high flow nasal cannula (HFNC), low flow oxygen) during the first week of life. | 0-14 days after birth | 
| Second co-primary non-inferiority outcome (safety): proportion of patients with hemodynamic support | - Intravascular fluid bolus is defined as the intravenous administration of a fluid bolus of 10ml/kg within 15-30 minutes. It is the first step in the treatment of hemodynamically unstable newborns due to sepsis. | 0-14 days after birth | 
| Third co-primary non-inferiority outcome (safety): proportion of patients referred to a NICU for sepsis treatment |  | 0-14 days after birth | 
| Fourth co-primary non-inferiority outcome (safety): proportion of patients with proven EOS | - Proven EOS is defined as a blood or cerebrospinal fluid (CSF) culture obtained within 72 hours after birth growing a pathogenic bacterial species. | 0-14 days after birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of antibiotic therapy | The total duration of antibiotic therapy: date and time of first administration of intravenous antibiotic therapy, and date and time of the last administration of intravenous antibiotic therapy. | 0-14 days after birth | 
| Antibiotic therapy started between 24-72 hours after birth | The proportion of antibiotic therapy started for suspected and, or proven EOS if symptoms started between 24-72 hours after birth. | 24-72 hours after birth | 
| Questionnaire: quality of life | To get an impression of the impact of (suspected) early-onset sepsis on the quality of life (QoL) of both parents/guardians and their child, parents/guardians will be asked to fill in a questionnaire on day 14 after birth. The first part collects information on medical factors after hospitalization (side effects, number of medical visits, readmission, and medication use) and basic needs of the newborn (sleep quality of the patient, (breast)feeding success rate). The second part addresses the subjective parental/guardian evaluation of the impact of newborns' admission, and parental/guardian projection of future QoL of their newborn. Statements with six possible answers will be used: 'not at all, a little, on average, more than average, a lot, not applicable' or 'poor, fair, good, very good, excellent, not applicable'. Participants will not score on a numbered scale but tick the answer (in text) that apply best. The last part of the questionnaire collects demographic data. | 14-28 days after birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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early-onset sepsis, neonatal, EOS calculator